eLife assessment

The function of specific proteins made by SARS-CoV-1 and SARS-CoV-2 is under debate, with diverging claims previously published regarding the ability of Orf3a proteins from either virus to form ion channels. The authors undertook a thorough characterization of Orf3a from CoV-1 and CoV-2 by combining data from a range of different structural and functional experiments, arguably providing the most compelling evidence to date that Orf3a from viruses is not an ion channel. Instead, the orthologue-specific interaction with a component of a larger protein complex suggests a role of one of the two membrane proteins in the endo-lysosomal pathway. The work is significant from a fundamental science perspective, for its implications for COVID antiviral development strategies, and also for establishing guidelines for future identification of true viral ion channels.

eLife assessment

The manuscript by Abramson and colleagues is a new analysis of previously published data from experiments in which rats ran on a treadmill in either fixed-time or fixed-distance trials. The valuable results provide solid evidence to demonstrate that time and distance cells are more common in fixed-time and fixed-distance trials, respectively. These findings suggest that the hippocampus flexibly shifts between representing variables depending on their relevance.

eLife assessment

In their manuscript, Dema et al. showcase an important tool to study the role of the microtubule end-binding protein, EB1. This important study is the first to locally inactivate EB1 in human neurons, and while the authors have previously published the effects of replacing endogenous EB1 with a light-sensitive variant, the novelty in this current study is that they use a one-step gene editing replacement method in addition to using human neurons derived from iPSCs. The data is of high quality and the evidence supporting the conclusions is solid, although including more controls are needed to strengthen the study. The findings of this work will be of interest to cell biologists and neurobiologists, while the methods utilized will have an even broader general interest.

eLife assessment

This study presents a valuable enhancer reporter of TGFb signaling in melanoma that has a conserved function in both human cell lines and zebrafish. The reporter data is solid and provides interesting insights into TGFb targets in melanoma. However, the model that macrophages preferentially phagocytose certain subsets of melanoma cells is still incomplete, and more data will be needed before this process is clearly understood.

eLife assessment

This important study advances our understanding of the molecular players downstream of the transcription factor Emx2 that establish planar cell polarity in hair cells of the mammalian inner ear. The conclusions, which are supported by compelling evidence, will be of interest to those studying the development and function of the vestibular system and mechanisms of planar cell polarity.

eLife assessment

This manuscript provides fundamental new insight into protein conformational transitions underlying the transport mechanism of Nramps, an important and widespread transporter family that facilitates the uptake and movement of essential transition metals. Eight new crystallographic structures of the prokaryotic homolog draNRMP in a variety of ligand-bound and conformational states, along with companion molecular dynamics simulations and metal binding and transport assays, provide compelling evidence supporting most of the conclusions. These findings will be of broad interest to scientists studying transport mechanisms and ligand recognition.

eLife assessment

This important work substantially advances our understanding of how human eye movements are shaped by social cues. Using clever experimental manipulations and innovative artificial intelligence analysis tools, the paper identifies distinctive patterns of saccadic eye movements tracking another person's gaze during dynamic video-scene viewing. This work will be of broad interest to psychologists, biologists, and neuroscientists interested in human social behavior.

eLife assessment

This study reports an important theoretical model with simulations of meiotic recombination hotspots and Prdm9 evolution. By integrating recently identified biological properties of Prdm9, the model provides compelling evidence for novel features of hotspots and Prdm9 evolution. Yet, the model, the different steps in implementing parameters, and the predictions are difficult to follow and would benefit from clarification.

eLife assessment

It is well established that valuation and value-based decision making is context-dependent, but the exact form of normalization has remained an open question. This study provides compelling evidence that values during reward learning are normalized based on the range of available values. These findings will be important for researchers interested in reward learning and decision-making.

eLife assessment

This important manuscript describes how methylation of a single arginine residue in a transcription factor, C/EBPα, can alter dynamics of cell fate transition. The study provides one of the most striking examples of the transcription factor regulation by methylation and is well-executed, with compelling evidence to support the authors' claims.

eLife assessment

This study convincingly demonstrates that the splicing factor SRSF1 can be solubilized in the presence of short RS or ER-containing peptides, and uses this discovery to determine the solution NMR structure of SRSF1, as well as to map its interactions with RS peptides. These findings are important in that SR proteins are key regulators of alternative splicing but their study has been greatly hampered by their low solubility. The development of a general method that allows the structural and biochemical analysis of SR proteins in solution will have broad applications.

eLife assessment

This landmark study uses compelling approaches such as quantitative and screening mass spectrometry to identify peptides from tuberculosis bacteria that are presented by macrophages infected with this pathogen. The authors provide convincing evidence that the presentation of these antigens depends on a specialist bacterial secretion system. The study will be of interest to infectious disease specialists and of particular value for future vaccine development.

eLife assessment

Lemerle et al utilize advanced correlative light and electron microscopy and molecular biology approaches to convincingly demonstrate the presence of the membrane-bending protein Bin1 and caveolae containing rings capable of membrane tubulation in developing muscle. The data is highly significant as it potentially advances our fundamental understanding of how transverse tubules are formed, a significant gap in our understanding of excitation-contraction coupling and muscle biology more broadly.

eLife assessment

The work presented is fundamental to the field of negative-sense RNA viruses. It showcases a compelling set of ideas and approaches to study some physicochemical properties of organelles in live cells during a viral infection. However, the conclusions could benefit by adding a deeper theoretical approach and additional experimental support.

eLife assessment

The present study presents the important finding that HIV infection activates the NLRP3, IFI16, and AIM 2 inflammasome pathways and that treatment with the anti-caspase 1 inhibitor VX-765 moderately reduces inflammasome activation and CD4 T cell depletion in a humanized NSG mouse model. The evidence supporting that inflammasome activation may play an important role in CD4 T cell depletion and that anti-caspase-1 inhibitors may reduce harmful inflammation is for the most part solid, although not always complete. The results will be of interest to scientists and physicians working on HIV immunology, pathogenesis and cure strategies.

eLife assessment

This important study provides evidence for CPC-3 mediating induction of the transcription factor CPC-1 in starved Neurospora cells, with CPC-1-mediated recruitment of Gcn5 and acetylation of the FRQ promoter counteracting the function of histone deacetylase HDA1, which in turn maintains high occupancy of the transcription factor WCC and attendant circadian rhythm of FRQ expression. The findings are significant in showing how the well-established pathways for circadian rhythm centered on FRQ gene expression and cross-pathway control centered on CPC-1 induction are integrated to maintain rhythmic cell growth in the face of amino acid limitation. However, the evidence for these claims is incomplete in certain respects and additional statistical analyses and experimental evidence are needed to better support the claims of rhythmic CPC-1 binding at FRQ, of the role of GCN-5 in rhythmic FRQ transcription in starvation conditions, and of rhythmic transcription of CPC-1-regulated amino acid biosynthetic genes.

eLife assessment

This work is of significant interest to those studying neurodegeneration, demonstrating key pathologies in PLA2G6-associated disease in both patient-derived neuronal models and a novel trans heterozygote mouse model. Moreover, it identifies a number of possible compounds that could potentially be re-purposed for therapeutic use in PLA2G6-associated neurodegeneration. Lastly, it shows a proof-of-principle in a mouse model that gene therapy with human PLA2G6 can rescue defects in PLA2G6 deficiency. Whilst the majority of the data are solid and convincing, there are a number of consolidatory experiments that would add greatly to the overall impact and novelty of the work.

eLife assessment

This important study presents insights into how conformational dynamics differentially influences drug specificity and affinity in myosin isoforms using computational approaches. The evidence supporting the conclusions is convincing, establishing a relationship between inhibition and protein dynamics using state of the art computational techniques followed by experimental validation. The work will be of broad interest to computational biophysicists and medicinal chemists.

eLife assessment

This study provides further detailed analysis of recently published Fly Atlas data supplemented with newly generated single cell RNA-seq data. Through characterizing these datasets, the authors define different germ cell and somatic cell clusters throughout the testis. This work confirms and extends previous observations regarding the changing gene expression programs these cells exhibit during their differentiation. This manuscript provides an important and detailed foundation for future studies of these lineages.

eLife assessment

This work provides an important pipeline for high-throughput screening platform to be used for drug discovery. The current data are incomplete. Further validation of human patients-derived iPSC clones and functional assays in mice will strengthen the conclusion.

eLife assessment

This paper is a first report of a human subject with an MCAT mutation showing reduced mitochondrial activity, but without defining the molecular mechanism connecting the loss of MCAT activity to mitochondrial dysfunction. It adds to the important field of mitochondrial disease genes and how they impact human physiology.

eLife assessment

This paper reports important findings on the mechanisms by which death pathways are activated by Shigella infection to impact the host response. The methods used provide compelling evidence for the involvement of multiple death cell pathways in the pathogenesis and host response to murine shigellosis. The results presented therein will be of interest to investigators in the field of bacterial pathogenesis, infectious disease and immunology.

eLife assessment:

This article reports the fundamental discovery that interfering with the function of the tyramine receptor causes a rapid decline in responses to olfactory stimuli in the honey bee. While tyramine signaling might specifically control the process of latent inhibition without affecting appetitive conditioning, the present analysis is incomplete in terms of ruling out the possibility that tyramine affects other functions of the antennal lobe. Nonetheless, compelling data highlight the role of one of the most highly expressed biogenic amine receptors in the insect olfactory system.

eLife assessment

This important study explores the question of "what gives rise to micro-diversity in ecological settings", and proposes a scenario of spatiotemporal chaos, in which interactions between strains drive large changes in the relative abundances of strains. The presented theoretical approach is compelling and goes beyond the current state of the art. This innovative theoretical work is of broad interest to the field of ecology and evolution.

eLife assessment

This is an important contribution to the field of dinosaur palaeontology. The authors provide convincing evidence for sexual dimorphism in dinosaurs, based on limb bones of ornithomimosaurs from the Cretaceous of France. The article makes several valuable and important contributions -- including the use of a large dataset and robust statistical approaches -- and will serve as a benchmark for future studies on dinosaurs and other fossil reptiles.

eLife assessment

This study presents a valuable finding of the role of under investigated pathway associated with development of placental oxygenation during pregnancy. The evidence supporting the claims of the authors is incomplete, although inclusion of a larger number of patient samples and an animal model have strengthened the study. The work will be of interest to developmental biologists working on placental function.

eLife assessment

This study demonstrates ultrafast real-time decoding of place fields in the hippocampus thanks to a head-mounted microscope for calcium imaging and to a novel data processing pipeline. This is a useful tool that aims at obtaining real-time capabilities that will enable closed-loop experiments that include decoding of a wide neuronal population, which could be applied in a variety of neuroscience fields. This will be of interest to anyone studying behaviors or functions that involve the hippocampus.

eLife assessment

In this important project, the authors used single-cell RNA-sequencing (scRNA-Seq) technology to profile the transcriptome of alveolar bone marrow single cells and demonstrated the protective role of mesenchymal stem cells (MSCs) during apical periodontitis. With comprehensive data, the authors identified new inflammatory biomarkers associated with the pathogenesis of oral inflammatory diseases. Their study suggests that certain MSC subsets may have a potential role in healing bone lesions.

eLife assessment

The primary goal of this paper is to characterize retinal dysfunction and retinal ganglion cell degeneration in the Wfs1exon8del murine model of Wolfram Syndrome 1. The study provides fundamental insight into the timelines of degeneration as well as valuable transcriptomic and proteomic datasets. The methodologies performed are generally rigorous and the conclusions reached are mostly well supported by the data, however, the interrogation of the mechanism is largely circumstantial and the relevance to disease is primarily speculative. The results of this study are highly relevant for molecular mechanisms in Wolfram Syndrome 1 and are of potential interest to scientists interested in oligodendrocyte and neuron communication.

eLife assessment

This study systematically integrates multi-omics data to identify the metabolic at-risk profiles within people living with HIV on antiretroviral therapy and presents findings that have focused importance and scope. The methods, data, and analyses as described now only partially support the primary claims.

eLife assessment

This manuscript starts from the hypothesis that a model of mitochondrial disease, the NDUFS4 knockout mouse, causes iron dysregulation, and that iron status may modify the neurological phenotypes that result in the mouse. This study has the potential to inform how body iron homeostasis can modify neurological phenotypes caused by mitochondrial disease. This study will be of interest to a broad audience of neuroscientists, particularly those with an interest in mitochondrial diseases.

eLife assessment

This impressive study presents the most comprehensive analysis of the Argonautes, their small RNA partners, their targets, and their biological functions in any species to date. The work provides new insights into Argonaute-based pathways, it includes extensive validation of existing models, and describes overall a treasure-trove of reagents and datasets for future exploration of the vast Argonaute world in C. elegans.

eLife assessment

Scientists had previously discovered that humans and neanderthals mated leading to parts of neanderthal DNA becoming part of the human genome today. More recently, it was found that a genetic region, carrying which has been associated with manifestation of severe COVID-19 symptoms, is one that was "introgressed" into humans from neanderthals. This region contains many genetic variants, and this study set out to identify which of these genetic variants may be causally involved in creating severe symptoms in response to COVID-19 infection. The main critiques of the study stem from details of the functional assays to establish the regulatory role of the 4 variants in creating severe COVID-19 symptoms. In particular, the two genes (critical chemokine receptor genes: CCR1 and CCR5) that the authors identify as down-regulated by these variants are actually up-regulated in severe COVID-19 patients, leading to doubt about the role of these variants in changing response to COVID-19 through the regulation of these genes. In that regard, it seems necessary to conduct follow-up experimental and computational analyses to establish the role of these variants in altering CCR1 and CCR5 gene expression.

eLife assessment

The study presents valuable findings on a gene called bero that affects the way larval Drosophila respond to nociceptive stimuli. This discovery is followed-up by the identification of neurons in which bero function is relevant for the modulation of nociceptive behavior, and by the additional identification of likely signaling molecules for conferring such modulation. The work will be of interest to neurobiologists working on genes, neural circuits, and behavior. While both interesting and methodologically elegant and diverse, important genetic controls for leaky expression of transgenes seem to be missing, as are alternative scenarios for results that, as the authors acknowledge, are unexpected or seemingly contradictory.

eLife assessment

This study presents important findings on the hunting strategies and energy intake of a bat in the wild. It combines several methods (biologging, captive experiment, and DNA metabarcoding) to provide convincing evidence for the claims. While relevant for researchers in the broad field of animal ecology, in its the current form, the significance of the results may be hard to appreciate for a general audience.

eLife assessment

In this study, the authors presented the novel findings that PTH signaling plays a significant role in bone formation in hypertrophic chondrocyte (HC)-derived osteoblasts and MMP14 cleaves PTH1R and inhibits PTH signaling. These studies significantly contribute to our understanding of molecular mechanisms of postnatal bone formation and adult bone remodeling, especially the HC cells in this process. The study was well-designed and well-conducted. The data in this study are convincing and support the conclusion made by the authors.

eLife assessment

This paper should be a high priority for neuroscientists interested in the role of connectivity in generating cognitive functions, especially with respect to the cerebellum (which has more neurons than any other part of the human brain). This study makes a compelling case for convergent connectivity from cortex to cerebellum supporting a variety of cognitive functions in the cerebellum. However, insufficient details were provided for proper evaluation of claims, and some of the claims (such as directionality of cortico-cerebellar inferences) may not be supported by the analyses.

eLife assessment

This very well-written paper advances our understanding of the mechanism of activation of the thrombopoietin receptor (TpoR), a very important cytokine receptor that regulates megakaryocyte differentiation and platelet production. The authors supply an elegant combination of NMR and cell biology experiments to support their conclusions and the data are of high quality.

eLife assessment

This important study reports the physiological role of Ssh2 in spermatogenesis as a critical factor for acrosome biogenesis. Loss of SSh2 in round spermatids prevents the fusion of proacrosomal vesicles leading to fragmented acrosomes due to impaired actin bundling and dephosphorylation of COFILIN. This work would be more convincing if mutations in this gene could be identified in human infertile men. Moreover, the proposed mechanism needs cross-validation in future work.

eLife assessment

This paper is of potential interest for scientists who study bone marrow stem/progenitor cells, bone remodeling, and metabolism. Using Adipoq-Cre-based conditional deletion of Csf1 and scRNA-seq approaches, the authors provide compelling evidence that a subset of cells in murine bone marrow, characterized by AdipoQ expression, are a major source of M-CSF to regulate osteoclast formation and bone remodeling. This is a well-written, well-executed set of studies, the data from which largely support the above key claim.

eLife assessment

This study presents an important reanalysis of a prior dataset testing effects of D2 antagonism on choices in a delay discounting task. While the prior report using standard analyses showed no effects, the current study used a DDM to examine more carefully possible effects on different subcomponents of the decision process. This approach revealed compelling evidence of contrasting effects of D2 blockade on the effect of reward size differences and bias on choice behavior, findings which should be of broad interest to neuroscientists trying to understand dopamine function or the factors influencing choice behavior.

eLife assessment

Humanized transgenic mice represent an important tool for antibody discovery and vaccine profiling but their similarity to human immune responses has not been established so far. In this manuscript, Richardson et al. comprehensively characterize IgH repertoires of Ky mice that carry human immunoglobulin heavy (IgH) and light chain (Igk and l) genes. The data presented here will be useful for setting a foundation for the use of this model, as well as other similar transgenic models, in future studies.

eLife assessment

This is a valuable contribution to the SARS-CoV-2 modelling literature that will be of interest to infectious disease modellers studying the impact of spatially heterogeneous interventions for transmission control. The calibration and analysis of the proposed model is sound and and the results provide convincing evidence that supports the claim that localised interventions could potentially reduce societal impact while maintaining outbreak control. However, the paper provides little insight into what drives the regional diffusion in the Netherlands and how that diffusion could be affected by local lockdowns and a more thorough exploration of the model is warranted. There is also an opportunity to consider behavioural consequences, feasibility, and potential ethical implications of the proposed approach in greater depth.

eLife assessment

The effect of helminth infection on vaccination against tuberculosis infection and disease is an important area of study. In this manuscript, the authors build off of a large body of prior data showing that mycobacterial antigens upregulate MINCLE whilst the cytokine IL-4 downregulates MINCLE. As IL-4 is upregulated during Helminth infections, this can antagonize Th1/Th17 responses. By using two different models of helminth infection, the authors demonstrate an organ-specific impairment of Th17 responses in a vaccination setting with a MINCLE-dependent adjuvant. The work is topical and may have important translational implications for patients with tuberculosis and helminth co-infections and/or vaccination regimens for patients with helminth infections. The study will be of interest to individuals studying the convergence of different infectious diseases.

eLife assessment

Host directed therapies (HDTs) have the potential to improve management of tuberculosis (TB) through shortening of the duration of standard 6-month chemotherapy and promoting recovery of respiratory sufficiency. Several such agents have come to the fore recently and in this study, the authors investigate the use of sertraline (SRT) and demonstrate that it potentiates the activity of anti-tubercular drugs in macrophages as well as in the murine model of TB infection. The authors propose a model whereby SRT acts through modulation of the inflammasome.

eLife assessment

The purpose of this study was to determine whether heme oxygenase -2 deficiency translates to deficiencies in motor neuron function. This paper plays a plausible mechanism by which heme oxygenase-2 deficiency can lead to obstructive apneas. Indeed, this is among the first papers to comprehensively describe a signaling pathway in motor neurons and the consequences of its deficiency. Furthermore, the work completed here may be relevant to other diseases in which motor neuron signal transmission is a key contributor.

eLife assessment

This study presents a valuable finding that the combined use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy against HER2+/HR+ breast cancer cells. The evidence supporting the claims of the authors is rather solid. The work will be of interest to medical biologists and clinical doctors working on breast cancer.

eLife assessment

Upregulation of PCA3 and downregulation of PRUNE2 in prostate cancer were first discovered in this work, which innovatively demonstrated that PCA3 and PRUNE3 function as an oncogene and a tumor suppressor gene respectively. The conclusion is further enhanced by the use of two distinct patient cohorts, which highlights the clinical significance. Functional experiments will be needed to more comprehensively validate the findings.

eLife assessment

This valuable study by Sonobe et al uses transfected cells and patient iPSC-derived neurons to define mechanisms underlying translation of the antisense C4G2 RNA strand expressed in C9orf72-associated ALS and FTD. The authors design a series of constructs to explore the start codon required to produce toxic PR and prominent PG dipeptides in disease. Using these constructs they provide solid data that translation in the PR and PG reading frames occur due to the presence of AUG codons within the 5'UTR of the RNA strand. However, in its current form the paper is incomplete and the conclusions require additional experimental support.

eLife assessment:

This important study describes converging cellular phenotypes in human neural progenitor cells derived from individuals with differing genetic forms of autism spectrum disorders. These convincing data demonstrate that altered mTOR signaling occurs in all cases of autism examined in the study, providing a common starting point for understanding the etiology of neuronal deficits in autism. The work will be of broad interest to neurobiologists especially those studying molecular mechanisms of brain development and disease.

eLife assessment

This important study presents an interesting example of how complexities of communities may be reduced by showing that the joint effects of two or more species on a focal species are generally not additive, but rather dominated by the strongest single effect. The evidence, enabled by over 14,000 measurements using nanodroplet-based microfluidics, is compelling, although the generality of the conclusion awaits further studies. This paper is of interest to microbial ecologists.

eLife assessment

The work of Caspy and coworkers resolves the cryo-EM structures of stacked and unstacked PSII supercomplexes of Dunaliella, revealing unexpected connectivity and conformational flexibility, with intriguing implications for the function and regulation of photosynthesis.

eLife assessment

This study uses top-notch spatial profiling methods to present a valuable account of the number of different neuron types in the central nucleus of the amygdala of the mouse. The approaches and evidence presented are compelling, but the analysis is incomplete and would benefit from increases in sample size. With this aspect strengthened, this paper would be of interest to neuroscientists investigating the function of the central amygdala.

eLife assessment

Here, Morgan and colleagues report a novel synthetic lethal interaction between nucleoporin inhibition and KRAS-driven hepatocyte hyperproliferation. The authors show that nucleoporin inhibitor treatment or heterozygosity of nucleoporin genes (ahctf1 and/or ranbp2) suppresses KRAS-driven zebrafish larval liver overgrowth, providing impetus for developing Nup inhibitors as hepatocellular carcinoma treatment. Their data provide insights into the consequences of nucleoporin inhibition in cancer, demonstrating that disrupting ahctf1 decreases proliferation and promotes apoptosis by impairing nuclear pore formation and mitotic spindle assembly through a mechanism that may be at least partially dependent on tp53.

eLife assessment

This study addresses whether the composition of the microbiota influences the intestinal colonization of encapsulated vs unencapsulated Bacteroides thetaiotaomicron, a resident micro-organism of the colon. This is an important question because factors determining the colonization of gut bacteria remain a critical barrier in translating microbiome research into new bacterial cell-based therapies. To answer the question, the authors develop an innovative method to quantify B. theta population bottlenecks during intestinal colonization in the setting of different microbiota. Their main finding that the colonization defect of an acapsular mutant is dependent on the composition of the microbiota is valuable and this observation suggests that interactions between gut bacteria explains why the mutant has a colonization defect. The evidence supporting this claim is currently insufficient. Additionally, some of the analyses and claims are compromised because the authors do not fully explain their data and the number of animals is sometimes very small.

eLife assessment

There is an urgent need to improve prognostication of diabetic kidney disease in different diverse populations so this study is valuable in identifying specific predictive factors in a cohort of South East Asian populations whose baseline risk is higher. There are some limitations: the assumptions the authors make and the methods would benefit from some more investigation/validation.

eLife assessment

This is an important study that shows how Snf1/AMP Kinase fine-tunes TORC1 signaling in response to glucose starvation. Their observation that Snf1 phosphorylation of the TORC regulator Pib1 and the TORC effector kinase Sch9 provides new mechanistic information on this important pathway involved in cell growth. The combination of phosphoproteomics, genetic, biochemical, and physiological experiments is generally convincing, although the results with the Pib2 SA and SE mutants are somewhat inconsistent.

eLife assessment

This fundamental study presents solid evidence for T1r (sweet /umami) taste receptors as chloride (Cl-) receptors, based on a combination of state-of-the-art techniques to demonstrate that T1r receptors from Medaka fish bind chloride and that this binding induces a conformational change in the heteromeric receptor. This conformational change leads to low-concentration chloride-specific action potential firing in nerves from neurons containing these receptors in mice, results that represent an important advance in our understanding of the logic of taste perception.

eLife assessment

This valuable study presents a potentially interesting contribution on animal caching behaviour. At present, evidence that the flying squirrels themselves modified the nuts is incomplete, but there are clear video observations of them associating with the nuts. Either way, the images of the modified nuts and the detailed descriptions of the caching behaviour describe a new technique for storing nuts in a tropical rainforest.

eLife assessment

This valuable study substantially advances our understanding of the phenotypic divergence of the plague-causing bacterium, Yersinia pestis, from a closely related species, Yersinia pseudotuberculosis, which causes much milder disease. The authors provide convincing evidence that a frameshift mutation in the Y. pestis rcsD gene changes a signaling pathway that contributes to the flea-mammal transmission of plague. The work shows how small genetic differences can alter pathogenicity and stress survival.

eLife assessment

Exploiting the power of the Drosophila larva as a model, Liu et al.'s important study sheds light on the neuronal mechanisms of speed regulation during locomotion. The data obtained using a combination of functional and structural approaches are mostly rigorous and convincing, but there are concerns about the small number of animals analysed in some of the behavioural experiments.

eLife assessment

This important study offers compelling evidence, in the form of a rigorous and clear analysis of SARS-CoV-2 mutations observed within non-human animal hosts, of viral mutations that may provide an adaptive advantage within hosts. The authors could, however, improve the description of some elements of their methods and analysis approach, and they should cite additional relevant literature. The findings are relevant to those interested in the ecology of infectious disease, epidemiology, and specifically those who are interested in the genetic underpinnings of pandemic potential.

eLife assessment

This paper introduces a fundamentally new automated method for assigning cell types and distinguishing organs in electron microscope (EM) reconstructions, a process that was previously manual. The authors present compelling evidence that their approach works as well or better than human efforts, in at least one species. This new method can help avoid a known bottleneck in EM reconstructions, one that will otherwise limit the ability of EM to scale up to larger volumes and target additional animal species. The main limitation is that the method has only been tested on a single species, but if tests show similar performance on other animals, the method will likely become a mainstay of EM reconstruction efforts.

eLife assessment

This manuscript has a number of important findings in the interesting area of attempts to rescue neurodevelopmental phenotypes in the postnatal setting. Ameliorating some of the symptoms of Angelman syndrome at later stages is potentially of major clinical significance and this study provides support for that possibility. More generally, this study also shows that treatment of a syndrome like Angelman with antisense oligonucleotides to modulate allele-specific expression at later stages of life has potential.

eLife assessment

This manuscript presents a theory of generalization in neural population codes and proposes sample efficiency as a new normative principle distinct from efficient coding. The theory suggests that, with small numbers of training examples, generalization performance depends exclusively on the population code's 'kernel' (pairwise similarity between population activity patterns), and that sample-efficient learning depends on whether the task is aligned with the population's inductive bias (i.e., the top eigenfunctions of the kernel). The theory can be used to identify the set of 'easily learnable' stimulus-response mappings from neural data which makes strong behavioral predictions that can be easily evaluated.

eLife assessment

The authors present an important study of the effects of chronic hepatic FGF21 overexpression on the development of non-alcoholic steatohepatitis (NASH) in a model of obesity and dyslipidemia, i.e. ApoE3-Leiden CETP transgenic mice fed a western diet. NASH is a major global health problem and exogenous FGF21 treatment has been explored as a therapeutic strategy. The authors find that chronic overexpression of FGF21 blocks weight gain on the western diet, and even induces some weight loss compared to the control diet. The findings are convincing and methodologically sound.

eLife assessment

This manuscript provides a valuable resource for scientists who wish to manipulate second messengers in zebrafish using optogenetics. The authors provide solid evidence, based on behaviour, monitoring of heart beat and imaging, that several of the opsins tested can have an effect in larval fish. Opsins that lack an effect are also described. As the second messengers affected by the tools are found in multiple cell types, the results should be of interest of scientists working in a variety of areas.

eLife assessment

This work provides a potentially useful resource for scientists who wish to use optogenetics to manipulate GPCR signalling in larval zebrafish. It compares the physiological effects of different vertebrate and invertebrate rhodopsins expressed in either reticulospinal neurons or cardiomyocytes. The evidence for light-induced effects on behavior (either tail bending or heart beating) is solid, although only limited cell types and conditions are tested.

eLife assessment

In this important work, the authors develop a theory for the co-evolutionary dynamics of bacteria and phages, where the major evolutionary pressure comes from CRISPR-Cas adaptive immunity in bacteria. Through extensive stochastic numerical simulations and analytical calculations, the paper presents a compelling analysis of the emergent properties of immune interactions, in the regime of a single proto-spacer and a single spacer. Some of the trends highlighted by the model are recovered from experimental data. The main results concern how diversity in both phage and bacteria population are linked and are shaped by immunity, and should be of broad interest in immunology.

eLife assessment

This is a valuable paper that relates the function of Ephrin-B1 to diastolic dysfunction via its actions on maturation of cardiomyocytes. The mechanisms of diastolic heart failure remain poorly understood, and this work contributes to advancing our understanding. The hypothesis is novel and the manuscript is fairly extensive and well-illustrated. The data, methods and analyses are presented to the community in a solid manner. The work represents an interesting insight into potential mechanisms of diastolic dysfunction and heart failure with preserved ejection fraction.

eLife assessment

This manuscript is of interest to neuroimaging scientists and neurophysiologists studying the glymphatic system. Using a multi-modal approach including magnetic resonance and histological methods, this work provides substantial data interrogating the effect of removing of aquaporin-4 (AQP4) from the mouse brain parenchyma on the structural morphology and interstitial fluid dynamics stagnation. In particular, the authors provide evidence that deletion of AQP4 in mice results in increased interstitial volume, likely due to increased resistance to parenchymal CSF efflux.

eLife assessment

This valuable study describes the effects of endocrine therapy in a large series of Chinese patients treated with mastectomy (both efficacy and side effects). Whilst there are some caveats regarding the methodology (retrospective, small numbers of events, and some potential methodological bias in data collection) this is a solid piece of work and with further, ideally prospective data collection, has the potential to improve the management of patients with DCIS.

eLife assessment

In this valuable study, authors convincingly show that epistasis between mutations plays an important role in the evolution of broadly neutralizing influenza antibodies. Although the data are convincing, several parts of the manuscript require more accurate description.

eLife assessment

The study provides a fundamental framework for linking human genome variation to targetable mechanisms of disease. The authors provide compelling evidence that a strong candidate locus associates with body weight in humans acts through adipocyte MTIF3. Thus, the generalized approaches taken in this study have the potential to inform genetic association studies in general and lay a foundation for future functional genomics studies.

eLife assessment

How the pathogens Pseudomonas aeruginosa and Staphylococcus aureus compete and co-occur within opportunistic infections is a topic of broad significance, but the major drivers of these interactions remain unclear. Here the authors defined parameters that predict the coexistence of these microbes using their absolute growth in certain nutritional conditions, leading to questions about how other nutrients lead to the dominance of one or the other during infections. Within a confined context, this valuable study provides solid support for a novel framework in which to evaluate this clinically important species interaction.

eLife assessment

The authors provide novel evidence for a connection between fibroblast activation and eutherian stromal decidualization. This important work substantially advances our understanding of decidua biology and its contribution to pregnancy. The authors are using solid evidence to support the findings. The methodology includes in vivo mouse and human stroma cells is broadly supports the claims with only minor weaknesses.

eLife assessment

Authors provide valuable evidence identifying a lncRNA transcribed specifically in the pDC subtype from the +32Kb promoter region which is also the region for the enhancer for Irf8 specifically in the cDC1 subtype. With convincing methodology, they provide in-depth analysis about the possible role of lncIrf8, and its promoter region and cross-talk with Irf8 promoter to identify that it is not the lncIRF8 itself but its promoter region that is crucial for pDC and cDC1 differentiation conferring feedback inhibition of Irf8 transcription. The work will be of interest to immunologists working on immune cell development.

eLife assessment

Slusarczyk et al demonstrate that red pulp macrophages (RPM), specialized splenic cells that clear senescent red blood cells through erythrophagocytosis, show diminished function in aging mice. This impairment leads to retention of hemolytic red blood cells and formation of extracellular aggregates which further exacerbate RPM demise. Iron restriction alleviates most of these symptoms in aging RPMs. They propose RPM collapse as an early indicator of aging that could be reversed through iron limitation.

eLife assessment

This useful study highlights the contribution of the medial temporal lobe (MTL), and the DG/CA3 hippocampal pathway in particular, to neural activity during the working memory delay period. The evidence supporting this is compelling, using diverse state-of-the-art approaches to neural data analysis and relating it to behavioural data. The work will be of significant interest to neuroscientists specialising in the research area of human working memory.

eLife assessment

The authors present valuable findings about the mechanisms inducing IL-10 production by B cells in neonates. The evidence supporting the claims of the authors is solid, although the manuscript would be strengthened by amendments to the presentation of the data and explanation of some experimental choices.

eLife assessment

Using in-vivo proximity labeling using three different presynaptic proteins the authors have carried out a comprehensive proteome analysis of axonal dopamine release sites, resulting in the identification of many new presynaptic candidate proteins. Genetic deletion of the active zone protein RIM1 but not of the presynaptic calcium sensor synaptotagmin 1 resulted in a loss of enrichment indicative of a disruption of the active zone. Although the functional significance of many of the novel proteins will require future corroboration, the analysis provides a valuable and high-quality dataset as a starting point for future investigations.

eLife assessment

This paper describes a method for robust differentiation of the common marmoset induced pluripotent stem cells (iPSCs) into primordial germ cell-like cells and subsequently into spermatogonia-like cells when combined with testis somatic cells. The data suggest that marmosets are very similar to humans and macaques. The paper is nicely done but needs further characterization and a better explanation of the methodology.

eLife assessment

This fundamental work advances our understanding of how bacteria evolve to resist drugs used for cancer treatment and how this could potentially affect drug efficacy and treatment outcome. The data were collected and analyzed using a solid methodology and can be used as a starting point for functional studies of the interaction between microbiome interactions and cancer drug treatment. The findings will be of broad interest to microbiologists and organismal biologists interested in the role of microbiomes in drug responses.

eLife assessment

In this work, Monfared et al. construct a useful three-dimensional phase-field model for cell layers and use this to investigate the link of extrusion events to defects in cellular arrangement. The extension of existing 2D phase field models to three dimensions is an important contribution of this paper. Here the model is used to study the importance of cell-cell and cell-substrate interaction in extrusion from cell monolayers. Their claim that extrusion events can be distinctly linked to defects in nematic and hexatic orders in the monolayer need to be better justified to be fully convincing.

eLife assessment

Junctophilin has been traditionally known as a structural anchor to keep excitation-contraction proteins in place for healthy contractile function of skeletal muscle. Here the authors provide an interesting and important role in skeletal muscle for Junctophilin, where it translocates to the nuclei and influences gene transcription. The authors provide convincing evidence for a novel role of junctophilin beyond its structural role as a regulator of gene expression.

eLife assessment

The enrichment of Tfh17 cells in Tfh cell central memory compartment and the dominance of Tfh17 cell population and the Tfh17 transcriptional signature in circulating Tfh cells at the memory phase are nicely demonstrated, and may well be helpful for understanding the heterogeneity of memory Tfh cells and potentially providing clues for vaccine design. The in vitro differentiation system for mouse Tfh cells also provides a strategy for others to build upon in dissection of Tfh cell development and function.

eLife assessment

This important study addresses the ways in which bacteriophages antagonize or coopt the DNA restriction and/or recombination functions of the bacterial RecBCD helicase-nuclease. The evidence from both biochemistry and structural biology showing convergent evolution is convincing.

eLife assessment

This fundamental work advances our understanding of the cellular and molecular changes of the aged tendon. The evidence supporting the conclusion is convincing, using a DTR-based ScxLin cell depletion model along with state-of-art proteomic and scRNA-seq analyses. This paper is of potential interest to scientists and physicians who study the mechanisms of the tendon aging process.

eLife assessment

The author arrive at the convincing conclusion that STAT3 expression promotes TFIIIB assembly through miR-106A-5p-mediated inhibition of TP73 expression, thereby increasing Pol III transcription, which contributes to enhanced cell proliferation. The data are very good and clearly support the proposed model.

eLife assessment

This study presents the cryo-EM structure of the dynein regulator Lis1 bound to human dynein providing important insight into how these two proteins interact. The evidence supporting the claims of the authors is overall convincing though it requires some minor re-analysis. The work will be of interest to researchers working with motor proteins and neurodevelopmental disorders as it helps rationalize how mutations in Lis1 or dynein lead to disease.

eLife assessment

This manuscript generates a valuable new genetic resource for studying mosquitos and the pathogens that they carry. For 33 species of mosquitoes, the authors have sequenced and assembled the ribosomal RNA, which will dramatically improve the power of RNA sequencing in mosquitoes.

eLife assessment

Force generation by the myosin motor plays an important role during cell division. Myosin activity is regulated by phosphorylation, which activates myosin in animals but was thought to inactivate it in yeast. In this valuable study, the authors use a combination of convincing approaches to show that under some growth conditions, dependent on the carbon source of the growth medium, phosphorylation becomes essential for myosin function.

eLife assessment

The fundamental work by Starret et al advances the understanding of the etiological roles of viruses and other environmental factors in bladder cancers after solid organ transplantation. The evidence is compelling using cutting edge sequencing approaches of patient samples. This work will be immediately interesting to multiple fields (of viral oncogenesis, BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV), solid organ transplantation and whole genome and transcriptome sequencing) and may eventually influence care after organ transplantation.

eLife assessment

This study addresses a fundamental question about the spatiotemporal location of neurotransmitter release in a synapse with essential implications for postsynaptic signaling and neural excitability in general. The authors provide convincing evidence on non-overlapping nanometer scale organization of the two primary forms of evoked vesicle fusion (synchronous and asynchronous) in the synapse. They utilize tools for super-resolution assessment of synaptic transmission that were previously developed in their lab, in this way they help bridge earlier work based on imaging approaches that lack temporal resolution and electrophysiological results lacking spatial resolution.

eLife assessment

This is an important and valuable paper that uses H2B overexpression to quantify changes to chromatin compaction using elegant in vivo imaging approaches in the live epidermis in stem cells undergoing epidermal differentiation. The results confirm in vitro findings that changes to chromatin compaction precede cell fate commitment during epidermal stem cell differentiation. These conclusions are mostly supported by solid and convincing experimental and quantitative evidence and the recapitulation of chromatin and transcriptional phenomena in a live tissue setting using careful in vivo imaging and quantification is of value.

eLife assessment

This manuscript details the valuable development of population genetics theory that can be used to infer past changes in the selfing rate in natural populations. The inference procedure is solid, although the comparison to previous estimates can be improved, and deeper insight could be gained from further theoretical exploration. The work will be of broad interest to the field of mating systems evolution.

eLife assessment

Based on a large set of complementary experiments, the authors propose that the lncRNA LNCSOX17 regulates human definitive endoderm differentiation, although its function is not related to the adjacent SOX17 gene in the same topological domain (TAD). The findings are important and supported by convincing data, although the molecular mechanism by which LNCSOX17 regulates endoderm differentiation stays unresolved.

eLife assessment

This fundamental study presents a crystal structure of two proteins catalyzing histone H2B ubiquitination. Findings from the structural study are further validated by mutagenesis and functional assays. This is a well-executed study providing useful information to the field.

eLife assessment

This important work provides knowledge regarding how neuropeptides, which are highly expressed in the brain, can influence cortical plasticity. The conclusions are supported by compelling evidence from both in vitro and in vivo assays, although some control experiments are needed to further strengthen the conclusions. This paper will be of interest to neuroscientists studying cortical processing and neural plasticity, as well as cell biologists and biochemists interested in peptide function in general.

eLife assessment

This fundamental study substantially advances our understanding of interactions of consecutive memory tasks by identifying responsible molecules and neurons. The evidence supporting the claims of the authors is generally solid, although further contextualization of the interferences in memory consolidation and more rigorous measurements of the effects of genetic manipulation would have strengthened the study. The work will be of broad interest to neuroscientists working on learning and memory as well as learning psychologists.

eLife assessment

In this study, the authors provide important findings supporting a key role for TLP2 as a regulator of neurotoxic and pro-inflammatory cytokine and chemokine release following acute and chronic neuroinflammation. They provide convincing data supporting that the abrogation of TPL2 kinase activity ameliorates disease pathogenesis in a mouse model of tauopathy. This manuscript will be of broad interest to readers in the fields of neuroimmunology and neurodegenerative disease who are interested in the pathogenic effects of innate immune signaling pathways in disease.

eLife assessment

Rett syndrome is one of the most frequently diagnosed neurodevelopmental conditions. The gene mutated in the condition, Mecp2, encodes for a transcriptional repressor, but genes functioning downstream of Mecp2 have remained difficult to clarify. Here the authors identify an important candidate gene, Growth Differentiation Factor 11 (GDF11) regulated by Mecp2 via epigenetic mechanisms. Further studies in mouse models demonstrate that genetic reduction of Gdf11 ameliorates behavioral deficits of Mecp2 duplication mice, and can function to produce neurobehavioral deficits in mice alone. These findings will be of interest to scientists working in mouse cognition, behavior, neurodevelopment, transcriptional and epigenetics.

eLife assessment

This study provides important new insights into iron sulfur biosynthesis in the human malaria parasite Plasmodium falciparum. The work is based on elegant and robust genetic approaches, and not only confirms the essentiality of the plastid-hosted Suf iron-sulfur cluster synthesis pathway, but also highlights an important additional role for the cysteine desulfurase SufS in apicoplast maintenance via tRNA modification. The work provides compelling evidence for a dual function of parasite SufS, although impact on tRNA has not been established directly. These findings reveal a potential new target for metabolic intervention, and will be of interest to researchers studying apicomplexan parasites, and more broadly, in the field of plastid biology.

eLife assessment

There are no known effective treatments available to date for the treatment of osteosarcomas, the earliest identified bone cancer that can spread to other tissues. In this study, the authors have used novel approaches to identify calreticulin and procollagen C-endopeptidase enhancer (PCOLCE) as osteosarcoma tumor suppressor proteins that inhibit osteosarcoma growth both in animal and in vitro cell culture models. These important findings may provide a basis for the future development of more efficient targeted therapies for the treatment of osteosarcomas.

eLife assessment

This is an important and significant study that focuses on deriving ovarian granulosa-like cells from hiPSC lines. The strengths of the study include bioinformatics analysis to identify relevant candidate transcription factors that drive the iPSCs into the ovarian granulosa pathway, an attempt to derive ovaroid model by combining human PGC-like cells with the iPSC-derived granulosa-like cells, and a variety of endpoint analysis including hormone measurements. Some limitations of the study include poor quality of images, lack of convincing demonstration that follicle-like structures are indeed derived in vitro, lack of clear rationale for using different cell lines with different endpoints chosen for analysis, and lack of clear methods indicating stepwise which transcription factors were used.

eLife assessment

Cover et al., examine the pathway from the intralaminar nucleus of the thalamus (rILN) to the dorsal striatum (DS) in the reinforcement of behavior/actions. The rILN sends a large glutamatergic projection to the DS, but its role in action selection was unknown. The authors found that the rILN neurons that project to the DS were activated at both action initiation and with the reward. Activation and inhibition of this pathway increased the success or decreased the success of reward acquisition, respectively. The findings are an important advance our understanding of the function of rILN to DS projection in reward-based behavior. The manuscript has provided convincing evidence with the appropriate methodologies to support these claims.

eLife assessment

This study presents a valuable finding in identifying the roles of the pericytes in maintaining vascular volume and integrity of spiral ganglion neurons (SGNs) in the cochlea, the main hearing organ. The evidence supporting the authors' claims is solid using an inducible and conditional pericyte depletion mouse model and the co-culture models. While the study provides a modest translational contribution, understanding the roles of organ-specific pericytes is paramount, making this study timely and significant. The work will be interesting for biomedical biologists working on hearing, blood vessels, signaling, and cell-to-cell interactions.

eLife assessment

Illingworth et al. investigate the effectiveness of ribavirin and favipiravir on the treatment of a paediatric patient with chronic RSV and identify an increase in mutations caused by ribavirin while favipiravir had no apparent mutagenic effect. Strength of evidence is incomplete for the mathematical model and solid for the mutational load analysis with potential for improvement in both cases with clarification of the methods. Major strengths are an interesting hypothesis and appropriate modeling methodology that will be of interest to virologists, clinicians and evolutionary biologists. Weaknesses in methodology pertain to mutational load measures possibly also capturing clonal expansion of new mutants and lack of clarity about how viral fitness is related to viral load in the mathematical model.

eLife assessment

This study presents the important finding of an unusual uncompetitive inhibitor (ECSI#6) of the serotonin transporter that removes the neurotransmitter serotonin from the synaptic cleft. Through careful and comprehensive analysis, the authors convincingly show that the molecule most likely binds to the inward-facing and K+-bound state and that it assists in folding and targeting the transporter. The work will be of interest to those engaged in biophysical analyses of the serotonin transporter, and colleagues developing pharmacological chaperoning strategies for transporters in general.

eLife assessment

In this important paper, the authors have developed an approach for simultaneously optimizing the conformational ensemble and degrees of oligomerization, and this has been tested by applying it to a specific protein (SPOP). Comparison of the quality of fits with different models also provides valuable insights into structural features important to the assembly of oligomers. The approach, presented with compelling experimental support, is potentially applicable to other systems as well.

eLife assessment

This valuable study combines live cell imaging and mathematical modeling to show how an emerging model fungus engages in an oscillatory chemical dialogue to prepare for cell-cell fusion. Cell data and modeling are in compelling agreement but leave many open questions as to the nature of coordination between cells and the significance of oscillations, rendering the strength of evidence in support of the authors' inferences incomplete.

eLife assessment

This is an important manuscript that provides support for the hypothesis that the relative increase in NIH funding matches the rate of overall inflation. The level of evidence is solid, and a clearer description of the analysis will further strengthen the manuscript. This paper should be of relevance to funders, investigators who are currently funded, and those who are seeking federal support.

eLife assessment

This paper will be of interest to developmental biologists who study the gene regulatory mechanisms necessary for neuronal identity and circuit assembly. The study presents important findings regarding the role of the LIM homeodomain transcription factor Isl2 in the development of spinal motor neurons. While the importance of Isl2 for the acquisition of axial and visceral motor neuron development was already described in the literature, the data convincingly describe an additional role in the differentiation of a subset of limb-innervating motor neurons.

!- 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.