eLife assessment

This valuable manuscript describes a fully automated touchscreen cognitive testing system for rats that reduces the length of training required to learn a task and eliminates the need for daily handling. These features make it possible to assess cognitive behaviors in conjunction with other neurobehavioral paradigms during adolescence, an important advance in the field. The data convincingly show that cognitive flexibility does not promote susceptibility to severe weight loss in the activity-based anorexia (ABA) paradigm. However, support for the claim that cognitive deficits seen in rats that had been exposed ABA adequately capture an important clinical feature of the pathophysiology of anorexia nervosa is incompletely supported.

eLife assessment

This study provides fundamental insights into the relationship between single neuron activity in superficial layers of the cortex and electrical signals recorded at the cortical surface. Based on solid measurements, the results indicate a weak correlation between individual layer 2/3 neuron activity and multiunit activity recorded at the surface, whose interpretation could be reinforced. In particular, a strong contribution of layer 1 axons to surface signals is suggested but relies on incomplete evidence.

eLife assessment

This manuscript provides valuable insight into the molecular mechanism by which destabilized mitochondrial proteins 'clog' import channels and contribute to the pathologic mitochondrial and cellular dysfunction implicated in human disease. The evidence supporting this conclusion is solid, utilizing yeast, mammalian cell culture, and mouse models. However, additional characterization of import clogging in the mammalian model systems would strengthen this study. This work will be of broad interest to researchers in the fields of mitochondrial biology, protein quality control and proteostasis.

eLife assessment

This manuscript tests an important assumption about how sensory information is processed and used to guide motor choices. The widely held assumption is that sensory-motor circuits are capable of integrating evidence, but the validity and generality of this 'principle' have been recently questioned by studies suggesting that other computational operations may lead to similar psychophysical results, mimicking integration without actually performing it. This study makes a compelling case that the integration assumption was likely correct all along and that the model mimicry can be easily disambiguated by using appropriate sensory stimuli and task designs that permit rigorous analyses.

eLife assessment

This important study provides convincing evidence that locus coeruleus is activated during visuomotor mismatches. Gain of function optogenetic experiments complement this evidence and indicate that locus coeruleus could be involved in the learning process that enables visuomotor predictions. This study therefore sets the groundwork for the circuit dissection of predictive signals in the visual cortex. Loss-of-function experiments would strengthen the evidence of the involvement of locus coeruleus in prediction learning. These results will be of interest to systems neuroscientists.

eLife assessment

The paper provides a valuable, in-depth mathematical analysis of the coevolutionary dynamics resulting from a coupling of players' strategies and (collective) risk, as well as illustrative numerical simulations of the system's trajectories for different starting conditions. It is therefore a solid contribution to our understanding of how cooperation can be sustained when there is feedback between individual decisions and the global risk of disaster. This paper will be of interest to scientists working on mathematical biology/ecology, and more generally various aspects of human decision-making, the interplay between human decisions and the environment, and public goods provision.

eLife assessment

This study addressed a long-standing question in biology - the role of fever during infections. Using innovative research strategy, the authors provide compelling evidence for the positive impact of higher body temperature on both pathogen clearance and tissue repair. This study thus provides important advances in our understanding of host defense and its connection with physiology and behavior.

eLife assessment

This manuscript reports novel and important findings on the mechanisms of regulation of CRAC channels. Collectively, the work represents an important conceptual advancement, showing that stromal interaction molecule-1 is not necessary for Ca2+-dependent inactivation of the Orai1 channel and that Orai1 likely contains a Ca2+ sensor for autoregulatio. The experiments are carefully conducted, and the data is of high quality and support the major conclusions of the authors.

eLife assessment

This important paper advances the understanding, in the model plant Arabidopsis thaliana, of the molecular basis of the promotion of flowering in the spring by exposure to winter cold through a process known as vernalization. In Arabidopsis, there are two classes of long non-coding RNAs produced only when plants are in the cold, and this work provides compelling evidence that the cold-induced expression of one of these (COOLAIR) involves C-repeat binding factor proteins that bind to cognate binding elements in the COOLAIR promoter, but also that COOLAIR is not required for the vernalization-mediated promotion of flowering under standard laboratory conditions in which the vernalization response is measured.

eLife assessment

This study provides fundamental insight into the functional impact of CDK4 inhibition on cells in the tumor microenvironment, which is of high importance and interest to the field. The compelling conclusion that proliferative exhausted T cells are associated with response in HPV+ head and neck cancer is supported by the cohort of 14 patients with paired tumor and adjacent normal tissue and rigorous bioinformatic analysis of nearly 50,000 single CD3+ T cell transcriptomes. This work will be of interest to researchers across tumor types and in other immunological fields of study.

eLife assessment

In this work, the authors provide convincing evidence about the existence of two distinct osteoclast populations with specific expression profiles and properties and show that the probiotic yeast S. boulardii may be useful in managing inflammation-mediated bone loss, including estrogen deprivation-mediated osteoporosis. The reported study aims to bring the concept of heterogeneous osteoclasts into a proof-of-principle therapeutic application, which may mean that the use of probiotics might combat osteoporosis towards a better bone quality than current therapies. The molecular mechanism of how the probiotic yeast S. boulardii treatment acts via the receptors remains obscure since it might act via changes in the gut permeability or by components directly released by the fungus.

eLife assessment

This paper will be of considerable interest to researchers studying the psychological and neural basis of variation in prosocial behavior. The authors use a sophisticated combination of computational modeling and EEG to show that variation in generosity produced by changes in context (i.e., disadvantageous vs. advantageous inequality) and variation due to individual differences in concern for others both seem to occur early, during the perceptual or valuation stage of a choice, rather than later on during choice comparison. However, these two sources of variation also appear to operate through distinct mechanisms during this stage of processing, which spurs further questions about the drivers of human prosocial behavior.

eLife assessment

The authors examine the function of Tomosyn, in dense core vesicle fusion in neuronal cultures from mice expressing conditional alleles of tomosyn and tomosyn-2. The authors show here that while loss of tomosyns did not affect dense core vesicle exocytosis, it reduced the expression of several key dense core cargos, including BDNF. However, "rescue" experiments are needed to validate the specificity of the effects.

eLife assessment

This study presents valuable comprehensive data that underpin the enhanced ventricular arrhythmogenesis in elite trained athletes. The study is logistical challenge and the multiscale approaches used is a strength of the study. The data presented are strong and support most of the authors' claims.

eLife assessment

The study provides a recurrent network model of M1 for center-out reaches. The "neurons" in the model show uncorrelated tuning for movement direction during preparation and execution with dynamic transition between the two states. The continuous attractor model provides an interesting example of flexible switching between neural representations.

eLife assessment

This study describes the use of a new and valuable tool, namely phage display of Plasmodium falciparum proteome-wide peptides, for profiling of antibody targets. The study, conducted using plasma from Ugandan children and adults, represents an important aspect of naturally acquired antibodies with seroreactive responses to the intra-and inter-protein repeat regions. The results are, however, so far incomplete, and confirmatory data that antibodies to inter-protein repeat motifs do cross-react are needed.

eLife assessment

This highly important paper uses a Bayesian linear regression approach in a clinical trial to establish that ivermectin does not increase the clearance rate of SARS-CoV-2 relative to no study drug. The strength of evidence is compelling. Particular strengths are that the paper is clearly written, a novel and important adaptive study design, and linear mixed modeling to account for participant heterogeneity. The work will be of interest to clinicians, statisticians, and public health departments.

eLife assessment

In this useful study, the authors utilize state-of-the-art computational methods complemented with some experimental validation to investigate the dynamics of flexible loops of the L1 Metallo-β-lactamase enzyme, resulting in a better understanding of the various conformational states useful for the rational design of superior β-lactamase inhibitors/antibiotics. The evidence supporting the claims is solid, and the work will be of interest to computational, experimental biologists, and drug designers working on antibiotic resistance.

eLife assessment

This manuscript is of potential interest for a broad spectrum of researchers working on the nervous and muscular systems. By combining transcriptome and proteome analyses, the authors reveal the molecular makeup of the different compartments of the muscle spindle. The work is novel, makes important observations, and is well-executed and methodologically convincing to provide the field with new tools for dissecting the development and function of the muscle spindle.

eLife assessment

In this manuscript, the authors devised a new, useful mRNA-imaging approach by combining MS2 and SunTag labeling systems. The authors showed that this new method can be used to image the activation of gene expression and endogenous mRNA dynamics in live C. elegans. While the application in C. elegans has great future potential, this study is incomplete because it lacks essential characterization of the new imaging method to demonstrate that it does not interfere with RNA expression.

eLife assessment

Zhang et al. present convincing data describing a role for Polo-like kinase PLK-2 in restricting the activity of Chk2 kinase and coordinating synapsis of homologous chromosomes with the progression of meiotic prophase in C. elegans. By revealing PLK-2-dependent and -independent mechanisms of CHK-2 activity, this work provides a valuable understanding of the major regulators of meiotic progression.

eLife assessment

Li and colleague report observations that constitute a potentially fundamental advance, pointing to a mechanism by which non-neural cells can influence sleep regulation by neurons, The authors provide evidence in Drosophila showing that ecdysone synthesised outside the brain regulates sleep via ecdysone receptors in cortex glia. It further suggests that steroid signalling in glia can act on sleep through lipid droplet mobilization.

eLife assessment

In this manuscript, the authors provide mechanisms by which HLA-I polymorphism affects the capacity in the endo-lysosomal assembly of HLA-I molecules for constitutive expression and during cross-presentation. The findings may have implications for allotype-dependent variation in T cell responses to antigens localized in different subcellular compartments. However, additional biochemical and quantitative data is essential to bolster the central claims of the paper.

the word disability has been used for such a long time that it has its definition tied to sociopolitical beliefs, therefor when there was an attempt by the community to change its meaning to be more accurate many people still refuse to do so.

ableist and ableis is the way to identify the individuals who see themselves as superior because they are able bodied. theres not enough awareness to make the public asses what is ableist

basically this page talks about how in the previous definition of disability was based on medical terms whose purpose was to sell an idea to the public

eLife assessment

The study is important in that it investigates the effect of reading acquisition on neural responses experimentally, randomly assigning children to one of two training groups. The results provide solid evidence for learning-related changes in the (late) neural response to words, but it is not clear whether this reflects category-specific changes in visual cortex tuning. As such, the study may not yet provide a clear answer to the neuronal recycling debate within which it was framed. This paper is of potential interest to a broad audience of neuroscientists, as it addresses fundamental questions regarding the re-organization of functional cortical responses associated with learning to read.

eLife assessment

This important paper provides detailed cellular and molecular characterization of the olivocochlear efferents that project to the inner ear. These specialized motoneurons are the only source of feedback from the brain to the ear and have been difficult to access. This study convincingly categorizes the efferents, using single nucleus RNA-sequencing and 3D reconstructions of individual fibers and their pre-synaptic contacts onto target neurons in the cochlea.

eLife assessment

This study presents important findings on the regulation of the phosphate export cycle and identify the phosphatase Sit4 as a crucial player in regulation of the inner membrane potential of mitochondria. Whereas some of the data are convincing, the analyses will profit from deeper insights concerning metabolism alterations (carbon sources, amino acids). The major strength however is a new insight on how the cells use alternative ways for maintaining a critical mitochondrial inner membrane potential, and therefore this study is interesting to the broad audience with interests spanning from bioenergetics, metabolism and organellar and cell biology.

eLife assessment

This interesting and important methodologic study presents exciting new data identifying approaches to evaluating the cell biology of lung disease. Namely, the ability to identify and track dynamic and coordinated activities of multiple composite cell types in response to experimental interventions. They have developed an interesting label-free approach that collects biologically-encoded autofluorescence of epithelial cells by 2-photon imaging of mouse tracheal explant culture over 2 days. This study has the potential to inform a variety of experimental conditions in lung injury and repair.

eLife assessment

This study is of interest to epidemiologists and geneticists studying the association between telomere length and lung cancer risk. This work provides useful insight into risk factors for lung cancer. Overall, the results of this study are solid, as the genetic instrument used here is better powered and the battery of MR analysis makes this broad set of results convincing compared to previous work.

eLife assessment

The study is a careful investigation of the physical properties of hagfish slime and the underlying cellular framework that enables this extraordinary evolutionary innovation. It is a careful and detailed measurement with clear images. However, there is a need for a better contextualizing of the findings as a broader biological question, including the evolution of functional novelty, the adaptive processes, and the links between genetic and phenotypic evolution. Furthermore, the conclusions on the evolutionary origins and underlying genetics of hagfish slime based on comparative transcriptomic data need to be better supported.

eLife assessment

The manuscript aims to provide a comprehensive insight into the development of the tuberal hypothalamus of the chick embryo. It thus presents a useful tool for scientists working in this particular subfield. However, the manuscript is incomplete as it is impossible for the reader to follow the conclusions made by the authors because the presentation of the data is not streamlined and the text is difficult to follow, even for experts.

eLife assessment

This study presents important evidence that boosting with the Sinovac Coronavac inactivated vaccine would provide considerable protection from ancestral SARS-CoV-2 in terms of elicited neutralizing antibodies but would offer minimal protection against Omicron subvariants. The evidence supporting the claims of the authors is solid, although using a dilution series instead of one plasma dilution for Omicron neutralization would have strengthened the study. The work will be of very wide interest to the biomedical community and beyond, since it points to the need for a better booster vaccine in China.

eLife assessment

This work presents valuable findings that advance our understanding of the roles of the CA domain in specific binding of HIV-1 Gag to the viral genomic RNA. The compelling evidence obtained using the modified CLIP-seq and chemical crosslinking approaches support the authors' conclusion that the initial Gag lattice formation mediated by CA is essential for Gag recognition of the 5' Ψ sequence. This work will be of interest to virologists working on gRNA packaging of not only HIV-1 but also other RNA viruses.

eLife assessment

Drug-resistant tuberculosis (TB) is a growing threat to global public health. By analysing a large database of clinical Mycobacterium tuberculosis isolates, the authors of this study identify previously unrecognized genetic mutations that might be implicated in improved mycobacterial survival under antibiotic treatment. Using laboratory and experimental infection models, they present evidence that these mutations should be considered potential genetic markers of reduced antibiotic efficacy and accelerated acquisition of TB drug resistance.

eLife assessment

This important study defines new functions for the ER-resident protein HSP47 in the quality control of multi-pass membrane receptor proteins. The evidence supporting the conclusions is solid, with rigorous biochemical assays employed in appropriate models. However, additional consideration regarding the mechanism of HSP47-dependent regulation of membrane protein quality control would have strengthened the study. This work will be of broad interest to cell biologists and biochemists interested in the fields of proteostasis membrane protein quality control, and neuroreceptor signaling.

eLife assessment

This fundamental study is important and carefully executed, providing important insights into the allosteric regulation of GPCRs with exceptional strength of evidence. This work will be of interest to a wide audience in drug discovery and receptor biology. The major strengths are the comprehensive structural and pharmacological characterization with only minor weaknesses, most notably a concern regarding the approach used to quantify efficacy.

eLife assessment

The authors have developed a useful model for how proteins that mediate a connection between invariant components of the T cell antigen receptor and leukaemic cells antigens, called bispecific engagers (BiTEs), mediate immunological synapse formation and impact T cell search for tumour cells in vivo. The model was compared against the in vitro experiments and in vivo data following a solid approach. The developed framework could provide a direction for employing computational mechanistic models for evaluating various strategies for BiTE treatments.

eLife assessment

This important study uses state-of-the-art methods to explore the evolution of dosage compensation between two closely related nematode species. The evidence supporting the rapid evolution of the recognition motifs on the X chromosome, despite a general conservation of the mechanism, is compelling. Provided the discussion on the evolutionary aspect of the findings is improved, this work will be of broad interest to cell biologists and evolutionary biologists.

eLife assessment

This potentially important article identifies an apparent oligogenic architecture for an ecologically relevant trait, the circalunar reproduction of marine midges, which contributes to assortative mating, is likely under divergent selection, and supports reproductive isolation in sympathy. A claim for a causal role of chromosomal inversions in this system is made, but the support for this claim is incomplete.

eLife assessment

This study presents a careful evaluation of the distribution of monocytes and dendritic cells in the the blood and nasopharyngeal aspirates of patients with mild respiratory tract infections. There are some interesting differences between monocytes and dendritic cells and variations with patient age. This is an important contribution to understanding monocyte and DC subset specific functions in dependency on the tissue microenvironment.

eLife assessment

This work provides valuable new insights into the mechanisms by which 25-hydroxycholesterol (which is known to be rapidly produced in macrophages and other cells during acute infections) acts to protect cells and animals from microbial infection. The authors provide compelling evidence that the cholesterol-esterifying enzyme acylCoA:cholesterol acyltransferase (ACAT) that is induced by 25-hydroxycholesterol promotes the depletion of an accessible pool of plasma membrane cholesterol, producing anti-microbial effects.

eLife assessment

This manuscript provides important findings that have practical implications for reproductive medicine and would be of interest to IVF specialists. Based on the compelling strength of evidence, the authors present significant results on improving the predictive value of the live birth model based on blastocyst evaluation and clinical features. However, some methodological information should be added to improve the reproducibility of the study results.

eLife assessment

The authors report the results of three experiments assessing how one or both eyes open under a patch influence resting EEG activity, contrast sensitivity, and binocular balance in normally sighted subjects. Their results suggest that the state of eye opening temporarily, but significantly, influences shifts in ocular dominance with relevance for treatment of binocular visual disorders such as amblyopia that are treated with periodic monocular occlusion. The evidence supporting their conclusions is solid and the findings are important for the field.

eLife assessment

This study highlights a significant concept whereby a retained memory of disease during stem cell reprogramming (likely via epigenetic modifications) affects the chondrogenic differentiation potential of osteoarthritis (OA)-iMSCs. The evidence supporting the conclusions is compelling, with rigorous RNAseq analysis of genes and signaling pathways. The relevance of this research is highlighted by the valuable role of iPSCs as a potential cell source for regenerative medicine. The work will be of broad interest to skeletal stem cell biologists working on osteoarthritis and cartilage regeneration.

eLife assessment

Sorkac et al. present a novel genetically encoded retrograde synaptic tracing method that has the potential for unbiased identification of presynaptically connected neurons. Retro-Tango is based on the previously developed anterograde method trans-Tango, promising high applicability and rendering the significance of this contribution important. The strength of the evidence is convincing.

eLife assessment

This manuscript presents an important mathematical analysis on metabolic "co-substrates" and how their cycling can affect metabolic fluxes. Through mathematical analysis of simple network motifs, it shows the impact on constraining metabolic fluxes and the applied mathematical modeling/simulation approaches and the statistical analysis to compare predictions with data from previous studies offer convincing support for the potential biological relevance of co-substrate cycling. The work will be of interest to researchers who study microbial metabolism and metabolic engineering. However, part of this analysis remains unclear and would benefit from clarification.

eLife assessment

This important analysis helps to shed light on the relationship between blood type and the occurrence of ICD-based phenotypes in a hospital setting. A particularly compelling strength is the analysis' reliance on a population-based patient registry. The results would be further strengthened by an exploration as to whether these phenotypes are driven by patient characteristics (e.g. ethnicity, SES) and not just blood type. Additionally, differences across blood types are driven, in part, by differences in prevalence, somewhat limiting the scope of the analytical findings.

eLife assessment

The study shows that human inflammasome-forming sensor CARD8 contains a specific motif that allows cleavage by the proteases of HIV-1 and its direct precursor infecting chimpanzees. In comparison, CARD8 proteins from non-human primates contain changes in this motif and seem largely resistant to proteolytic activation. The results are important, and the data on the cleavage of CARD8 in HEK293T cells are convincing, while effects on inflammasome stimulation and cell death in primary viral target cells are insufficiently supported.

eLife assessment

This work provides important new insights into the mutational pathways of SARS-CoV-2 to achieve antibody escape, as well as how these pathways are shaped by epistasis. The evidence supporting the conclusions is compelling based on rigorous analyses of data from a high-throughput binding assay. The study is important for evolutionary medicine and biology and relevant for human health.

eLife assessment

The current study employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with NSC-derived exosomes extracted from NSCs to treat cerebral ischemia, and they made an important observation. Remarkably, NSC-derived exosomes could promote NSCs differentiation, reduce the oxidative stress and inflammation, and alleviate the formation of glial scars after ischemia and reperfusion, and as a result, could enhance the therapeutic effects of NSC transplantation, which is compelling. The solid experimental evidence strongly supports their major claims.

eLife assessment

Experimental models of simple cell-like compartments can help us to understand how biology operated early in its history. The authors convincingly show how the properties of coacervate droplets can be influenced by the activity of ribozymes inside them. This important result potentially provides a new route for biologists or chemists to establish cell mimics that support the evolution of biomolecules within.

eLife assessment

Through theoretical analysis, the authors argue that the proliferation of neurons in the outer subventricular zone, which is specific to humans, decreases the distance between neighboring sulci in the cerebral cortex and increases cell density in the ventricular zone. Though the exact mechanisms remain to be further elucidated, the compelling data and approach represent a valuable foundation for the study of cortical folding from the underpinning cellular level as well as the coupling role of mechanics and cellular biology. This study will be of particular interest to the large community of scientists studying the mechanisms of brain development and disorder and even possibly beyond.

eLife assessment

This fundamental work reports an analysis of microbial abundance similarities among individuals over time in a longitudinal wild baboon cohort from Amboseli, Kenya. The authors provide compelling evidence that there are remarkably consistent dynamic associations over time in microbial abundances between baboons, despite individual baboons having individualized microbial signatures. The authors further identify universal microbial associations that appear to go beyond the studied baboon cohort, extending to human microbiomes. This study adopts a novel powerful statistical approach to analyzing longitudinal microbial dynamics at the individual level, which will likely make this work become a key reference study in the field of microbial ecology.

eLife assessment

This important study shows the sexually dimorphic dynamics of the components of meiosis-specific chromosome structure and the gene-dosage effect of the components on meiotic recombination. The experimental evidence in the paper is solid with cytological analysis with Fluorescence Recovery After Photobleaching (FRAP). The work will be of interest to researchers working on meiosis and chromosome dynamics.

eLife assessment

Rossi et al. carry out a valuable characterization of the molecular circuitry connecting the immunomodulatory cytokine BAFF (B-cell activating factor) in the context of cellular senescence. They present solid evidence that BAFF is upregulated in response to senescence, and that this upregulation is partially driven by the immune response-regulating transcription factor (TF) IRF1, with potential cell type-specific effects during senescence. Ultimately, these results strongly suggest that BAFF plays a senomorphic role in senescence, modulating downstream senescence-associated phenotypes, and may be an interesting candidate for senomorphic therapy.

eLife assessment

This important work provides new insights into the structure and function of respiratory complex I. The cryoEM data are convincing but the assignment of different conformations of the enzyme complex to specific functional states has not yet been conclusively determined. This work will be of interest to researchers studying the molecular basis of energy metabolism, the evolution of respiratory enzyme complexes, and mitochondrial diseases.

eLife assessment

This manuscript provides an important advance in our understanding of burn-associated T-cell responses. The evidence is convincing and the techniques are using the latest single-cell RNA-seq approaches in a rigorous manner. The studies are done directly on human skin so are highly clinically relevant.

eLife assessment

The work by Lindmark et al. provides us with an important natural experiment on fish that challenges current literature on relationships between temperature, growth rate, and size. The strength of their results is compelling, as Lindmark et al. mixed a unique warming setup with a large battery of models and statistics. The work will be of interest to ecologists and physiologists interested in the impacts of global warming on natural communities.

eLife assessment

The findings of this article provide valuable information on the spatial dynamics of the human oral mucosa in chronic inflammatory disease. The strength of evidence presented is solid and should yield a better understanding of common mucosal diseases in humans.

eLife assessment

This study presents an application of a deep learning approach (adult-trained variational autoencoder) to describe the development of the functional brain connectome in human fetuses and neonates. The results suggest that this may lead to a better characterization of the complex patterns of brain maturation during this period. The evidence is convincing but the impact of other confounding factors in addition to maturation on the results could be explored and further analysis should be considered to highlight how this method can account for non-linear patterns of development, as well as the biological plausibility of the observed brain states. This work is of potential methodological interest to researchers exploring functional brain networks and brain development notably with deep learning.

eLife assessment

This is an important survey of disulfide-rich peptides (DRPs), which comprise a large fraction of the most functionally important components of spider venom. While spider DRPs were thought to have evolved independently numerous times throughout the spider tree of life, the authors make a solid case for the idea that they all stem from a single common ancestral protein. The study makes a significant advance towards formalizing the diversity of spider venoms, which will be of interest both to scientists working on protein evolution and to those working on functional venomics.

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.