eLife assessment

In vertebrates, ciliary motility is powered by axonemal dyneins, known as OADs, tethered to doublet microtubules by a pentameric docking complex including the Armc4 and Calaxin subunits. This valuable study combines zebrafish genetics with cryo-electron tomography to convincingly show that Armc4 plays a critical role in the docking of OAD and that Calaxin stabilizes the molecular interaction. The work will be of interest to those studying the structure and function of the axoneme, and motile cilia in general.

eLife assessment

This important study combines behavior, computational modelling and magnetic resonance spectroscopy to address the question whether age-related declines in learning are driven by declines in working memory or deficiencies of the RL system. The general approach is solid, but the presented evidence to support the papers' main claims could be stronger. With additional analyses and adaptation of the main claims, the paper could be of high interest for researchers in the field of cognitive aging and decision making.

eLife assessment

The authors present a manuscript aiming to understand the mechanism(s) underlying myeloid bias in HSCs, specifically focused on the role of Pcgf1, and therefore PRC1.1, in the regulation of hematopoiesis. This important work is of interest to the community of researchers interested in myeloid differentiation, lineage fate decisions in hematopoietic stem cells, and the molecular mechanisms that contribute to the initiation of myeloid malignancies. The methods are rigorous and the results convincingly support the authors' conclusions.

eLife assessment

This is a valuable paper describing an attempt to reconstruct the evolution of Dicer. Using ancestral reconstruction approaches, the authors carefully examine the biochemical characteristics of reconstructed proteins at various junction points in the animal lineage. They provide solid evidence that the deepest ancestrally reconstructed protein has double-stranded RNA stimulated ATPase activity and that this characteristic was lost along the vertebrate lineage. This paper will be of interest to scientists in the RNA-protein interaction and protein evolution fields.

eLife assessment

The authors have established new formulas to predict maximum oxygen uptake for cyclists and runners based on submaximal exercise testing and anthropometric characteristics. This is an important study with a large and comprehensive dataset, which may be helpful for many exercise labs. The work is convincing, using appropriate and validated methodology in line with the current state-of-the-art, as shown by references to common exercise books.

eLife assessment

In the current manuscript, the authors study the effects of hypoxia or genetic and pharmacologic modulation of the hypoxic pathways on T cells. The findings about T cells sense hypoxia and how hypoxia affects T cell (and CAR T cell) differentiation and function are significant and interesting for the field. The data supporting these findings are mostly robust, yet some questions remain open and some statements seem unsupported by evidence.

eLife assessment

This fundamental work substantially advances our understanding of polymer physics underpinnings of genome folding, organization, and regulation. The conclusions are supported by both convincing computer simulations and analytical theory. The work will be of significant interest to the genome folding community.

eLife assessment

This manuscript will be of interest to scientists in the field of tissue injury and repair. It provides novel molecular mechanisms of a transcription factor, Prrx1, in fibroblast activation following lung injury. Overall, the work suggests that PRRX1 plays a functional role downstream of TGFb1 to elicit some aspects of the fibrotic response and that PRRX1 could represent an important therapeutic target to treat fibrosis. The strengths of this work are the multiple approaches applying human and mouse lung tissue used by the authors to test the role of PRRX1 in lung fibrosis, however, in its current form, major limitations need to be addressed.

eLife Assessment

The study has advanced our mechanistic understanding of lung regeneration. While the importance of regeneration of alveolar capillaries for long response to injury has been long recognized, the regulation of this process has not been well understood. Your study provides novel, comprehensive, and compelling evidence that the expression of the transcription factor Atf3 in alveolar capillary endothelial cells plays a critical role in the regeneration of alveolar capillaries following lung injury.

eLife assessment

This study concerns an important area, that of monoallelic expression, but the study does not provide sufficient information about the candidate regulatory RNA to provide a significant advance over previous work, which should also be discussed in more detail.

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 study examines the principles according to which neurons connect to each other in the brain. The authors find that data could be best explained by the homophillic wiring principle where neurons preferentially connect to neurons within overlapping groups. The work will provide a valuable resource to the neuroscience community once analyses are standardized across various datasets included.

eLife assessment

This valuable work advances our understanding of the acoustic features driving the attraction of female mice to male vocalizations. The evidence supporting the conclusions is solid, with well-designed place preference assays and manipulations of male song structure. The work will be of broad interest to neurobiologists and ethologists working on mouse social interactions, auditory processing and communication.

eLife assessment

This manuscript combines cryo-EM and a suite of compelling whole cell and proteoliposome transport assays to establish the mechanism and structure of the full-length human SLC26A6 chloride/bicarbonate exchangers, including the first partial view of the previously unresolved IVS region of an SLC26 STAS domain. In combination with prior studies on additional SLC26 paralogs, including the SLC26A9 paralog initially reported by the same group, the current study provides important insight into the mechanistic diversity of the SLC26 transporters. This study is of interest to the biophysics community and the field of membrane transport.

eLife assessment

This study evaluated how naturalistic behaviors are encoded in the striatum by analyzing neural ensembles engaged during grooming behavior. The study shows that neural responses are highly heterogeneous during grooming, but ensembles were detected in which units were more correlated during grooming than during the entire session. This study presents an important contribution to the field by shedding light on how ensembles of neurons encode innate behavior. The results are convincing.

eLife assessment

This important study uses an innovative genome-wide approach and targeted testing to identify S. aureus genes that affect susceptibility to serum, serum-derived antimicrobial products, and commonly used antibiotics. The findings are significant in that they highlight evidence of evolution of virulence determinants in the setting of exposure to host stressors expected to be present during bacteremia and antibiotic therapy. The evidence is solid, but the presentation could be improved by providing details that clarify the methods and highlighting the limited current understanding of the major target, tcaA.

eLife assessment

This contribution provides important insights into the thermodynamic landscape of cation transporters of the Cation Diffusion Facilitator (CDF) superfamily, together with a detailed structural investigation of the role of the three zinc(II) binding sites of YiiP. Despite the relatively low resolution of the cryo-EM structures presented in this work, the combination of structural, functional and modeling techniques yields solid evidence for the proposed model. This work will be of interest to biologists and biophysicists that work with membrane transporters; it is an excellent example of how different techniques can be combined to obtain relevant information on the complex mechanism of action of a transporter.

eLife assessment

This important study combines behavioral and imaging experiments to understand how levels of important brain chemicals shape the processing of information in the brain in children and young adults. The sample size and data quality are outstanding and some of the data are quite convincing. However, the calculation and interpretation of the brain chemical concentration measurements as well as the interpretation of the model-based behavioral parameters are not fully justified and support for the overall conclusions is incomplete. This work will be of interest to neuroscientists, psychologists, and neuroimaging researchers investigating the developing brain in health and disease.

eLife assessment

This is a valuable addition to the literature as it helps us understand the role of tRNA modifying enzymes in Mycobacterium tuberculosis. By knocking out one of the enzymes, the authors convincingly demonstrate the importance of tRNA-modifying enzymes for intra-host growth of tubercle bacteria. Some of the claims regarding modification as well as the role in virulence could be strengthened through further bioinformatics and phylogenetic analyses as well as experimental approaches. The work will be of interest to microbiologists.

eLife assessment

Müller glial cells of the zebrafish retina can differentiate into all neural cell classes following injury, providing full regenerative capabilities of the zebrafish retina. This study presents a valuable description of transcriptional changes of Müller glia cells in the adult and regenerating retina using single-cell RNA sequencing. The overall evidence supporting the main claims of the authors is solid, but some aspects of the analysis are incomplete and would benefit from additional experimental evidence to support the existence of different types of Müller glia and their distribution in the retina.

eLife assessment

This valuable study provides insights into mechanisms of placental aging and its relationship to labor initiation. The authors provide solid evidence and have thoroughly investigated the molecular characteristics of normal placental aging using in vivo and in vitro model systems and human placental tissue analysis to corroborate their findings. This work contributes to existing work in placental aging and preterm birth and will be of interest to reproductive scientists.

eLife assessment:

This valuable study presents convincing evidence that metabolite levels in Escherichia coli bacteria from a long-term evolution experiment have changed in consistent ways, which in turn can be explained by recurrent mutations in regulatory genes that affect enzyme expression levels. The use of high-resolution mass spectrometry measuring bulk metabolite levels, in combination with existing gene expression and DNA sequencing datasets provides valuable information linking changes in an organism's genome, transcriptome, and metabolome. The current version of the paper lacks clarity in parts, most critically in the introduction, and would benefit from some rewriting to improve its structure, precision, and readability.

eLife assessment

This study reports important findings regarding the systemic function of hemocytes controlling whole-body responses to oxidative stress. The evidence in support of the requirement for hemocytes in oxidative stress responses as well as the hemocyte single-nuclei analyses in the presence or absence of oxidative stress are convincing. In contrast, the genetic and physiological analyses that link the non-canonical DDR pathway to upd3/JNK expression and high susceptibility, and the inferences regarding the function of hemocytes in systemic metabolic control are incomplete and would benefit from more rigorous approaches. The work will be of interest to cell and developmental biologists working on animal metabolism, immunity, or stress responses.

eLife assessment

Muroňová et al. provide valuable information about CDCC146 as a centriole and microtubule associated protein essential for sperm flagellar formation and male fertility. Mutations were identified in human patients suffering from MMAF syndrome, but the evidence that these human mutations were causative of the abnormal phenotype is incomplete. To further explore the causality, mouse models are generated and the findings from the mouse study, support that the key roles of CCDC146 for microtubule-based structures throughout sperm development in general but requires statical analysis.

eLife assessment

This important study reports investigation of the dynamics of PKA at the single-cell level in in vitro and in epithelia in vivo. Using different fluorescent biosensors and optogenetic actuators, the authors dissect the signaling pathway responsible for PKA waves, finding that PKA activation is a consequence of PGE2 release, which in turn is triggered by calcium pulses, requiring high ERK activity. The evidence supporting the claims is solid. At this stage the work is still partly descriptive in nature, and additional measurements would increase the strength of mechanistic insights and physiological relevance.

eLife assessment

This manuscript reports important findings regarding the potential for self-policing and a division of labor among biofilm-inhabiting Bacillus cells. Overall, this work is robust in its use of various techniques and provides solid insights into the intersections of well-understood regulatory controls and the suppression of cheaters. Despite some concerns about the data, all reviewers were excited by the potential impact of this work. Colleagues interested in microbial social interactions should find this study's narrative about the internal mediation of cell differentiation particularly valuable.

eLife assessment

This study presents important findings on the mechanism as to how Mycobacterium-containing vacuoles are recognized by host cell factors and subjected to membrane repair or autophagic degradation using Dictyostelium discoideum as a useful model. The evidence for the role of TrafE in damaged-membrane repair and xenophagy induction is convincing, but that in autophagosome closure is rather incomplete.

eLife Assessment:

Zemel and colleagues provide a report on the fundamental electrophysiological properties of motor neurons driving song in the zebrafish and provide complementary information about cell morphology, pharmacological sensitivity, and ion channel expression and heterogeneity. They provide mainly convincing data supporting the claim of a particular ion channel class, Kv3, that plays an important role in fast electrical spiking (action potentials) in song-related neurons.

eLife assessment<br /> <br /> Within this paper, the authors describe a rapid and easy-to-implement CRISPR/Cas9-mediated knock-in approach to precisely insert large transgenes in the African turquoise killifish. The established method will be instrumental for many researchers working with unusual model species, and, in particular, will expand the killifish community toolbox. It will revolutionize the field and bring the killifish, an emerging animal model in aging biology and disease modeling in vertebrates, into the spotlight even more.

eLife assessment

This valuable study addresses the anticipated but poorly understood interconnections between ER proteostasis and lipid metabolism. The authors discovered key metabolic enzymes required for integration of ER stress and lipid synthesis and followed up with several direct experiments that provide solid evidence for a broad conservation of the described interactions.

eLife assessment

Motivated by previous demonstrations that cognitive modulation of heart beat evoked responses (HER) might distinguish minimally consciousness state and unresponsive wakefulness syndrome patients, the present work sought to determine whether contextual processing of auditory regularities (local-global paradigm) differentially affects HER in these patient groups. The results provide preliminary evidence for the usefulness of EEG and oddball paradigms in informing diagnosis of the state of consciousness. This paper will be of interest to those researchers studying signs of consciousness in post-comatose patients and more broadly to those studying brain-body interactions. However, some aspects of the study design and data analysis need to be clarified, particularly as these affect the conclusions that can be drawn.

eLife assessment

Hernandez-Perez et al. perform a detailed analysis of Kazrin, a widely expressed protein that appears to be involved in many diverse cellular processes, but whose exact function is unknown. The authors employ mouse embryonic fibroblasts and biochemistry to investigate the function of Kazrin and determine that Kazrin promotes the dynein/dynactin-dependent transport of early endosomes. These findings are valuable to those in the field of intracellular transport, but the story will benefit from additional experiments to prove the main claims, or from textual modifications.

eLife assessment

In the current study, Mondoloni and colleagues reveal how a selective nicotine receptor in the interpeduncular nucleus is involved in nicotine consumption, which is an important contribution to the understanding of individual differences in drug addiction. However, the preferred hypothesis would benefit from testing in additional experimental models, metabolic assessment, and cell-type specificity.

eLife assessment

The cerebellum plays a critical role in motor learning, but exactly which forms of synaptic plasticity contribute to learning, as well as the underlying molecular mechanisms, remain poorly understood. In this study, Wang and colleagues show that presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapse is required for one form of motor learning, and involves a previously-unknown signaling cascade, where EPAC activation leads to PKCε-dependent threonine phosphorylation of RIM1α. This study provides new insights into the underlying mechanisms and functional consequences of presynaptic LTP.

eLife assessment

This paper expands on prior work by using whole-brain calcium imaging in Drosophila to examine how spontaneous and forced walking and turning affect neural activity in the brain. The measurements presented will serve as a valuable resource for the fly systems neuroscience community and suggest many testable hypotheses that may serve as the basis for future studies. Analyses of the data are solid, but conclusions drawn should be presented with more caveats. This article will be of interest to neuroscientists engaged with the central problem of how behavior modulates neural activity.

eLife assessment

This paper provides valuable new information on the mechanisms by which Vibrio cholerae integrates and responds to environmental signals. While the strength of the evidence provided in the paper in support of the conclusions made and the model proposed is solid, there are several issues that if addressed will strengthen the study further. The work is relevant for a broad audience of microbiologists interested in the mechanisms by which bacteria sense their environment.

eLife assessment

This is a valuable study on DNA gyrase that provides further evidence for its mode of action via a double-stranded DNA break and against a recently-proposed alternative mechanism. The evidence presented is solid and is derived from state-of-the-art techniques. The work casts new light on the interactions that occur between gyrase molecules and will be of interest to biochemists and cell biologists.

eLife assessment

This study makes a valuable contribution to our functional understanding of the atypical amino-acid transporter SLC6A177 at nerve cell synapses and the role of SLC6A17 variants in certain forms of intellectual disability. The reported evidence that disease-linked SLC6A17 variants cause behavioral abnormalities is convincing. However, corresponding molecular underpinnings, i.e. the molecular role of SLC6A17 in synapses and the functional molecular consequences of disease-related SLC6A17 variations, remain unclear because corresponding informative experimental approaches are missing - most importantly direct measurements of the transport activity of SLC6A17 in the various genetic contexts studied. This limits the robustness and validity of key mechanistic conclusions drawn from the present work.

eLife assessment

This valuable work in human subjects reports that sounds that were associated with specific memories during waking behaviors can trigger the reactivation of these memory representations during REM sleep. However, the evidence supporting the conclusions is currently incomplete. Still, the work has the potential to expand our understanding of memory processing during sleep.

eLife Assessment

Using a novel multi-depth plan display, this study reveals a valuable finding regarding crowding - it decreases with small depth differences between the target and flankers but increases with larger depth differences. The evidence supporting this finding is convincing, although the explanation of the findings is somewhat speculative. This paper will be of interest to visual scientists, neuroscientists, and ophthalmologists, especially those working on visual crowding and depth perception.

eLife assessment

This study presents useful findings on an important question in cognitive neuroscience - whether the brain can form sensory predictions during sleep. The paradigm used is compelling but evidence supporting the claims of the authors is incomplete. Major issues pertaining to large differences between the pattern of brain responses observed here relative to effects reported in the literature previously, and some evidence that the study might be underpowered to make strong conclusions about certain aspects of the data.

eLife assessment

The authors ask if brain regions change based on the functional constraints or developmental constraints. To address this, they introduce an automated method for brain segmentation based on the zebrafish tool to study brain evolution in Astyanax. A caveat is that it is difficult to test the functional constraint hypothesis using this method, though it works well for testing developmental constraints.

eLife assessment

Antimicrobial peptides (AMP) are a class of antibiotics that are inspired by natural components of innate immunity, which raises the specter of bacteria becoming resistant to both. The author this important study test this idea and find compelling evidence that a plasmid that encodes resistance to the AMP colistin also increases resistance to AMPS produced by humans, pigs, and chickens, enables the bacteria to grow better in low levels of AMP, and increases bacterial virulence in an insect model of infection. The study will be of interest to both evolutionary biologists and microbiologists focused on antimicrobial therapy and suggests that the evolution of resistance to these compounds can have collateral effects on immune evasion as well.

eLife assessment

This important study provides compelling observations of the organization and architecture of haptomonads, a distinct and poorly understood developmental form of Leishmania found in sand fly vectors at later stages of infection. The authors used 3D electron microscopy techniques, including serial block face scanning electron microscopy and electron tomography, to visualize the colonization sand fly by haptomonads in impressive detail.

eLife assessment:

Sampaio and colleagues utilize an elegant approach to manipulate fluid dynamics in zebrafish Kupffer's vesicle to ask if fluid movement or something in the fluid governs the break in symmetry. These valuable results support a role for fluid movement and detection as important in breaking symmetry in a ciliated left-right organizer and help set a time window when fluid flow is critical for this process. However, as the fluid extraction experiments affect both chemical and physical features, the authors need to provide further convincing evidence to support their mechanosensory hypothesis or temper the claims.

eLife assessment

In this important study, the role of NBR1 in the degradation of photodamaged chloroplasts is analyzed, advancing our knowledge of chloroplast homeostasis in response to environmental stress. The evidence presented is convincing, in some parts even compelling, and the results are valuable for the plant and the autophagy research community.

eLife assessment

This valuable manuscript presents resources for genome-wide genetic perturbation in the fruitfly, Drosophila. The evidence for the usefulness is solid, with the authors demonstrating that they can identify novel genes that affect an important pathway, the mTOR pathway, which plays key roles in cell proliferation and cell death. The genetic resources are significant for their availability to colleagues in the Drosophila community seeking to to identify genes with important cellular functions.

eLife assessment<br /> <br /> Descovich et al examine the important decision between proliferative (planar) and differentiation (perpendicular) divisions in the basal layers of the skin and find a key promoter of perpendicular divisions is inhibited by its paralog to specify planar divisions. The authors use sophisticated mouse genetics and imaging and discover that LGN and its paralog AGS3 function antagonistically in determining perpendicular vs. planar divisions. Some statements need to be tamed or further backed up, but overall this study provides a significant advance in the field.

eLife assessment

This is an important study on the role of a bacterial cell wall component, D-alanylated lipoteichoic acid, as a bacteria cue in Drosophila melanogaster-microbiome interactions. Overall, the evidence supporting the conclusions is compelling, with a solid approach combining crystallography with biochemical and cellular assays, that take advantage of both fly and bacterial mutants, to demonstrate a physiological role in juvenile growth promotion. The work will be of broad interest to those studying host-microbe interactions, especially as it is related to immunology and metabolism mediated by the microbiome.

eLife assessment

The manuscript describes a fundamental study of the atypical MAPK, ERK3, in the activation of RhoGTPase Cdc42 and the formation of actin-rich protrusions and cell migration. The results show that ERK3 is required for the motility of tumor cells in vivo, providing a new target for fighting metastasis.

eLife assessment

These are important findings that show that pupil size is not only governed by the locus coeruleus but also by other neuromodulatory subcortical systems. Furthermore, the authors demonstrate that using a standard hemodynamic response kernel is not appropriate for capturing the activity of these systems, at least at rest. Thus, this paper presents compelling evidence against two prevalent working assumptions among researchers in the field.

eLife assessment

This important work utilizes a model organism, zebrafish, to explore changes to the proteome and the role of KLHL40, a component of the ubiquitin-proteasome system, in the development of skeletal muscle disease. Using mass spectrometry, the authors demonstrate a major and selective role for proteome remodeling in development. They identify a specific role for KLHL40 deletion in regulating the expression of Sar1 - a key component of biosynthetic secretion, where the resulting elevated levels of Sar1 expression potentially lead to collagen secretion defects in the disease state. The findings are incomplete as further experimental characterization of the overall morphological changes and secretion defects, in particular ones derived from the deregulation of Sar1 levels, is required.

eLife assessment

In this useful study, a GWAS-type analysis is applied to clinical Mycobacterium tuberculosis isolates to discover genetic polymorphisms linked to poor tuberculosis outcomes. The evidence for the detected associations is still incomplete, as the corresponding polymorphisms are not adequate to power a prediction model for infection outcome, although key host factors - including patient age, sex, and duration of diagnostic delay (which have stronger predictive value) - appear to enhance predictive capacity.

eLife Assessment:

The manuscript by Godoy and colleagues is an important contribution to the understanding of how lung endothelial regeneration progresses following endothelial ablation. The novelty and elegance of this study are rooted in the regional and specific ablation of lung endothelial cells using diphtheria toxin without the massive inflammatory activation that is seen with lung injury induced by bacterial infections, viral infections, or lipopolysaccharide. The data convincingly demonstrate that there is an emergence of a highly proliferative lung endothelial subpopulation that drives endothelial regeneration. The translational implications of the study include the identification of potential therapeutic targets to augment endothelial regeneration as a treatment for ALI/ARDS. This study will be of interest to vascular biologists, lung biologists, and researchers studying adult tissue regeneration.

eLife assessment

This is an important contribution to colorectal cancer research to understand how we can predict high-risk patients for recurrence. The strength of the evidence is solid and looks at a novel approach but an approach that still has opportunities to improve.

eLife assessment

This study provides an important demonstration that loneliness is associated with smaller hippocampal volume, reduced cortical thickness, and worse cognition in healthy older adults. This has theoretical or practical implications beyond a single subfield. The strength of evidence is solid given the cross-sectional and longitudinal design with a few weaknesses. With the analytical and interpretational part strengthened, this paper would be of interest to gerontologists, and dementia/cognitive aging researchers.

eLife assessment

This paper provides strong evidence for the important point that microtubule function is required for the proper localization of Glut4 glucose transporters in an insulin responsive compartment. This membrane localization is required in turn for effective translocation of Glut4 to the muscle cell surface in response to the hormone.

eLife assessment

This paper deals with an important unsolved problem in developmental biology of how cells execute their dynamics at the right time. The study combines compelling quantitative single cell and single transcript experiments with genetic perturbations and computational modelling and provides important insights into how the timing of transcription is regulated. The work would be strengthened by better integration of modeling and data.

eLife assessment

This important study uses two well-established colorectal cancer models to estimate the potential impact of disruptions in screening caused by the COVID-19 pandemic. By dividing the population into separate cohorts based on age and pre-pandemic screening status, the authors provide convincing evidence for the adverse impact of delays in screening, switching regimens, and screening discontinuation. The finding that discontinuation has a much greater impact on screening-associated gains in life expectancy than shorter-term delays or switching of regimens suggests that access-related barriers to screening resumption may lead to the worsening of current disparities.

eLife assessment

This is an interesting study investigating the propagation dynamics of ripples recorded from the dorsal hippocampus of mice using an open-access dataset. Findings may have theoretical and practical implications for the study and manipulation of sharp-wave ripples, a main oscillatory event underlying memory consolidation. While the strength of evidence is solid and claims broadly supported, there are some points requiring additional analysis to clarify issues regarding the anatomical axes involved and to reinforce mechanistic insights.

eLife assessment<br /> <br /> This study presents valuable findings on how the ectopic expression of the Lck protein tyrosine kinase in Chronic Lymphocytic Leukemias (CLL) contributes to malignant transformation. The evidence supporting the claims of the authors is solid, although the use of gene editing to directly explore the functions unique to LCK in a CLL model would increase the appeal of the work.

eLife assessment

This study provides valuable insight into the diversity within the NRAMP superfamily of transporters. Evidence of divalent metal ion transport and the structure (obtained without added metal ions) are convincing. However, molecular insight into Al3+ recognition and transport is incomplete, and the work would be strengthened by the determination of a metal-bound structure or additional experiments (such as molecular dynamics simulations or quantitative Al3+ binding/transport assays) to support the proposed Al3+ binding site. The work will be of interest to structural biologists and biophysicists studying NRAMP transporters.

eLife assessment

The authors use data from 3 cross-sectional age-stratified serosurveys on Enterovirus D68 from England between 2006 and 2017 to examine the transmission dynamics of this pathogen in this setting. Understanding these dynamics, including how it changes over time, may help uncover potential changes in the transmissibility of the virus. While the topic is relevant, interpretation of the results challenging largely due to the great uncertainty around how to interpret the serological (serostatus) data, and the impact this has on the inferences made. We ask the authors to perform some additional analyses and to provide more intuition to understand some of the key findings of this analysis.

eLife assessment

In this manuscript, a method to test a large number of drug combinations in a single cell culture sample is presented. The strength of the evidence lies in their multiple experiments with different combinations of agents. The paper suggests that results from this application are feasible and the methodology could be applied in other laboratories to use drug combinations for defined outcomes.

eLife assessment

The authors' finding that Btk kinase activation relies on specific interactions with the Grb2 scaffold protein, including for recruitment into signaling clusters on membranes, is an unexpected finding that will potentially be of broad interest. The authors make a case for reinterpretation of the "Saraste dimer" of Btk as a signaling entity and assign roles to the component domains in the Src module in Btk activation, but the data provided are not yet fully convincing for this scenario.

eLife assessment

This is a very interesting and important study that convincingly demonstrates a descending pathway for the control of nociception in non-mammalian organisms.

eLife assessment

By combining electrophysiological analysis of mutant channels and molecular dynamics simulations, this important study identifies a common binding site for two structurally distinct activators of KCNQ1-KCNE1 channels. The findings represent an important advance for the field, with convincing functional data to support it. The simulations are still partially incomplete and would benefit from additional data and discussion. The work will be of interest to those studying the binding of small molecule drugs to membrane protein complexes.

eLife assessment

This is a valuable study that shows the involvement of phosphoinositide 3-kinase (PI3K) signaling downstream of platelet-derived growth factor receptor alpha in latero-medial migration of cardiomyocytes during the formation of the early heart tube during zebrafish development. The authors provide convincing evidence using multiple drugs and expression of a dominant negative PI3K subunit, to inhibit the pathway, approaches that show the strong alignment of phenotypes, and which are quantified using live imaging. The demonstration of cardiomyocyte protrusions biased in the direction of migration, and randomised after PI3K inhibition, is a promising area for future exploration.

eLife assessment

The study integrates experiments and data of various kinds to address the important biomedical problem of carbapenems resistance in Klebsiella. The authors present compelling evidence for loci that are sufficient for carbapenem resistance in this strain, with further evidence of their fitness cost. This study will be of interest to those across multiple audiences, including the microbial evolution community, and those interested in the biomedical problem of antibiotic resistance.

eLife assessment

The authors describe the first full-length crystal structure and solution conformation of the GAC protein from Toxoplasma gondii. The data are convincing and support a model in which GAC uses multiple conformations and lipid-binding surfaces. This paper presents an important contribution to our understanding of the molecular machinery involved in host cell invasion, but questions remain about how this protein links to the cytoskeleton and functions during the invasion process.

eLife assessment

This study explored practitioners' assessments of the impact of the pandemic on cervical cancer screening and follow-up. This is a very important topic that could continue to have implications for how this screening process is delivered now, after the pandemic. The authors need to more fully describe their methodology and temper conclusions to fit within those limitations.

eLife assessment

This valuable study discovers that zinc ions can activate some OTOP proton channels, identifying a pharmacological tool for research, and further establishing that OTOP channels gate. The data presented provide convincing support for the conclusions made by the authors, and the study is expected to be of considerable interest to physiologists investigating OTOP and other proton channels.

eLife assessment

This study provides important evidence regarding the development of concept representations, using functional brain imaging to compare concept structure in people with different amounts of language experience. The analyses, which are overall solid, suggest that representations in the left lateral anterior temporal lobe differ as a function of childhood language experience.

eLife assessment

This useful paper describes a sensitive method for identifying the contributions of different behavioral and stimulus parameters to neural activity. The method has been convincingly validated using simulated data and applied to example state of the art data sets from mouse and zebrafish. The method could be productively applied to a wide range of experiments in behavioral and systems neuroscience, but it remained unclear how it relates to or improves on similar, existing methods.

eLife assessment

The authors present an important contribution to the field of deep brain stimulation (DBS) for depression by providing further evidence for the validity of the lateral habenula as a DBS target. The evidence provided is compelling and particularly strong in its use of fMRI to delineate target subregions best corresponding both to clinical and downstream fMRI response. This study provides information relevant to both surgical targeting and the mechanism of action for this DBS target.

eLife assessment

This important paper provides new insight into the effect of extra-copies of a chromosome, thus aneuploidy, on body metabolisms in mammals. The authors used various solid analyses on the metabolisms and physiology of the transgenic mouse with most of human chromosome 21 and presented convincing results to support the authors' claims. The work would be of interest to researchers who work on the physiology and biochemistry of body metabolisms in mammals.

eLife assessment

The authors present a novel and precise method for determining boundaries of cortical layers from multi-electrode recordings in marmosets and macaques. Their method requires less data than current approaches to finding a systematic relationship between slow local field potentials and spiking across cortical columns. This approach may be broadly useful to those doing electrophysiological recordings in the primate brain.

eLife assessment

In this important study, Di et al., examine the mechanism by which potassium channels are activated prior to NLRP3 inflammasome activation. The main strength of the study is that it uses a combination of cell culture work and a mouse model to address the cell biology of inflammasome activation. However, certain aspects of the study including the characterization of inflammasome activation and the evidence to support the role of Rab11a in the translocation of TWIK2 are incomplete.

eLife assessment

This paper will be of interest to sensory and computational neuroscientists. In it, the authors find maximally informative dimensions for primate retinal ganglion cells and use models based on these analyses to examine features of early visual processing that impact predictive coding of visual motion.

eLife Assessment:

This study is fundamental to understanding the intrinsic driving forces of gene losses during mammalian genome evolution, linking the propensity for gene losses to the local genomic features such as mutation rate and spatially restricted expression. In general, the study is methodologically convincing because independent gene losses in at least two mammalian lineages were identified as "elusive human genes". However, additional (comparative genomics and statistical) analyses would make the current study more rigorous. This manuscript will appeal to readers interested in the evolutionary fates of genes across the phylogenetic tree.

eLife assessment

This important study uses genomically-engineered glypican alleles to demonstrate convincingly that Dally (not Dally-like protein [Dlp]) is the key contributor to formation of the Dpp/BMP morphogen gradient in the wing disc of Drosophila. The authors provide solid genetic evidence that, surprisingly, the core domain of Dally appears to suffice to trap Dpp at the cell surface. They conclude with a model according to which Dally modulates the range of Dpp signaling by interfering with Dpp's internalization by the Dpp receptor Thickveins.

eLife assessment

The authors address the function of dorsal horn inhibitory neurons that express neuropeptide Y in adulthood. They find relevant functions in pain and itch control that should be of broad interest to people working in the field. This valuable study changes the view of this cell class and the authors provide compelling data that goes beyond the current state of research.

eLife assessment

This paper presents important findings into the response of epithelial monolayers to the combined effects of surface curvature and hydraulic stress, offering insights into how these cues contribute to epithelial cell extrusion. Most of the evidence is convincing, relying mainly on a combination of imaging-based techniques, though some parts would benefit from a more rigorous analysis and some claims require more evidence to be justified. This paper is of interest to a broad and growing community of biologists, biophysicists, and engineers interested in cell-geometry interactions.

eLife assessment

This important report provides solid evidence that neutrophils can remove apoptotic hepatocytes in vivo and in vitro by burrowing into apoptotic hepatocytes. The findings could have profound implications with respect to the role of neutrophils and the etiology of autoimmune liver disease. The findings are of broad interest in medicine and in particular in hepatology.

eLife assessment

This manuscript will be of interest to scientists who study cardiomyocyte homeostasis and contraction. It assesses the functional consequences of cardiomyocyte-specific knockout of Palladin, leading to the identification of a compensation mechanism when Palladin is deleted in embryogenesis, but not in adulthood. In addition, the authors identified new Palladin interactors, revealing a role for Palladin in the maintenance of intercalated disc structure.

eLife assessment

This is a valuable study that quantifies CD8 T cell movement in different tissue environments and concludes that T cells display more confined movement in the inflamed lung than in lymph nodes or intestinal villi. The evidence supporting conclusions is solid with well-defined measurements and sufficient statistical analysis. The work will stimulate further efforts to understand the mechanisms behind the different behaviour of T cells that are important in host defence against intracellular pathogens and cancer.

eLife assessment

This valuable study reports improvements in methods and tools for curating complex pathogen-host interactions. A compelling framework is described, using rigorous approaches and to considerable extent validated by the biocuration community. The developed ontologies and controlled vocabularies could be extended beyond host pathogens, e.g. ecological contexts with multi-species and multilevel interactions.

eLife assessment

This work presents a multimodal approach to ascertain links between risk and resilience to depression and Alzheimer's disease in a large pediatric sample. The authors find two latent imaging variables that may be associated with resilience to adverse life events and disease risk, which show some spatial overlap with disease relevant gene-expression patterns and neurotransmitter expression. Such findings could be important for understanding mechanisms underlying resilience in neurological disorders, however, the analyses are inadequate for fully supporting the interpretation of the variables involved in these models, or for supporting some of the overall conclusions of the work.

eLife assessment

The manuscript by Eyraud and colleagues examines the role of interactions between fibrocytes and CD8 cells as drivers of disease progression in COPD (chronic obstructive pulmonary disease). The findings that there exist bidirectional interactions between CD8 cells and fibrocytes are supported by solid evidence that combines histology of clinical lung samples, in vitro studies obtained from circulating blood fibrocytes and CD8 cells, as well as a computational model that predicts how bidirectional interactions could promote disease progression over the course of 20 years. The study, which is based on patient samples, thus provides fundamental insights on COPD progression.

eLife assessment

This useful study uses untargeted metabolomics to help us understand how some herbivores are able to be generalists, rather than specializing in the metabolism of specific plant species. This is an important area, since little is known about how generalist insect species metabolize their food. In its current form, the study lacks ecological relevance due to the exclusive use of refined sampling procedures, and the metabolomic analysis is incomplete.

eLife assessment

This important study should be of interest to vision scientists and those seeking to model naturalistic image processing for humans in simulated or real navigational [walking] situations. The experiments aim to provide information about the statistics of "retinal" motion patterns generated by human participants physically walking a straight path in real terrains that differ in "smoothness". State-of-the-art eye, head, and body tracking allowed simultaneous assessment of eye movements, head movements, and gait, with convincing evidence for an asymmetrical gradient of flow speeds during walking, tied predominantly to vertical gaze angle, together with a radial motion direction distribution tied most critically on horizontal gaze angle. While not a major weakness per se, additional details on analytical methods used and estimations of variance across observers would strengthen these results and clarify the basis of the global claims made about visual motion information across the visual field in walking humans.

//Summary* - The central question of the Anthropocene: - why did behaviorally modern humans gain the unprecedented capacity to change an entire planet? - cannot be answered by genetic changes in human behavior. - To explain why human societies scaled up to become a global force capable of changing the Earth and why there are so many different forms of human societies and ecologies shaped by them, - explanations must be sought beyond the theories of - biology, - chemistry or - physics. - Here I introduce a new evolutionary theory, sociocultural niche construction, - aimed at explaining the origins of human capacity to transform the Earth . - As will be seen, this theory also explains why - behaviorally modern human societies came to - transform ecology in so many different ways over the past 50,000 years as they expanded across the Earth. //

eLife assessment

This valuable study provides solid results on the molecular signaling mechanisms of CaM kinase kinase-1 (CKK-1) in the context of the nociceptive behaviors of C. elegans. The authors report previously undescribed elements that control the nuclear/cytoplasmic shuttling of CKK-1, suggesting a complex interplay of multiple nuclear localization and export sequences. Therefore, the work will be of broad interest to scientists studying behavior, neuronal signaling, and signal transduction in general.

eLife assessment

This important study proposes a phenomenologically motivated theoretical framework to explain observed patterns of the temperature dependence of microbial diversity. The methodology is overall convincing, but the explanations of approximations and assumptions, and of their regime of validity, are incomplete. The manuscript should be of interest to microbial ecologists.

eLife assessment

In this study, the authors made important progress in understanding bone metabolic defects of T2D. They have established a valuable model that could mimic some aspects of T2D in mice. Particularly, the study provided important evidence showing bone turnover and metabolism were in defects, and changes in glycolysis would rescue bone defects in T2D. Overall, the authors provide compelling evidence from dynamic histomorphometry, C13 isotype labeling in vivo, scRNA-seq, and metabolic assays to demonstrate that the defective glucose metabolism causes osteopenia associated with T2D.

eLife assessment

The current study provides important, mechanistic insight into the potential contribution of antisense C4G2 expanded RNA to disease in C9orf72-associated ALS/FTD. The authors convincingly demonstrate that expression of this RNA species activates the PKR/eIF2α-dependent integrated stress response. They further provide evidence that this can contribute to disease phenotypes using multiple models and post-mortem patient samples.

eLife assessment

This important study reports a unique N-terminal motif of Staphylococcus aureus GpsB and the co-crystal structure of GpsB with the C-terminus of PBP4. It provides convincing evidence demonstrating the interactions of GpsB with PBP4 and FtsZ, shedding light on the role of GpsB in the pathogen's cell division. However, the functional characterization of GpsB's new motif caused and the structural characterization of GpsB and FtsZ's interaction is incomplete.

eLife assessment

This fundamental work shows the absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity. The evidence supporting the conclusions is compelling, with rigorous PET investigations and state-of-the-art cognitive assessments in a large sample. Given the high interest in the role of dopamine, the work will be of very broad interest to basic neuroscientists, clinical neuroscientists, and clinicians including neurologists and psychiatrists.

eLife assessment

This important manuscript describes a series of cellular phenotypes associated with the depletion of TANGO2, a poorly characterized gene product but relevant to neurological and muscular disorders. The authors present solid data indicating that TANGO2 associates with membrane-bound organelles, mainly mitochondria, impacting lipid metabolism and the accumulation of reactive-oxygen species. A few additional experiments would help to understand the link between the lipid changes reported and the cellular phenotype.

eLife assessment

The paper is of interest to neuroscientists, developmental biologists, and those interested in mechanisms that underlie intellectual disability. The study is well executed and brings new insight into the role of WDR62 and its role in causing microcephaly. The key claims of the manuscript require additional data.

eLife assessment<br /> <br /> This work provides a valuable allele-specific gene editing therapeutic approach to selectively target the human RHO-T17M mutation, one of the most frequent genetic causes of autosomal dominant retinitis pigmentosa. However, the current data are incomplete. Further validation of gene editing efficiency in rods at cellular level in vivo and use of Rho-T17M mice will strengthen the conclusion.

eLife assessment

The present manuscript addresses the controversial issue of the regeneration potential of cerebellar Purkinje cells in zebrafish and their integration into functional circuits. The authors use interesting genetic models to induce Purkinje cell-specific ablation to demonstrate regeneration of Purkinje cells can occur until adulthood and is accomplished by ptf1a+ progenitors. They further show that regenerated neurons reestablish electrophysiological properties and support appropriate behavior. These are important results that may help understand why mammalian neurons do not have similar properties and fail to regenerate. The conclusions on the source of regenerated neurons will however need additional experimental support.

eLife assessment

In this manuscript, Gonzalez et al investigated the dynamics of dopamine signals in the lateral shell of the nucleus accumbens (LNAc) in response to different types of carefully defined visual stimuli. Contrary to reigning theories of dopamine signaling, the authors presented convincing evidence that LNAcc dopamine transients tracked visual sensory transitions rather than any immediately apparent motivational variable. These important findings based on compelling evidence point to a potentially new role for dopamine signaling in the ventral striatum.

eLife assessment

Based on the Cryo-EM structure of human ETB in complex with the vasoconstricting peptide ET-1 and the inhibitory G-protein (Gi), this valuable study presents convincing data on how agonist binding is coupled to Gi-protein binding. The complex structure is solid and will appeal to the GPCR and pharmacology communities.

eLife assessment

Nearly all organisms require a ribonucleotide reductase (RNR) to convert ribonucleotides to their deoxyribonucleotide counterparts. In this important study, the reader learns how the model organism Escherichia coli can adapt to survive without any of its three RNRs. Compelling microbiology experiments to develop this model and analysis of compensatory mutations reveals patterns that are conserved in the few known pathogens that have also eliminated their dependence on an RNR. The manuscript will be of interest to microbiologists, biochemists, and those who work on the evolution of microbial metabolism.

eLife assessment

This work provides a promising first pass at providing an integrative model for how decisions arise from neural circuits. The approach is novel but lacks a more rigorous vetting against alternative model formulations to be able to determine its true significance. More stringent evaluations of the model in the context of existing work, as well as a clearer description of the goals and implementation of the approach, would help to address these concerns.

eLife assessment

The study represents an impressive effort to use atomistic simulations to probe cryptic binding sites in the envelope of six flaviviruses. Moreover, using constant pH simulations, the authors suggest that a cluster of ionizable residues contribute to the pH dependent conformational rearrangements required in the infection process. Therefore, the study provides new mechanistic insights that can be helpful in future efforts to develop drugs that target flaviviruses.

eLife assessment

This is an important study that investigates the impact of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia. Through a combination of pre-clinical in vivo measurements, clinical data, and computational modeling, the authors present solid evidence regarding the heterogeneous effects of TKIs in patients and how the response to treatment may be improved. With the assumptions about differences between normal and leukemic cells addressed, this study would be of interest to those working in the fields of mathematical oncology and cancer biology.

eLife assessment

The authors revisit fundamentals of synaptic transmission using a combination of advanced optical methods capable of visualizing calcium influx and neurotransmitter release at single release sites. By doing so, the authors present evidence for silencing of neurotransmitter release at single release sites as a function of external calcium. The data have relevance to a wide range of phenomena including neural plasticity and inhibitory modulation of synaptic communication.

eLife assessment

This important study presents a machine learning-based classifier that can accurately determine the geographic origin of a Salmonella enterica sample from its whole-genome sequencing data in under five minutes leading to actionable public health insights. Applying the method to 2,313 whole genome sequences collected in the United Kingdom and several external validation datasets, the authors provide convincing evidence that Salmonella genomic data can be used to identify the likely geographic source of a food-borne outbreak and, in most cases, correctly identify the country of origin of an infection acquired overseas. The work presents an excellent case for the potential utility of routine genomics coupled with machine learning for public health microbiology and the methods are likely to be applicable to other pathogens besides Salmonella enterica.

eLife assessment

The findings in this study are important as they establish a rat model of a classic form of early-onset osteoporosis and demonstrate that osteoporosis medications are effective in the model. The evidence supporting the authors' claims is compelling.

eLife assessment

This important landmark paper identifies three distinct stellate ganglion nerve cell subtypes stratifiable in terms of their neuropeptide Y expression correlating these with gene expression and electrophysiological properties. Their innovative use of viral tracing techniques compellingly established their conclusions. This major contribution to cardiac sympathetic excitation is relevant to a wide scientific and clinical audience.

eLife assessment

This important work demonstrates a significant asymmetry between the connectivity statistics of the left and right hemispheres of the Drosophila larva brain. The evidence supporting the conclusions is compelling and represents a first step toward the development of statistical tests for comparing pairs of connectomes more generally. This work will therefore be of interest to the broad neuroscience community.

eLife assessment

This paper will be of interest to scientists involved in understanding the function of long non-coding RNAs. The authors found two genes previously reported as lincRNAs in early studies encode micropeptides in zebrafish. Zebrafish mutants lacking these micro-peptides show altered gene regulatory networks that preferentially affect oligodendrocytes and cerebellar cells in the embryonic brain. The data presented in the study are solid and present convincing additional evidence for the versatile functions of micro-peptides.

eLife assessment

This study is an important contribution to the understanding of Buruli ulcer transmission in Australia. The authors provide compelling evidence that the carriage of Mycobacterium ulcerans by possums, within their small home range, can predict cases of Buruli ulcer disease in individuals who visit those areas. While not directly relevant to the transmission of Buruli ulcer in West and Central Africa, the work will be of great interest to those studying the transmission of opportunistic environmental pathogens.

eLife assessment

This study employs live imaging to investigate the movement of mesodermal cells in early mouse embryos. By examining the dynamics of cell behavior in normal and mutant embryos, the authors propose that apical constriction of cells results from pulsed contraction guided by crumbs2 signals. The paper presents beautiful images and adds to the molecular understanding of cell migration during early development.

eLife assessment

In this Tools and Resources article, Sapiro et al. overcome the technical burden of low Borrelia burgdorferi numbers during infection by physically enriching for spirochetes prior to RNA-sequencing/mass spectrometry. This work is important as it provides technical advances for the study of global transcriptomic changes of B. burgdorferi during tick feeding and builds on the knowledge already collected by the field. The evidence presented is compelling, and the strategy described here could benefit researchers in the field and possibly support broader applications.