eLife assessment

This study describes a useful method to monitor the behavior of Drosophila larvae in a uniform environment over much longer time scales than was possible with previous methods. The authors provide a solid characterization of aspects of the method and show that the behavior of single larvae can be quantified over several hours. The experiments offer a proof-of-concept for a robotic device that will enable the investigation of behavior in long-term experiments in ways that were previously unimaginable.

eLife assessment

This manuscript provides a structural analysis of bushy cells in the mouse cochlear nucleus. These neurons receive a large synaptic contact from the auditory nerve termed an endbulb that preserves the temporal information present in the auditory nerve and are key elements of binaural sound localization circuits. The analysis combines volume electron microscopy techniques with computational models to predict heterogeneous bushy cell responses. The analysis takes morphological analysis of bushy cells to a new level, and the modeling is well done.

eLife assessment

This potentially important paper investigates the mechanisms that contribute to building inhibitory synapses through differential protein release from microtubules. The experiments are generally designed well, but the evidence supporting the conclusions is incomplete. This manuscript will be of interest to neuroscientists and cell biologists interested in intracellular trafficking and synapse maturation.

eLife assessment

These valuable findings presented by Wu et al. advance our understanding in novel cell signaling regulators of hepatic metabolism. The evidence supporting these conclusions are solid, utilizing in vivo and in vitro gain and loss of function studies. These work will be of interest to biologists working in the field of hepatic steatosis.

eLife assessment

The paper provides important insight into the function of FAM76B protein as a regulator of inflammation. The knockout/overexpression data are solid, however, the mechanism of regulation and the role of FAM76B in neurodegeneration is incomplete and requires additional experimentation. The work will be of interest to researchers studying inflammation, particularly neuroinflammation.

eLife assessment

This important study shows that exercise improves cerebrovascular function during aging using convincing methods, the authors show that aerobic exercise reverses aging-induced deficits in microvascular perfusion and oxygenation and potentially improves short-term memory. This work will be of broad interest to researchers and clinicians studying vascular function, age-related cognitive decline, and the effects of aerobic exercise on reversing age-related dysfunction.

eLife assessment

This valuable study identifies three independent patient mutations in MAD2L1BP (p31 comet) that cause infertility. Consistent with the known functions of p31 comet, solid experiments in mouse oocytes imply that infertility could be caused by a failure to silence the spindle assembly checkpoint, though the mechanism was not determined. Although the sample size is small, a rescue experiment in human oocytes promises the potential for therapy.

eLife assessment

This report is a useful demonstration of how to predict the mutational pathways to antimicrobial resistance (AMR) emergence, particularly in the enzyme DHFR (dihydrofolate reductase). The methodology is overall solid but some of the claims are only partially supported. The work will be of interest to microbiologists and evolutionary biologists interested in antimicrobial resistance and its population genetics dynamic.

eLife assessment

In this interesting manuscript, Pietsch et al. develop innovative machine learning approaches for automated analysis of budding yeast live-cell imaging data obtained with a dedicated microfluidic device that retains mother cells. Developing such tools is crucial to enable high-throughput image analysis. These methods will be useful for researchers studying these cells, and may also inspire similar approaches for other types of cells.

eLife assessment

Extracellular vesicles (EVs) are emerging as important mediators of cell-to-cell signaling. Lee et al show convincingly that Stranded at second (Sas), a Drosophila cell surface protein, is trafficked by and localized to Drosophila EVs. However, the data supporting interaction with dArc and whether Sas facilitates the intercellular transfer of dArc protein or mRNA is incomplete. Moreover, almost all experiments rely on gain-of-function and over-expression of Sas, thus the relevance to normal physiological signaling is unclear.

eLife assessment

This is an elegant study combining virally-delivered lineage-tracing with single cell RNA-sequencing of the developing chicken enteric nervous system, showing potentially differential contribution of cell identities from the sacral and vagal neural crest. Addressing this important issue is pivotal to understanding basic enteric nervous system development as well as to devise therapeutic approaches to enteric neuropathies. The study is therefore generally interesting and in particular to researchers in the fields of enteric neuroscience and peripheral nervous system development. Lack of a basic classification scheme of neuronal cell types in the chicken, limited computational and functional analysis on a relatively immature stage and makes the conclusions of this work preliminary in its current state.

eLife assessment

The creation of a single-cell atlas of normal and degenerative human anterior cruciate ligament (ACL) tissues using a single-cell RNA sequencing method is an important approach to understanding the pathological mechanisms of ACL degeneration. The data of this study showed the existence of fibroblasts, endothelial cells, pericytes, and immune cells in healthy ACL, and their ratios altered in the degenerative ACL, mainly exhibited as an increase in fibroblasts and immune cells. The data analysis suggests that alterations of spatial transcriptome and changes in gene expression and signaling pathways may contribute to ACL degeneration.

eLife assessment

This important study pinpoints nitrite oxide synthase 2 activity and decreased microtubule acetylation as distinct regulators of altered autophagic flux that may contribute to pathogenesis in a mouse model of Duchenne muscular dystrophy. While most of the evidence to support these claims is convincing, the claim that autophagy is improved with increased microtubule acetylation is incompletely supported. This work may be of broad interest to muscle biologists and has translational potential for the treatment of Duchenne muscular dystrophy.

eLife assessment

The authors used the Multiethnic Cohort (MEC) study to study how COVID-19 impacted access to cancer screenings and treatment. This study's important findings served to identify key factors associated with cancer-related screening and healthcare-seeking during the pandemic. This investigation provides solid evidence to inform future policies, particularly in older and vulnerable populations.

eLife assessment

This is an important study that examined multiple biological age measures in children, which has been lacking in literature. The findings of this study provided convincing evidence to interpret and understand the aging and developmental processes in children.

eLife assessment

The authors analyze changes in the gene expression of different immune cells during heart regeneration using single-cell RNA-sequencing and assess changes upon drug treatment that depletes macrophages. They find that drug treatment affects the gene expression profiles of different and abundance of immune cells. The work provides a wealth of gene expression data and a nice analysis supporting immune cell interactions during heart regeneration, so will be a useful resource.

eLife assessment

Roe et al. provide a large-sample analysis of hemispheric lateralisation in brain structure, synthesising local cortical thickness and surface area data from 7 different datasets. The study provides a rich descriptive catalogue of phenomena related to hemispheric anatomical asymmetries. These results are convincing and will prove an important point of reference to neuroscientists who might want to compare their own future results to the ones from this large and varied data set.

eLife assessment

This valuable manuscript delineates the role of YAP/TAZ-dependent transcriptional suppression in a mechanodransductive feedback loop. The evidence presented in the manuscript is generally solid. Additional validation using an in vivo system would significantly strengthen the model proposed by the authors.

eLife assessment

This important study demonstrates a link between an acute high fat diet, microglial metabolism and improved higher cognitive function. The evidence supporting the proposed model is incomplete at this stage and would benefit from additional experiments probing the link between microglial metabolism and higher cognitive function. Following more mechanistic dissection, this work will be of interest to a broad audience in the field of neuroscience, metabolism, and immunology.

eLife assessment

This important study demonstrates a link between an acute high fat diet, microglial metabolism and improved higher cognitive function. The evidence supporting the proposed model is incomplete at this stage and would benefit from additional experiments probing the link between microglial metabolism and higher cognitive function. Following more mechanistic dissection, this work will be of interest to a broad audience in the field of neuroscience, metabolism, and immunology.

eLife assessment

The study is important as the authors successfully developed a human telencephalon-eye organoid model that exhibited remarkable pathfinding and growth of retinal ganglion cell (RGC) axons. The identification of cell-surface markers for RGCs could have significant implications for understanding the molecular mechanisms involved in RGC axon development and regeneration. While the authors' data on the developmental patterning organoid model are compelling, the reviewers had significant concerns, implying that the study could still be substantially improved.

eLife assessment

This important manuscript reveals signatures of co-evolution of two nucleosome remodeling factors, Lsh/HELLS and CDCA7, which are involved in the regulation of eukaryotic DNA methylation. The results suggest that the roles for the two factors in DNA methylation maintenance pathways can be traced back to the last eukaryotic common ancestor and that the CDC7A-HELLS-DNMT axis shaped the evolutionary retention of DNA methylation in eukaryotes. The evolutionary analyses are solid, although more refined phylogenetic approaches could have strengthened some of the claims. Overall, this study should be useful for researchers studying DNA methylation pathways in different organisms, and it should be of general interest to colleagues in the fields of evolutionary biology, chromatin biology and genome biology.

eLife assessment

This paper provides valuable new information on the mechanisms by which Vibrio cholerae integrates and responds to environmental signals. The strength of the evidence provided in support of the conclusions made and the model proposed is solid. The revision resolved many of the issues raised by the reviewers and improved the manuscript. The work is relevant for a broad audience of microbiologists interested in the mechanisms by which bacteria sense their environment.

eLife assessment

This is an important study that describes the coordinated regulation of cellular size and protein translation in response to chronic stress as an adaptive mechanism regulated by the heat shock response. The evidence supporting this conclusion is solid, utilizing diverse methods to monitor and manipulate cell size and evaluate stress resistance; however, it is currently unclear in the manuscript to what extent the effects observed are confounded by cell overcrowding. Additionally, the study could be strengthened by the inclusion of more experiments focused on defining the mechanistic basis of this coordination. This work will be of broad interest to researchers interested in diverse fields including cellular proteostasis, stress-responsive signaling, and aging and senescence.

eLife assessment

This study provides an important connection between cellular metabolism and proteostasis through MAGIC, a previously proposed protein quality control pathway for clearing cytosolic misfolded and aggregated proteins by import into mitochondria. Using a split-GFP reporter system, the authors reveal the role of Snf1, a yeast AMPK, in preventing the import of misfolded proteins to mitochondria for MAGIC, controlled by transcription factor Hap4 as a function of cellular metabolic status. The experimental evidence provided by the authors is still inadequate for explaining the regulatory mechanism of MAGIC by Snf1 or HAP4 and incomplete for explaining the cellular mechanism of substrate selection for MAGIC.

eLife assessment

This manuscript provides a useful reconstruction of the structure of the sirtuin-class histone deacetylase Sirt6 bound to a nucleosome based on cryo-EM observations, and additional characterization of the flexibility of Sirt6 based on molecular dynamics simulations. The analysis of the cryo-EM data is incomplete for some of the conclusions, and certain elements of the presentation were inadequate to allow sufficient evaluation. Biochemical validation of the conclusions is not provided, but some of this evidence has been published recently by two other groups in their analyses of the same complex. While much in this manuscript is confirmatory, the work also includes new insights into the potential dynamics of Sirt6 bound to a nucleosome.

eLife assessment

This valuable study contributes to understanding how retinal activity shapes the response properties of excitatory and inhibitory neurons in a major visual target, the superior colliculus. The evidence supporting the claim is solid: the work is technically excellent but the interpretation was limited without more detailed knowledge of cell types involved and the lack of loss or gain of function manipulations. This work will be of interest to visual neuroscientists.

eLife assessment

This study presents a novel, and potentially valuable transhumeral prosthesis control method based on artificial intelligence and virtual reality. The data were collected and analyzed using solid and validated methodology with several participants, including people with limb difference. Results are compelling and can be used as a starting point for further clinical work. Care should be taken when generalizing the results to issues not directly tested in the experiment, for example as treating phantom-limb-pain, which were not investigated in the experiments.

eLife assessment

This study presents a valuable finding that TNFAIP2 interacts with IQGAP1 and Integrin β4. Moreover, Integrin β4 activates Rac1 through TNFAIP2 and IQGAP1 and confers drug resistance in triple-negative breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer or drug resistance.

eLife assessment

The findings of this article provide valuable information on the changes of cell clusters induced by chronic periodontitis. The observation of a new fibroblast subpopulation, which was named as AG fibroblasts, was quite interesting, but needs further evidence. The strength of evidence presented is incomplete.

eLife assessment

This study by Koh et al reports an important role of key fatty-acid synthesis enzyme, acetyl-coA-carboxylase 1 (ACC1) in development and homeostasis of invariant natural killer T iNKT cells, as well as its significance in asthma etiology. The findings reveal that ACC1 induces de novo fatty acid synthesis via fatty acid- binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR)γ axis in iNKT cells, which is critical for iNKT cells survival and their pathogenic roles in allergic asthma. The data reported in the manuscript are convincing, and the work adds to our understanding of the metabolic regulation of iNKT cells.

eLife assessment

This important study uses an innovative GWAS approach and targeted testing to highlight S. aureus genes that modify susceptibility to serum, serum-derived antimicrobial products, and commonly used antibiotics. These 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. Compelling results build on a foundation of work attributing loss-of-function mutations in tcaA to glycopeptide non-susceptibility.

eLife assessment

This study is of fundamental importance, addressing the regulation of the carbon concentrating mechanism in cyanobacteria. It is a well-controlled investigation of low affinity regulatory binding of small molecules, processes that are typically difficult to examine. The work provides compelling evidence that the adenylate pool, rather than any single metabolite, regulates a key bicarbonate transporter (SbtA) to provide efficient bicarbonate supply while preventing futile cycling that can result from escape of unfixed CO2.

eLife assessment

This is a fundamental work identifying the components of the N6-methyladenosine methyltransferase complexes in yeasts and showing its major differences with the same complexes in mammals and flies. The evidence supporting the conclusions is convincing, with rigorous high-throughput sequencing approaches and detailed functional analysis. This work will be of broad interest to those in the RNA modification and meiosis fields.

eLife assessment

This is an important study that addresses the interesting question of whether stimulation of Ventral midbrain input to prefrontal cortex (PFC) during adolescence can be used to rescue genetic defects in PFC function. The conclusions are solidly supported by the data and will of interest to a broad group of neuroscientists.

eLife assessment

The authors provide an important demonstration that pharmacologically enhanced catecholamine levels and increased voluntary spatial attention have largely dissociable effects on perceptual decision making. Their findings provide solid evidence that neuromodulatory arousal and selective spatial attention shape perception in qualitatively different ways.

eLife assessment

This important study expands on current knowledge of allosteric diversity in the human kinome by C-terminal splicing variants using as a paradigm DCLK1. The authors provide solid evolutionary and some mechanistic evidence how C-terminal isoform specific variants generated by alternative splicing can regulate catalytic activity by means of coupling specific phosphorylation sites to dynamical and conformational changes controlling active site and substrate pocket occupancy, as well as protein-protein interactions. The data will be of interest to researchers in the kinase and signal transduction field.

eLife assessment

This useful study aims to characterize patterns of demographic aging in naked mole rats by quantifying mortality rates in a captive colony, up to approximately the median age of death. The study system is a fascinating case of unusual longevity and physiology in mammals, but because of limited sampling at older ages and missing analyses, the evidence for the main conclusion--that naked mole rats do not experience actuarial senescence--is incomplete for younger animals and inadequate for older animals. The work nevertheless provides data of interest to biodemographers and biomedical researchers interested in naked mole rats as a model for aging.

eLife assessment

This important study combines extensive phenotyping of genome-wide deletion mutants and machine learning-based prediction to generate a large scale resource for understanding the functions of thousands of fission yeast protein-coding genes. This resource is supported by compelling phenotyping data and state-of-the-art bioinformatic analyses.

eLife assessment

This manuscript provides important findings on the role of individual cysteine residues of FGF2 in its unconventional secretion through the plasma membrane. The experimental results are of generally high quality and solid. The work should interest researchers working on protein trafficking and secretion.

eLife assessment

This work presents a valuable online platform designed to facilitate the exploration of genes and genetic pathways implicated in human aging. Leveraging a new inference methodology, the tool enables the identification and visualization of key genes and tissues impacted by aging, facilitating scientific discovery. However, since the methods have not been fully explained, there is only incomplete support for the platform, which could be improved upon for usability and reproducibility.

eLife assessment

This useful manuscript presents a new approach to transform multi-omics datasets into images and to exploit Deep Learning methods for image analysis of the transformed datasets. As an example, the method is applied to multi-omics datasets on different cancers, but the evidence for the method working as advertised is currently incomplete.

eLife assessment

This study offers important insights into the transcriptional regulatory networks driving female gametocyte maturation in rodent malaria parasites. The carefully designed and executed experiments convincingly show how two female-specific transcription factors, AP2-FG and PFG (aka Fd2), co-operate to up-regulate the expression of genes required for development after fertilization occurs in the mosquito midgut. This study will be of interest to scientists working on sexual differentiation and gene regulation in Plasmodium and other apicomplexan parasites.

eLife assessment:

This fundamental study provides evidence that de novo beige adipogenesis from Pdgfra+ adipocyte progenitor cells is blocked during early aging in subcutaneous fat. The depth of the data at early ages is compelling, with rigorous cell tracing methodology employed. The study will aid in identifying new approaches to switch dormant adipocytes into an active thermogenic phenotype, and should be of interest to cell biologists at large.

eLife assessment

This study presents a potentially valuable discovery which indicates that activation of the P2RX7 pathway can reduce the degree of lung fibrosis caused by other inflammatory pathways. If confirmed, the study could clarify the role of specific immune networks in the establishment and progression of lung fibrosis. However, the presented data and analyses are incomplete as they rely on limited pharmacological treatments and because there is an absence of key control studies, validation experiments and statistical analyses.

eLife assessment

The study by O'Reilly and Delis provides a valuable data-driven framework for extracting task-related muscle synergies in a step towards the understanding and practical use of synergies in real scenarios (e.g., evaluation of patients in a clinical environment). The approach is incomplete since the authors did not compare their method with classical physiologically grounded approaches for assessing muscle synergies. In this sense, the comparisons with classical approaches would clarify if physiological assemblies were preserved and were not altered to incorporate task space variables. Despite limitations, the proposed framework would interest motor control and neural engineering researchers.

eLife assessment

The authors report that an interaction between the sodium-activated potassium channel Slack and Nav1.6 sensitizes Slack to inhibition by quinidine. This is an important finding because it contributes to our understanding of how the antiseizure drug quinidine affects epilepsy syndromes arising from mutations in the Slack-encoding gene KCNT1. The results are largely compelling, although additional data would strengthen the claims of a direct channel-channel interaction in vivo.

eLife assessment

This study presents a valuable finding on developing a generative model of brain electrophysiological signals to explain temporal decoding matrices that have been widely used in cognitive neuroscience. The evidence supporting the claims of the authors is convincing, although adding more neurobiological interpretation of signal properties and the underlying brain mechanism would have strengthened the study. The work will be of interest to cognitive neuroscientists using electrophysiological recordings.

eLife assessment

This valuable study combines chronic widefield calcium imaging of dorsal cortex activity at the mesoscale level with electrical recording of single neurons in specific cortical and subcortical locations. This work provides compelling evidence for recording neuronal activity at multiple temporal and spatial scales by combination of optical and electrophysiological methods. This work will be of broad interest to system neuroscientists studying neural circuits.

eLife assessment

This study addresses an important question using approaches that link molecular, circuit, and behavioral changes. The findings that Netrin-1 and UNC5c can guide dopaminergic innervation from the nucleus accumbens to the cortex during adolescence are solid. The data showing that the onset of Unc5 expression is sexually dimorphic in mice, and that in Siberian hamsters, environmental effects on development are also sexually dimorphic are solid. While this work is novel and on an interesting, understudied topic, the reviewers also identified significant gaps in experimental data and agree that support for the main claims is incomplete.

eLife assessment

This is a valuable paper demonstrating validity of a novel task that could advance the field of reinforcement learning to better incorporate threat processing in approach-avoidance-conflict. A compelling methodology includes the use of online samples and computational modelling, psychometrics, discovery/replication and pre-registration. This work provides a solid foundation for future work, which is required to address potential confounds and establish this task as relevant to psychopathology and treatment.

eLife assessment

This valuable work provides a near-complete description of the mechanosensory bristles on the Drosophila melanogaster head and the anatomy and projection patterns of the bristle mechanosensory neurons that innervate them. The data presented are solid. The study has generated numerous invaluable resources for the community that will be of interest to neuroscientists in the field of circuits and behaviour, particularly those interested in mechanosensation and behavioural sequence generation.

eLife assessment

This study provides useful insights into the mechanisms of electron transport in STEAP proteins, consistent with current models. The work strengthens and supports previously published biochemical and structural data. The experimental results are of solid technical quality, although the presentation of the data and the connections between the results and the questions addressed in the study could be improved. The manuscript will be of interest to colleagues who work on STEAP proteins and related electron transfer systems.

eLife assessment

This important paper advances our ability to understand feeding behavior in fruit flies and begins to address the challenging question of motivation. With innovative methods based on the detailed monitoring of interactions between foods of different qualities at different hunger states, they present compelling evidence for non-homeostatic feeding not driven by metabolic need.

eLife assessment

This is an important paper that combines methods ranging from agronomy and plant breeding to Arabidopsis functional genetics, to construct a plausible argument that polymorphism in a single gene affects crop yield by affecting root cell elongation and drought stress resilience in a poorly studied crop. The overall argument is plausible but rests on a diverse set of claims that are supported by solid, but also partly incomplete evidence.

eLife assessment

This study presents Bactabolize, a useful tool for the rapid genome-scale reconstruction of bacteria, applied here to strains of Klebsiella pneumoniae. Using a solid and validated methodology, the tool takes reference reconstructions as the input and can generate new reconstructions for target strains from these. However, the evidence to substantiate all of the justifications and practical applications of the models produced is still incomplete, and the work would benefit from more rigorous approaches regarding the accuracy of the predicted models.

eLife assessment

This paper describes useful tools for the light-induced degradation of proteins in bacteria, which will be appreciated by the community. The methods and data analyses are solid but the strength of evidence for the tool working as advertised is still incomplete. The study will be of interest to colleagues in the fields of microbiology and synthetic biology.

eLife assessment

This is a valuable investigation of the chromatin dynamics throughout the cell cycle by using fluorescence signals and patterns of GFP-PCNA and CY3-dUTP, which labels newly synthesized DNA. The authors report reduced chromatin mobility in S relative to G1 phase. The technology and methods used are solid, but the significance of the work is reduced by the model system employed, the HeLa cell line, which has a greatly abnormal genome.

eLife assessment

This manuscript provides useful information on the evolution of gene expression levels and plasticity in tissues impacted by hypoxia during colonization of a high-altitude environment. The strength of evidence is still inadequate because of limitations in the methods and analyses. The work will be of interest to biologists working at the interface of ecology and evolution.

eLife assessment

This important study describes the protective role of group 2 innate lymphoid cells (ILC2s) in tissue physiology and contributes to immunity, inflammatory pathology, and metabolism in maintaining homeostasis during pregnancy. The authors provide convincing evidence that ILC2s have new roles distinct from parasite protection and allergy inducers. Uterine ILC2s are key immune cells during normal and complicated pregnancies.

eLife assessment

This study presents valuable new insights into the role of the extracellular matrix component (ECM) Perlecan in axon integrity, with downstream consequences for the maintenance of synaptic structures. The evidence for Perlecan's role in this process is solid, although negative results for Perlecan's mechanism of action should be strengthened with the addition of appropriate controls centered on the relevant pathways and mechanisms involved as well as more careful analyses and interpretations. The authors provide convincing data identifying and describing the cellular sequence from ECM perturbations to axonal and synaptic degeneration, but additional data pinpointing the requirements of Perlecan for axonal maintenance would further improve the impact of this study.

eLife assessment

The present study offers valuable insights into the remodeling of Merkel cells and their innervating sensory axons in the skin. This remodelling seems to be mostly played out independently between the two synaptic partners revealing significant Merkel cell turnover and axonal plasticity. The authors employed live imaging and quantification tools using genetic models in which parts of the mechanosensory organs of the skin are labelled with distinct fluorescent proteins. While most of the data, and their interpretations are solid, the analyses of Merkel cell number homeostasis remain incomplete.

eLife assessment

This study offers an inventory of proteins and their phosphorylated sites that are up- and down-regulated in the adipose tissue and skeletal muscle of women with PCOS. The data were collected and analyzed using rigorous and validated methodology, making it a useful resource for identifying targets and strategies for future PCOS treatments. However, even though some of the predicted targets are compelling, further functional validation is required to ensure the accuracy of these identified targets. If confirmed, the findings of this study would be of significant interest to a wide range of readers.

eLife assessment

This paper investigates host and viral factors influencing transmission of alpha and delta SARS-CoV-2 variants in the Syrian hamster model and fundamentally increases knowledge regarding transmission of the virus via the aerosol route. The strength of evidence is solid and could be improved with a clearer presentation of the data.

eLife assessment

In this useful study, Holzinger et al. present compelling evidence that scorpionfish bactericidal/permeability-increasing protein (scoBPI) exhibits remarkable antibacterial activity against multi-drug resistant Pseudomonas aeruginosa. These findings open new avenues of research for identifying novel chemotherapies to treat Pseudomonas infections and have broader implications in developing chemotherapies against other drug-resistant Gram-negative bacterial infections. The work will be of interest to individuals investigating novel cystic fibrosis antimicrobials.

eLife assessment:

This important paper highlights the clonal organization of the dorsal telencephalon, a major region of the vertebrate brain, and analyzes the distinctive gene expression and chromatin accessibility present in each clonal using the adult teleost fish medaka. High-quality data were collected using convincing and solid methods and these were used to identify synaptic genes with a distinct chromatin landscape and expression in one of the regions of the dorsal pallium, with the goal of ascribing an evolutionary origin to these neurons.

eLife assessment

This paper is of potential interest to both the hippocampal and computational neuroscience fields because it provides a framework for understanding how adult-born granule cells in the hippocampus contribute to network processing. It contains novel interesting ideas, such as the analysis of input-output transformation by SRM models and the establishment of "greedy networks". However, not all major conclusions are sufficiently supported by the data. The paper demonstrates that mixed networks show better encoding performance than pure networks, but the differences are small and only visible with specific performance metrics. Intuitive explanations are not provided.

eLife assessment

In this study, the authors use high-speed and high-resolution imaging to investigate the role of the yeast syntaxin homolog Tlg2p in endocytic vesicle sorting. They obtain compelling data to show that the Tlg2p-residing compartment within the trans-Golgi network functions as an early/sorting compartment, where endocytic cargos are sorted to either the recycling pathway or the endo-lysosomal pathway. The authors also describe additional molecular details of this sorting process, and overall provide important insights into the mechanism of endocytic vesicle sorting in budding yeast.

eLife assessment

This valuable study shows that new, virulent genotypes of Xanthomonas oryze pv. oryzae, that are similar to strains present in east Asia, cause outbreaks of bacterial blight of rice in Tanzania. The authors' use of CRISPR-based gene editing on multiple pathogen targets in an elite African rice variety to create lines resistant to both endemic and emerging pathogen strains in Africa makes for a compelling contribution to meet this alarming development. The work describing the new strains of the pathogen is solid but could be stronger if there were genome sequence data for all strains examined and a clearer presentation of recent disease outbreaks and their severity.

eLife assessment

The findings in this study are important, as this brainstem region is implicated in a multitude of functions. The experimental procedures are difficult to implement and the preparation used and the skill required are impressive. The methods and data are solid, however, some analyses are incomplete, and the strength of evidence is also incomplete because the claims are only partially supported by the data. This work will interest those who study respiration, airway protection, and other oral behaviors.

eLife assessment

This manuscript explores the potential regulatory role of a previously unstudied phosphorylation site in the Src kinase SH3 domain. A mutant intended to mimic the phosphorylation of this site, Y90E, shows enhanced activity and transforming capacity, reduced mobility in the lipid bilayer, and a more open catalytic structure. In general, these findings are supported by compelling evidence. The paper will be of interest to biochemists and structural biologists studying new mechanisms that are capable of modulating the allosteric regulation of multi-domain protein kinases.

eLife assessment

Using chemogenetic manipulation, the authors induce or suppress activity in D1 spiny neurons in the dorsomedial striatum of mice. The results effectively demonstrate that excitation or inhibition of this class of neurons results in a consistent behavioral effect that is linked to an impact on local dynamics in thalamic regions that project to this part of the thalamus, as well as cortical regions that can be more readily defined as unimodal as identified by a classification approach. This work has clear relevance to the field of neuroimaging, getting at the broader hemodynamic signatures of direct pathway stimulation in the striatum, but requires critical revisions to justify their main conclusions.

Using chemogenetic manipulation, the authors induce or suppress activity in D1 spiny neurons in the dorsomedial striatum of mice. The results effectively demonstrate that excitation or inhibition of this class of neurons results in a consistent behavioral effect that is linked to an impact on local dynamics in thalamic regions that project to this part of the thalamus, as well as cortical regions that can be more readily defined as unimodal as identified by a classification approach. This work has clear relevance to the field of neuroimaging, getting at the broader hemodynamic signatures of direct pathway stimulation in the striatum, but requires critical revisions to justify their main conclusions.

eLife assessment

This paper reports a detailed functional analysis of the Rab1 effector Uso1, and it provides a fundamental advance in our understanding of how ER-derived vesicles deliver their cargo. The authors provide compelling evidence that the key function of Uso1 is promoting SNARE complex formation rather than tethering vesicles as generally assumed. These insights will be of interest to cell and structural biologists who study membrane traffic.

eLife assessment

This study makes an important effort to observe and quantify synaptic integration in a large and active network of cultured neurons, using simultaneous patch-clamp and large-scale extracellular recordings. They developed a method to distinguish excitatory and inhibitory contributions, showing compelling evidence that the subthreshold activity of these neurons is dominated by few presynaptic neurons. They provide basic statistics about connectivity and network dynamics, but their statistical analysis of the interplay between excitatory and inhibitory inputs is incomplete, mainly showing examples and averages, with little quantification of variability and therefore requiring additional analysis to better support their claims.

eLife assessment

This important study details an enrichment of the IL-6 signaling pathway in human tendinopathy, and applies transcriptional profiling to an advanced in vitro model to test IL-6 specific phenotypes in tendinopathy. Overall, the strength of evidence is solid yet incomplete, as transcriptomic measurements provide clarity, though functional studies including analysis of proliferation are needed to confirm these findings. This work will be of interest to stem cell biologists and immunologists.

eLife assessment

This paper describes useful results from studies investigating circuits in the brain that underlie behavioral responses in fearful situations. They identified a role for a class of neurons that are sufficient to cause these stereotyped behaviors including freezing behaviors. These solid studies will increase our understanding of brain pathways regulating these types of behaviors.

eLife assessment

This study is important as it examined the role of Perk (Protein kinase RNA-like endoplasmic reticulum kinase) and Atf4 (Activating Transcription Factor-4) in the integrated neurodegenerative and regenerative responses following the optic nerve injury. The evidence is convincing as the authors relied on both newly generated transcriptomic data and publicly available databases to support their research. While there are some limitations in data quality and interpretations, the study is likely to be of interest to researchers studying optic neuropathies and axonal regeneration.

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

This important paper reports recent improvements and extensions to stdpopsim, a community-driven resource that is built on top of powerful software for performing simulations of population genomic data and provides a catalog of species with curated genomic parameters and demographic models. In addition to describing the new features and species in stdpopsim, the authors provide a set of practical guidelines for implementing realistic simulations. Overall, this convincing manuscript serves as an excellent overview of the utility, challenges, common pitfalls, and best practices of population genomic simulations. It will be of broad interest to population, evolutionary, and ecological geneticists studying humans, model organisms, or non-model organisms.

eLife assessment

This valuable paper informs on the role of type I PRMTs in programming muscle stem cell identification. The evidence presented is mostly solid, with some weaknesses in the evidence regarding the proposed mechanism. The paper will be of particular interest to those who study skeletal muscle satellite cell biology.

eLife assessment

The important study by Barreat and Katzourakis examines the evolutionary history of eukaryotic viruses (and related mobile elements) in the Bamfordvirae kingdom, and evaluates potential alternative scenarios regarding the origin of different lineages in this highly diverse kingdom. Through convincing phylogenetic analyses, the authors propose a new evolutionary model for the origin of this kingdom where their last common ancestor is inferred to have been an exogenous, non-virophage DNA virus with a small genome. This work advances our understanding of the deep evolutionary history of viruses, the interaction between viruses and the first eukaryotes, and the diversification of viral lineages.

eLife assessment

This paper describes an important new marine reptile specimen. A solid ostelogical description of the saurosphargid Prosaurosphargis yingzishanensis, the earliest known member of this group, combined with a large-scale phylogenetic analysis enhances our understanding of the affinities of a wide range of Triassic reptiles. As such the relevance of this paper goes far beyond the immediate importance of this remarkable fossil - it also sheds light on the position of several important Triassic groups, including Testudinata and Archosauromorpha.

eLife assessment

Vocalizations are controlled by neural circuits connecting the amygdala and periaqueductal gray. This study presents valuable measures of the neurons that suppress vocalization in appropriate contexts using a rich variety of behavioural, imaging, optogenetic, and tracing methodologies. The evidence supporting the claims of the authors is solid, although their results only hint at the mechanisms that could underlie the hierarchical control of vocalization. The work will be of interest to neurobiologists working on motor control and vocalization.

eLife assessment

This study presents valuable findings on the risk factors of avascular osteonecrosis in patients with Gaucher disease. The evidence supporting the claims of the authors is convincing. The work will interest clinicians who treat patients with inborn errors of metabolism.

eLife assessment

This study presents valuable findings regarding the functional diversification of flavodoxins from diatoms, a protein initially described as an Fe-sparing substitute for ferredoxin in Fe-poor open ocean environments. The evidence supporting the claims of the authors is solid, although the study could be strengthened by using a wider gradient of oxidative stress in the experiments and using Fe limitation methodology, which allows more certain differentiation between a low Fe and oxidative stress response.

eLife assessment

This valuable study combines population genetic theory and deep learning approaches to estimate the extent of assortative mating and sex bias in modern admixed populations in the Americas. The new approach provides solid evidence for their main conclusions that socially constructed hierarchies have influenced mating behaviors, though certain results would benefit from further consideration. This paper would be of interest to human population geneticists and social scientists, particularly those studying demographic processes.

eLife assessment

This compelling study brings together two earlier observations: that Ca2+ influx can trigger exosome release from multivesicular bodies, and that plasma membrane repair after wounding requires Ca2+ and involves Ca2+-binding annexin proteins. This important work takes these earlier findings in an interesting new direction by showing that exosome release from MVBs is also triggered by Ca2+ influx during plasma membrane wounding and requires the annexin isoform ANX6. The study suggests a few possible mechanisms (such as Ca2+-dependent tethering of MVBs to the plasma membrane by ANX6) and raises the interesting possibility that cell injury and repair may contribute to the release of exosomes into biological fluids.

eLife assessment

This manuscript reports an important finding that spermatogenic defects in Parl KO mice, a genetic model for Leigh syndrome, may result from mitochondrial defects leading to ferroptosis. The finding, if confirmed, would be of great significance because male germ cell ferroptosis has not been well characterized. However, the criteria for determining male germ cell ferroptosis were vague, and the supporting data were inadequate.

eLife assessment

This study presents important findings on the decision-making capacities of honey bees in controlled conditions. The evidence supporting the study is solid, however, the explanation of the methods, importance, and novelty of the study requires further clarification. With a deeper development of the relevance of this study, the reader will have a clear idea of how this study contributes to the field.

eLife assessment

This paper will be of broad interest to immunologists that study T cell responses and formation of the peripheral T cell compartment. Using elegant live imaging approaches, the authors provide convincing evidence in support of a revised model for how positive-selected thymocytes are called to the thymus medulla to interact with distinct antigen-presenting cells. The work makes an important contribution to the field by identifying previously unappreciated complexities related to cellular movement during T cell generation.

eLife assessment

This study presents valuable findings on how gender-neutral vaccination against human papillomavirus can help improve program resilience in the case of vaccination disruptions. The evidence supporting the claims of the authors is convincing, although the results are only applicable to India and other countries with a similar HPV context; researchers can adapt the model for their local context and use it as a starting point for future research.

eLife assessment

This paper reports on the role of RIF1 during early stages of zebrafish embryonic development, with the important finding that Rif1 seems to be required predominantly to establish the correct embryonic transcriptional program first, followed by a switch to a more replication-timing centered later function. The evidence is convincing, with the major strength being the elegant system and the possibility to also address the problem of the maternal pool of Rif1. A weakness is that the study remains descriptive and the presentation slightly disconnected, with limited mechanistic insight. The work will be of interest for researchers both in the transcription and the replication field, especially for scientists investigating the interplay between the two processes.

eLife assessment

This important study reports a novel mechanism linking DHODH inhibition-mediated pyrimidine nucleotide depletion to antigen presentation. Alternative means of inducing antigen presentation provide therapeutic opportunities to augment immune checkpoint blockade for cancer treatment. While the solid mechanistic data in vitro are compelling, in vivo assessments of the functional relevance of this mechanism are still incomplete.

eLife assessment

Gap junctions, formed from connexins, are important in cell communication, allowing ions and small molecules to move directly between cells. By determining the Cryo EM structure of the structure of connexin 43 in a putative closed state involving lipids, the study makes an important contribution to the development of a mechanistic model for connexin activation. The connexin 43 structure is solid and its presentation will appeal to the channel and membrane protein communities.

eLife assessment

This study presents fundamental new insight into the regulatory apparatus of PI3Kgamma; an important kinase in signaling pathways that control the immune response and cancer. A suite of biophysical and biochemical approaches provide convincing evidence for new sites of allosteric control over enzyme activity. The rigorous findings provide structure and dynamic information that may be exploited in efforts to control PI3Kgamma activity in a therapeutic setting.

eLife assessment

This important study provides an unprecedented overview of the subcellular organization of proliferative blood stage malaria parasites. The localization of multiple parasite organelles is comprehensively probed using three-dimensional super-resolution microscopy throughout the entire intraerythrocytic development cycle. This work provides a compelling framework to investigate in future more deeply the unconventional cell biology of malaria-causing parasites.

eLife assessment

This valuable paper reports the development of SCA-seq, a nanopore-based multiOME mapping method for simultaneously measuring chromatin accessibility, genome 3D and CpG DNA methylation. The methods, data and analyses are solid and largely support the claims. This new tool to interrogate genome structure-function relationships will be of broad interest to geneticists and many others.

eLife assessment

Tilk and colleagues present a valuable computational analysis of tumor transcriptomes to investigate the hypothesis that the large number of somatic mutations in some tumors is detrimental such that these detrimental effects are mitigated by an up-regulation by pathways and mechanisms that prevent protein misfolding. The authors address this question by fitting a model that explains the log expression of a gene as a linear function of the log number of mutations in the tumor and show that specific categories of genes (proteasome, chaperones, ...) tend to be upregulated in tumors with a large number of somatic mutations. Some of the associations presented could arise through confounding, but overall the authors present solid evidence that mutational load is associated with higher expression of genes involved in mitigation of protein misfolding - an important finding with general implications for our understanding of cancer evolution.

eLife assessment

The authors set out to study the development of high altitude polycythemia, which affects mice in a hypoxia chamber and humans staying at a hypoxic atmosphere at high altitude. The findings are useful both for initiating the discussion of the hypothesis that splenic red pulp macrophages, central to red cell survival, are impacted by hypoxia, and for providing some data that partially supports this hypothesis. However, the current data are inadequate to fully support the authors' conclusions.

eLife assessment

This important paper reports data on the cellular response to a single site-specific replication fork block in human MCF7 cells. Compelling evidence shows the efficacy of the bacterial Tus-Ter system to stall replication forks in human cells, with fork stalling leading to lasting ATR-dependent phosphorylation of histone H2AX but not of ATR itself and its downstream targets RPA and CHK1. The work will be of broad interest to students of DNA replication.

eLife assessment

The manuscript represents an important study on the pathogenesis of rubella virus tropism and neuropathology in human microglia-containing human stem cell derived organoids and human fetal brain slices. The strength of evidence is compelling, using state-of-the-art multimodal technologies. The findings will be of interest to neuroscientists, virologists, and epidemiologists, presenting novel hypotheses and generally useful tools.

eLife assessment

This valuable study uses multiple large neuroimaging data sets acquired at different points through the lifespan to provide solid evidence that birthweight (BW) is associated with robust and persistent variations in cortical anatomy, but less-substantial influences on cortical change over time. These findings, supported by robust statistical methods, illustrate the long temporal reach of early developmental influences and carry relevance for how we conceptualize, study, and potentially modify such influences more generally. The paper will be of interest to people interested in brain development and aging.

eLife assessment

This valuable study revisits the effects of substitution model selection on phylogenetics by comparing reversible and non-reversible DNA substitution models. The authors provide evidence that 1) non time-reversible models sometimes perform better than general time-reversible models when inferring phylogenetic trees out of simulated viral genome sequence data sets, and that 2) non time-reversible models can fit the real data better than the reversible substitution models commonly used in phylogenetics, a finding consistent with previous work. However, the methods are incomplete in supporting the main conclusion of the manuscript, that is that non time-reversible models should be incorporated in the model selection process for these data sets.

eLife assessment

This important 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 study provides broadly relevant insights 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 important study provides novel strategies to overcome certain limitations when investigating the metabolism of hematopoietic stem cells, mainly due to their low abundance. The study provides some solid evidence suggesting that hematopoietic stem cells mainly use glycolysis (rather than mitochondrial OXPHOS or TCA cycle) as their primary energy source, when proliferating in response to hematopoietic stress, as opposed to homeostasis. With the evidence further strengthened by more direct links between metabolic features and cell proliferation, and after consideration of alternative energy sources, this study would be of great interest to stem cell biologists.

eLife assessment

This important study uses CRISPRi to silence multiple effectors in the pathogen Legionella pneumophila. The paper provides a technique that will allow researchers to address functional redundancy amongst effectors, a problem that has persisted even after decades of study. The methodology used is convincing, and further improvement can lead to the identification of novel virulence factors.

eLife assessment

In this valuable paper, the authors analyze the functions of the five C-terminal repeat sequences in the Dux embryonic transcription factor and their role in recruiting cofactors for gene regulation. The evidence is solid and the work is carefully done. although additional experiments could strengthen the overall conclusions of the manuscript.

eLife assessment

This important paper exploits new cryo-EM tomography tools to examine the state of chromatin in situ. The experimental work is meticulously performed and convincing, with a vast amount of data collected. The main findings are interpreted by the authors to suggest that the majority of yeast nucleosomes lack a stable octameric conformation. Despite the possibly controversial nature of this report, it is our hope that such work will spark thought-provoking debate, and further the development of exciting new tools that can interrogate native chromatin shape and associated function in vivo.

eLife assessment

This important study unifies our current understanding of phosphate homeostasis and starvation responses in different eukaryotes, in which the nutrient messenger 1,5-InsP8 binds to one or several cellular SPX receptors, which in turn regulate very different, species-specific PHO pathway components. The evidence is compelling and supported by biochemical analyses, protein localization by fluorescence, and genetic approaches, but could still be strengthened by additional experiments. The work will be of interest to a broad community working on nutrient signalling in eukaryotes.

eLife assessment

This important study addresses both the native role of the Plasmodium falciparum protein PfFKBP35 and whether this protein is the target of FK506, an immunosuppressant with antiplasmodial activity. The genetic evidence for the essentiality of FKBP35 in parasite growth is compelling. However, the conclusion that the role of FKBP35 is to secure ribosome homeostasis and the claim that FK506 exerts its antimalarial activity independently of FKBP35 rely on incomplete evidence.

eLife assessment

The current manuscript investigates the energy landscape of the mammalian sugar porter GLUT5 using enhanced molecular dynamics simulations and biochemical assays. The approach generates important insights into the mechanism of GLUT5 conformational change, and into mechanistic diversity among the GLUT sugar porters more generally. The overall strategy is solid, but without an additional error analysis, the computational components remain incomplete. These findings will be of interest to the transporter and membrane biology communities.

eLife assessment

This useful study adapts methods from causal inference to develop analytical tools for determining the causal influence of single cells on downstream neurons. The simulation evidence is solid, suggesting that these causal methods produce better estimates under biologically-relevant confounds given enough data, although the practical application of the method and the biophysics it relies on is unclear. Nonetheless, this application of causal methods developed in econometrics and other fields could suggest new ways to think about largely observational datasets in neuroscience.

eLife assessment

Hyperpolarised-activated and Cyclic Nucleotide-gated (HCN) channels are the only mammalian channels to open under hyperpolarisation, being important for their roles in cardiac and neuronal cells. The authors of this study use atomistic simulations to enforce changing interaction distances that have been identified from a cryoEM structure and a homology model based on the hERG channel. The simulations suggest state-dependent interactions involving pore and voltage sensor helices, as well as with lipids, leading the authors to propose a domino-like mechanism of activation. These findings will be of considerable interest to the ion channel community.

eLife assessment

This is a comprehensive approach to understanding the genetic requirements of the VEGF family in the generation of brain capillary structure in zebrafish. The manuscript combines vascular brain/meningeal anatomy revealed with a variety of reporter lines, with mutants for Wnt/β-catenin signaling and angiogenic cues. In particular revealing genetic redundancy in VEGF receptor family in an essential function in vasculature development.

This paper is significant because it provides compelling evidence that features methods, data, and analyses more rigorous than the current state-of-the-art in analysis of brain vasculature development. The data derived from the reporter lines are convincing, and the germline mutations allow for solid visualization and quantification of results.

eLife assessment

This important study provides continuous maps of human brain gene expression and explores their relationship with a large variety of microscopic and macroscopic aspects of brain organisation. The authors provide convincing evidence for a relationship between gene expression maps with various aspects of the anatomy of adult brains, during development, and in the case of mental disorders. The data and methods introduced can be an important tool for neuroimaging research.

eLife assessment

These valuable findings will be of interest for the study of dystroglycanopathies and in the general area of axon migration and synapse formation. This work provides solid conclusions about how a range of dystroglycan mutations alter CCK interneuron axonal targeting and synaptic connectivity in the forebrain, and seizure susceptibility.

eLife assessment

This work represents an important contribution to our understanding of how phenomena associated with the theta rhythm in the hippocampus could be generated even in the absence of theta. This convincing computational work provides a parsimonious continuous attractor network model of how hippocampal place cell networks can briefly sweep forward to represent future locations and then sweep back, even in animal species in which theta oscillations are only weakly (or not at all) present.

eLife assessment

The study expands our understanding of the neural circuitry downstream of the cerebellum by describing pathways between the deep cerebellar nuclei and the nucleus accumbens. The authors use a combination of in vivo electrophysiology, electrical and optogenetic stimulation, and both anterograde and retrograde tracing to demonstrate two functional neural pathways. The experiments convincingly support the claims. The finding extends previous investigations about the connections between these two brain areas, and are important for elucidating the role of the cerebellum in influencing functions supported by the nucleus accumbens, such as motivation and reward.