eLife assessment

This study presents a fundamental meta-analysis on the causes of glucocorticoid variation in birds and mammals. It provides convincing evidence that an increase in metabolic rates also increases glucocorticoid concentrations. As such, the work will be of broad interest to animal physiologists.

eLife assessment

This valuable study provides insights into the IDA peptide with dual functions in development and immunity. The approach used is solid and helps to define the role of IDA in a two-step process, cell separation followed by activation of innate defenses. The main limitation of the study is the lack of direct evidence linking signaling by IDA and its HAE receptors to immunity. As such the work remains descriptive but it will nevertheless be of interest to a wide range of plant cell biologists.

eLife assessment

The manuscript reports useful findings by resolving the crystal structure of Sedoheptulose-1,7-Bisphosphatase (SBPase) from the green algae Chlamydomonas reinhardtii, which is involved in the Calvin cycle. The data presented are solid based on validated methodologies, which help in understanding the structure and function of this enzyme.

eLife assessment

This important study combines experiments and fluid mechanics modeling to determine the mechanism of the ultrafast ejection of the polar tube of the Microsporidia parasite and of transport through this tube. The methods and the analysis, based on the variation of the viscosity of the external medium, are solid, allowing for the first time to discriminate among proposed ejection mechanisms. More details about the model, regarding both the actual topology of the system and the pressure, would be, however, helpful for the reader. The approach implemented here, where simple physical principles are used for distinguishing between mechanisms when the precise geometry is inaccessible through imaging, is potentially applicable to other systems in microbiology.

eLife assessment

This important study used a battery of cutting-edge technologies including whole exosome sequencing, knockout/knockdown animal models and comparative proteomics to define the physiological roles of ZMYND21 in the regulation of sperm flagellar development and male fertility. The data supporting the conclusion are solid, although inclusion of more patients and ultrastructural studies would have further strengthened the study. This work will be of interest to clinicians and researchers who work on male fertility, but also those working on organs/systems containing motile cilia (e.g., trachea, oviduct, ventricular ependymal cells).

elife assessment:

This small-sized clinical trial comparing nebulized dornase-alfa to best available care in patients hospitalized with COVID-19 pneumonia is valuable, but in its present form the paper is incomplete: the number of randomized participants is small, investigators describe also a contemporary cohort of controls and the study concludes about decrease of inflammation (reflected by CRP levels) after 7 days of treatment but no other statistically significant clinical benefit.

eLife assessment

This manuscript represents a valuable study showing that microplastics indeed accumulate in both bovine and human ovarian follicular fluid. It also presented data that direct exposure of bovine eggs to polystyrene, a microplastic commonly found in follicular fluid, negatively affects oocyte maturation, probably through the downregulation of key proteins involved in oxidative stress, DNA damage, apoptosis, and oocyte maturation. Despite the solid supporting evidence, inclusion of the demographics and reasons for assisted reproduction of the human subjects used, as well as the details on quality control for proteomic analyses would further strengthen the study. The work will be of interest to reproductive toxicologists, regulatory scientists and reproductive health care professionals.

eLife assessment

This paper presents an important effort to develop an open source software framework for monitoring trends and variations in healthcare over time in England. They demonstrate a compelling example of how this system can track key health care indicators over the course of the COVID-19 pandemic. The paper will likely be mainly of interest to stakeholders in England, but could inspire the creation of similar systems in other countries.

eLife assessment

This is an important theoretical study providing insight into how fluctuations in excitability can contribute to gradual changes in the mapping between population activity and stimulus, commonly referred to as representational drift. The authors provide convincing evidence that fluctuations can contribute to drift, though certain modeling choices could benefit from justification or further exploration of alternatives. Overall, this is a well-presented study that explores the question of how changes in intrinsic excitability can influence memory representations.

eLife assessment

This useful study investigates the role of mechanotransduction channels in controlling food ingestion in Drosophila and localizes the role of some of these genes to sensory neurons in the fly pharynx. The evidence supporting several of the authors claims is incomplete and would benefit from additional investigation. With additional evidence, this paper would be of interest to biologists interested in mechanosensation and feeding behavior.

eLife assessment

This important study combines genetically barcoded rabies viruses with spatial transcriptomics in vivo in the mouse brain to decode connectivity of neural circuits. The data generated by the combination of these approaches in this new way is mostly convincing as the authors provide validation and proof-of-concept that the approach can be successful. While this new combination of established techniques has promise for elucidating brain connectivity, there are still some nuances and caveats to the interpretations of the results that are lacking especially with regards to noting unexpected barcodes either due to unexpected/novel connections or unexpected rabies spread.

eLife assessment

This valuable work proposes a new model of basal ganglia function termed the "Triple Control Model" consisting of one direct pathway and two indirect pathways. The study provides evidence that the firing dynamics of substantia nigra reflect action selection but not interval time or reward and makes a case for the need for the Triple Control Model to explain the results of their manipulations of D1 and D2 receptor-expressing cells in the striatum. Although this work may be of interest to neuroscientists who study basal ganglia, without additional analyses of the relationship of neural activity to movements, and direct experimental evidence of two indirect pathways, the evidence for this model is somewhat incomplete.

eLife assessment

The formation of the place cell map in the hippocampus is foundational to many models and is thought to form a substrate onto which memories can be structured. This paper presents an important new observation to our understanding of place cell formation - namely that task learning changes or interferes with the process of place cell map stabilization. Reviewers found that there was incomplete evidence for this result, however, in this version of the manuscript because of a confound between the duration of experience in an environment and task-specific learning.

eLife assessment

This study presents a valuable and comprehensive mutagenesis map of the AAV2 rep gene, which will undoubtedly capture the interest of scientists working with adeno-associated viruses and those engaged in the field of gene therapy. The thorough characterization of massive rep variants across multiple AAV production systems bolsters the claims made in the study, highlighting its utility in enhancing our understanding of Rep protein function and advancing gene therapy applications. Despite some limitations, such as the lack of measurements on AAV transduction efficiency, the evidence presented is solid and establishes a strong foundation that will stimulate and inform future research in the field.

eLife assessment

This study presents valuable findings on the organization of respiratory chain complexes in mitochondria, but the evidence supporting the main claims is currently incomplete, as the structural reasons for and significance of supercomplex formation are unclear. The work will be of interest to the community working on mitochondrial bioenergetics.

eLife assessment

This study presents a useful set of experiments to test how a salivary protein might facilitate planthopper-transmitted rice stripe virus infection by interfering with callose deposition. If the conclusions can be confirmed, the study will enhance our understanding of the mechanisms mediating tripartite virus-insect vector-plant interactions and would be of general interest in plant science research. Whereas most experimental data is compelling, the conclusions rely on inadequate evidence for the salivary protein carbonic anhydrase being present two weeks post injection in the plant, which seems unlikely.

eLife assessment

The full role of small RNAs, often key global regulators of gene expression in connection with environmental adaptation, in flagella regulation has not been determined. This study presents important findings regarding the function of small RNAs in bacterial motility and regulation of flagella biosynthesis regulation and number. The authors combine multiple methods, including RIL-seq, structural probing, RNA blots and reporter assays, to provide convincing biochemical evidence for direct effects of specific small RNAs, whose expression is dependent on flagella sigma 28 (FliA), on transcriptional attenuation of flagella operons via regulation of ribosomal proteins.

eLife assessment

This study presents a valuable finding on the immunophenotypes of cancer treatment-related pneumonitis. The evidence supporting the claims of the authors is solid, although the inclusion of controls, as suggested by one of the reviewers, strengthened the study. The work will be of interest to cancer immunologists

eLife assessment:

This important study represents a comprehensive computational analysis of Plasmodium falciparum gene expression, with a focus on var gene expression, in parasites isolated from patients; it assesses changes that occur as the parasites adapt to short-term in vitro culture conditions. The work provides technical advances to update a previously developed computational pipeline. Although the findings of the shifts in the expression of particular var genes have theoretical or practical implications beyond a single subfield, the results are incomplete and the main claims are only partially supported.

eLife assessment

This study presents important findings regarding the quantification of dynamics in fish communities in changing ecosystems by combining a large-scale environmental DNA metabarcoding time series with novel statistical approaches. The methods are convincing, with controlled experiments, thorough statistical analyses, and a substantial dataset covering two years of detailed observation, which can provide sufficient power to detect fine-scale ecological interactions. This work is relevant for informing future research on assessing community stability under climate change.

eLife assessment

This study makes valuable observations about the representation of "value" in the mouse brain, by using a nice task design and recording from an impressive number of brain regions. The combination of state-of-the-art imaging and electrophysiology data offer solid support for the authors' conclusions. The paper will be of interest to a broad audience of neuroscientists interested in reward processing in the brain.

eLife assessment

This manuscript provides a description of an approach for efficiently integrating diverse libraries into the C. elegans genome and tools that enable researchers to use the method. It is a valuable contribution for researchers carrying out experiments that would benefit from easy generation of such libraries, and the data for the effectiveness of the method is solid. The advantages of this approach in terms of ease and effectiveness relative to others with similar aims will emerge as they are put to more general use in addressing biological problems.

eLife assessment

This study makes a fundamental observation about the role of activity in the mouse thalamus on scalp recorded voltage fluctuations. The novel approach and sophisticated analysis of neural signals provides compelling support for the authors' observations. This work will likely be of broad interest to neuroscientists.

eLife assessment

This study presents a valuable examination into the role Notch-RBP-J signaling in regulating monocyte subset homeostasis. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for exploring the mechanisms involved in RBP-J signaling in non-classical monocytes.

eLife assessment

This paper provides a useful set of data examining the role of PTPMT1, a mitochondria-based phosphatase, in mitochondrial fuel selection. The data were collected and analyzed using solid methodology and can be used as a starting point for further studies that build on the findings here.

eLife assessment

The manuscript provides valuable findings that will have practical implications for high throughput cultivation of cardiac tissues. The results demonstrate convincing evidence regarding the ability to create functional cardiac tissues and maintain them over periods of days to weeks. Improving the success rate of tissue integrity over longer periods of time, reproducing the physiological isoproterenol response and studying the impulse propagation in the tissues would garner a further broad interest for the platform.

eLife assessment

This important and compelling study investigates the problem of intracellular acidification induced by commonly-used optogenetic stimulating opsins. The low proton permeability of two high-performance opsins is shown to reduce photostimulated acidification. The findings may be of broad interest in the fields of neuroscience research and optogenetic therapies.

eLife assessment

This fundamental work provides preclinical evidence to support that natural tannins derived from grapeseed can inhibit or prevent infection by the SARS-CoV-2 viruses. The evidence provided is mostly solid to convincing and supports the conclusions. This work will be of broad interest to cell biologists and physicians.

eLife assessment

This is an important study that uncovers a new molecular pathway that links traditional monoaminergic antidepressants with regulation of glutamate neurotransmission. The data provided for the model are convincing and demonstrate the pathway in human plasma and brain, mouse brain, and cultured cells, using the relative strengths of each system. The work will be of interest to psychiatrists studying depression as well as basic neurobiologists interested in monoamine signaling in the brain.

eLife assessment

Mizukami et al. propose a scenario for the evolutionary origin of the coronary artery in amniotes by comparing the morphologies of the vasculatures across several species and developmental timepoints. They show that the coronary arteries of non-amniotes most closely resemble embryonic amniote aortic subepicardial vessels (ASVs), which are replaced by the true coronary arteries during amniote development. While the identification of common vascular structures in diverse taxa is a valuable contribution, additional developmental evidence is needed to confirm that such vessels are truly homologous.

eLife assessment

This important study uses computational simulations to explore how spatial structure can affect the coexistence between different microbial species, ultimately helping to explain diversity in microbial communities. The evidence supporting the conclusions is solid, although the parameter values used in the simulations were deemed to be unrealistic. Further investigation on whether the conclusions would hold under more realistic assumptions would be very interesting to microbial ecologists quite broadly.

eLife assessment

Understanding the heterogeneity of the B cell response induced in autoimmune individuals is important for the development of therapies designed to target the cells underlying disease progression. Here the authors use a new mouse model of autoimmunity to assess the heterogeneity of the B cell response using single-cell RNA-sequencing and BCR-sequencing and found that these B cell responses are similar to those by exogenous protein immunization.

eLife assessment

This manuscript reports important findings that help to understand the function of glutamate transporters and their effects on synaptic function at D1- and D2-MSNs within the dorsolateral striatum. These findings were evaluated to be of interest and well-executed. Overall, the majority of claims are supported by high quality data, but the evidence for some underlying mechanisms and region specificity were incomplete in the manuscript's current form.

eLife assessment

This valuable study assesses how change in reward contingency in the environment affects the dynamics of a realistic large-scale neural circuit model, human choice behavior, and fMRI responses measured in the same individuals. It is not entirely clear which predictions of the neural circuit model go beyond previous work, the current results seem incomplete and could likely be substantially strengthened. This study could be of interest to scientists studying the neural and computational bases of adaptive behaviour.

eLife assessment

Traditional approaches for the analysis of brain rhythms typically rely on measuring spectro-temporal properties of individual oscillations or the interactions between two different oscillations. This manuscript presents a novel multivariate approach that uses a state space model to simultaneously analyze the dynamics and interactions of multiple hippocampal oscillations. Such an approach represents a step forward in the field that highlights the need of taking into account the complexity of network interactions rather than trying to understand each component of the system in isolation.

eLife assessment

This work reports important findings regarding the regulation of ion channels by polyunsaturated fatty acids (PUFAs) through the identification of novel aromatic PUFA analogs with potent effects on the IKs channels, which allow for mechanistic insights into their mode of action. The experiments are solid, combining site-directed mutagenesis, electrophysiological and pharmacological approaches to dissect the different molecular mechanisms and sites involved in the functional interactions. This work will be of broad interest to ion channel biophysicists, physiologists, and medical chemists interested in drug development for LQT syndrome. The study presents some limitations that may need to be addressed or further discussed, in order to strengthen the conclusions reached in the study.

eLife assessment

This study is an important contribution to our understanding of somatic mutation mechanisms in plants, uncovering a surprising constancy in the yearly accumulation of somatic mutations regardless of the species' growth rates. The authors provide compelling evidence, leveraging rigorous sequencing analysis and innovative bioinformatic techniques, to demonstrate that many plant somatic mutations are accumulated in a replication-independent manner. This research is poised to captivate not only scholars focused on plant evolution and development, but also scientists broadly interested in mutation mechanisms in multicellular organisms.

eLife assessment

This study highlights a valuable finding that chromosomal instability can change immunes responses, in particular macrophages behaviours. The convincing results showing that the use of CD47 targeting and anti-Tyrp1 IgG can overcome changes in immune landscape in tumors and prolong survival of tumor-bearing mice. These findings reveal a new exciting dimension on how chromosomal instability can influence immune responses against tumor.

eLife assessment

This article examines the effect of indole-3-acetate dietary supplementation on a fatty liver phenotype upon exposure to a western diet. The strength of evidence is solid and the significance is useful. The results while not necessarily unique, further support the possible therapeutic value of supplementation in treating fatty liver disease.

eLife assessment

This study presents a valuable conceptual advance of how Vitamin A and its derivatives contribute to atherosclerosis. There is solid evidence invoking the contributions of specialized populations of T cells in atherosclerosis resolution, including use of multiple in vivo models to validate the functional effect. The significance of the study would be strengthened with more detailed interrogation of lesions composition and consolidation with previous work on the topic from human studies.

eLife assessment

Kim et al. investigated the molecular mechanism by which uremic toxin indoxyl sulfate induces trained immunity, resulting in augmented pro-inflammatory cytokine production. They also provided convincing evidence demonstrating that uremic sera from end-stage renal disease patients can generate trained immunity in healthy control-derived monocytes. This work is important as it introduces the new concept of trained immunity and its clinical implication.

eLife assessment

This paper covers a large range of effects of delivering SAR-CoV2 spike protein to the airway of mice with some in vitro analysis of effect on human cells. The observations will be valuable to the field in raising the possibility that the SAR-CoV2 spike protein has pro-inflammatory effects following uptake by macrophages and may lead to neutrophil recruitment and netosis, a pro-inflammatory mode of cell death. Two of the three reviewers felt the evidence was incomplete, based on what were felt to be some weak controls, but another expert felt the evidence was solid.

eLife assessment

This important study increases our understanding of the role of heterochromatin domain dynamics during early embryonic development by annotating the change in chromatin-associated proteins as a function of cell state. The authors provide solid evidence to demonstrate that DNA Topoisomerase II Binding protein (TOPBP1) is an ESC-specific chromatin-bound factor that potentially regulates chromocenter reorganization during the 2CLC-ESC transition through interaction with the SWI/SNF complex component SMARCAD1. However, a lack of mechanistic studies to interrogate how TOPBP1 and SMARCAD1 contribute to the reorganization of H3K9me3-heterochromatin or chromocenter concomitant with alterations in stem cell state leaves the current work incomplete.

eLife assessment

This study reports a new approach to determine the architecture of peptidoglycan (PG), the primary component of the bacterial cell wall, validating the pipeline through an architectural analysis of several members of the human gut microbiota. The technique is potentially valuable for this sub-field as it would enable researchers interested in peptidoglycan in a range of organisms to easily assess muropeptide composition in an easy, automated manner. However, there is some uncertainty about whether the pipeline was fully automated. Additionally, the use of the technique to support that PG cross-bridge length is a determinant of cell wall stiffness resulted in incomplete evidence that would need substantiating, more direct support.

eLife assessment

This manuscript describes mechanisms underlying the activation of the receptor tyrosine kinase FGFR1 and stimulation of intracellular signaling pathways in response to FGF4, FGF8, or FGF9 binding to the extracellular domain of FGFR1. Useful data on quantitative binding experiments are presented to demonstrate that FGF4, FGF8, and FGF9 exhibit distinct binding affinities towards FGFRs. The analysis of the data, however, is inadequate.

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

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

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 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 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 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 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

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 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

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.