eLife assessment

Leptin is a fat-derived hormone that curbs appetite, and mutation of leptin causes obesity and diabetes. This manuscript investigates leptin-responsive neural circuits, revealing a key inhibitory connection from leptin-sensitive neurons in the arcuate nucleus of the hypothalamus (AGRP neurons) to neurons in the dorsomedial hypothalamus. Toggling this inhibitory connection impacted leptin effects on feeding and metabolism. The study contains valuable data, including several interesting molecular genetic systems and the demonstration of GABA signaling in the DMH for the control of food intake, however, there is inadequate information about experimental design, including a lack of quantification and controls, and unjustified assumptions.

eLife assessment

This fundamental study by Rose and colleagues addresses key challenges in demographic inference in non-model systems with an innovative approach to model parameter calibration based on known historical events. Using this approach, they convincingly show that human specialization in Ae. aegypti mosquitoes likely evolved due to a past climate event around 5,000 years ago, and that recent rapid urbanization has continued to fuel its spread in West Africa in the past 20-40 years. This work will be of broad interest to population geneticists working on demographic inference, and to mosquito biologists working on the monitoring and control of this important vector species.

eLife assessment

This manuscript presents a series of important findings about the roles of the BAR-domain containing protein SNX32 in endosomal cargo sorting and in neurite outgrowth. The authors provide convincing evidence for their claims, which will be of interest for those working not only in membrane trafficking but also for cell biologists in general with interest in neurobiology.

eLife assessment

The fundamental work represents an important contribution to our understanding of the diversity of photosynthetic mechanisms across the branches of phototrophic life, with the first high-resolution structure (2.9 Å) of a photosynthetic complex from a primitive green alga. This is a valuable resource for understanding function and evolution of light-harvesting antennas. The evidence is convincing in suggesting that the mechanism found here is distinct from the classical antenna state transitions seen in other organisms studied thus far.

eLife assessment

Sanz Perl and colleagues provide important insights regarding the application of computational brain models from neurodegenerative diseases to evaluate brain stimulation protocols in silico. Solid evidence is provided for the disease-specificity of the framework, however, the real-world impact of such stimulation protocols to alleviate psychiatric and neurological symptoms remains to be evaluated.

eLife assessment

This study uses single cell sequencing to characterize transcriptional profiles of cells in a brain region called the PVT that plays many roles in brain function. The authors combine these data with dataset of neuronal connectivity and conclude there are transcriptomically distinguishable populations of neurons in the PVT with different function. These data deepen our understanding of an important brain region.

eLife assessment

This important study of mouse genetic variation in atrial septum formation, a trait correlated with the patent foramen ovale (PFO) cardiac defect, provides convincing evidence for 37 quantitative trait loci (QTL) affecting this trait, combining genetic mapping with transcriptome analysis to zero in on relevant pathways and candidate genes within the QTL, and validating the role of one gene in tissue culture. The paper provides an important resource for hypothesis generation and future studies, which could lead to novel diagnostic or therapeutic approaches that target atrial septal defects in common congenital heart disease.

eLife assessment

In this study, neurons were recorded and combined across the parahippocampal area while rats performed a memory-guided spatial navigation task. Sophisticated analytical tools were used to provide convincing evidence that neuronal populations in these areas show behavior-related changes that might indicate the encoding of errors by the system. The valuable results suggest that rate remapping is a likely mechanism to support changes in representations that support memory-guided behavior in these regions, most interestingly in neurons that code head direction.

eLife assessment

This important paper advances our understanding of the role of lipid peroxidation in loss of muscle mass and force-generating capacity during aging and hind-limb suspension. The evidence is in general solid, drawing from experiments in vivo and cell culture using multiple types of manipulations of the formation of lipid peroxides although some weaknesses were identified. The results should be of interest to those who study the molecular basis for sarcopenia and disuse atrophy of skeletal muscle.

eLife assessment

In this manuscript, the authors investigate the role of histone deacetylases in the spatial epigenetic control of zygotic gene expression in early gastrulation. They discover HDAC1 binding is maternally-controlled and that inhibition of histone acetylation blocks gastrulation and disrupts cell lineage integrity, tied to both positive and negative regulatory effects on gene transcription in space and time. The study contributes to a growing body of evidence that highlights a central role of histone acetylation-deacetylation dynamics in epigenetic regulation of gene expression and cell fating in early tissue patterning of the embryo.

eLife assessment:

This study provides valuable insight into the molecular mechanism of ion selectivity in the broader family of ATP-gated P2X receptors. The experimental data are of high quality, the evidence supporting the conclusions is convincing, and the work will be of broad interest to biophysicists working on ion channel selectivity.

eLife assessment

This important study aimed to identify rhythms linked to primary symptoms of Parkinson's disease such as involuntary shaking of the limbs and slowness. The evidence supporting the conclusions is solid, although validating their behavioural measures and considering the relationship between signatures from different brain regions would have strengthened the study. The work will be of broad interest to movement control, movement disorders, and brain stimulation fields.

eLife assessment

When a neuron is born it correlates with where it targets in the neuropil and this has been best demonstrated in the olfactory lobe of Drosophila. This important study uses sophisticated genetics and advanced live imaging to provide a compelling description of how neuronal dendrites explore the targeting field, eliminate excessive branches, and assort into the correct region during development. In the process, it develops valuable tools. It brings us closer to a comprehensive understanding of how the birth order of a neuron translates to dendrite patterning within the Drosophila antennal lobe circuit

eLife assessment

Black et al., provide evidence that levels of Paternally Expressed Gene 10 (PEG10) protein are regulated by Ubqln2 and that proteolytic fragments from PEG10 cleavage induce changes in gene expression, in particular genes that encode proteins involved in axon biology. Based on these data and the finding of an increase in PEG10 levels and alterations of proteins regulated by PEG10 in the spinal cord of ALS patients, they propose that abnormal induction of PEG10-regulated genes is involved in ALS. However, the evidence for these claims and PEG10 involvement could be strengthened, and the rigor of the work could be enhanced in places.

eLife assessment

This important study provides a provocative potential challenge to explain sensitivity across the visual field by using cortical magnification factors. The evidence supporting this theoretical challenge is solid in general, although the inclusion of subject-specific measurements of cortical magnification factors would have strengthened the study. The work will be of interest to vision researchers of both basic and medical science.

eLife assessment

This valuable study by Pasquereau and Turner examined the activity neurons in the subthalamic nucleus (STN) while monkeys performed a task in which they had to withhold their response during a delay period whose length was defined by a specific cue. The results indicate that the activity of STN neurons was modulated by reward size and delay. The results are potentially important for understanding how STN regulates behavior such as self-control, but the reviewers thought that the study is incomplete as the analyses, at least in the presented forms, have some potential problems and some analyses require clarification.

eLife assessment

This manuscript reports important findings regarding the evolution of snake venom proteins. The conclusions are convincing and are based on appropriate and validated methodology in line with the current state-of-the-art. The findings will be of interest to biologists and biochemists interested in the evolution of venoms as well as those generally interested in the evolution of molecular novelties.

eLife assessment

In this potentially important study, Mahbub and colleagues examine how the small GTPase ARL15 regulates ion transport. Using a complementary array of techniques, the authors gathered solid evidence for the binding of ARL15 to CNNM proteins, resulting in a proposal how this may affect the function of the TRPM7 channel. Additional experiments are required to fully substantiate the claims.

this paragraph shows and explains the key diffrences and requirements of teachers and professors as college students we are adults and have to be treated as such.

eLife assessment

These authors provide compelling evidence that gestational intermittent hypoxia, a component of sleep apnea during pregnancy, increases inflammation in the spinal cords of male mice. Increased inflammation is robustly linked to deficits in respiratory plasticity both biochemically and via functional depletion assays. These data are important given the fact that male infants have worse outcomes in the NICU and are at higher risk of sudden infant death syndrome.

eLife assessment

Brodbeck et al. offer a timely and important contribution to how neural signals in response to continuous temporal modulations (as seen in speech and language processing) can be modelled effectively using temporal response functions. They offer a convincing new approach that includes a novel application of a boosting algorithm in addition to an accessible and didactically useful toolbox for analysis. With further comparison to existing toolboxes, or a more extensive comparison of boosting and ridge regression via simulation, this work will have a compelling impact on methods in speech and language neuroscience, as well as in cognitive neuroscience more broadly.

eLife assessment:

This important study advances our understanding of host-derived lipid droplets' interaction with intracellular pathogens. The use of amoeba species Dictyostelium discoideum as a host for Legionella pneumophila infection is compelling and goes beyond the current state of the art, but the strength of evidence is incomplete, and the main claims are only partially supported by the data. With the experimental part strengthened, this paper would be of interest to cell biologists and microbiologists working on the interaction of microbes with host cells.

eLife assessment

This useful work describes the establishment and characterization of new cell lines derived from specific tissues of the fruit fly Drosophila. The evidence supporting the claims of the authors is solid, although the characterization of the cell lines is incomplete and the genomic findings are not presented in a user-friendly manner. These lines could be a useful resource that complements in vivo Drosophila genetics, improving biochemistry and facilitating high-throughput screening.

eLife assessment

This important study examines the association between SARS-CoV-2 infection and close contact among household members, measured using proximity sensors deployed after the first case was identified in the household. The authors provide solid evidence that transmission of SARS-CoV-2 within households is not dependent upon close contact, but the study suffers from a number of limitations that are fully acknowledged.

eLife assessment

Regulation of gene expression in many biological systems occurs either through a binary mode where gene expression is either on or off (digital regulation), or through an analog mode leading to a graded modulation of gene expression. In this manuscript, the authors report how these two regulatory modes are integrated into a one-way switch pattern to control the expression of the Arabidopsis floral repressor gene FLOWERING LOCUS C (FLC). They suggest that an analog regulation in the autonomous pathway precedes a digital regulation conferred by Polycomb silencing before cold exposure, and this temporal switch correlates with the strength of transcription at the FLC locus in different genetic backgrounds.

eLife assessment

This study combines different approaches to unravel the genetic basis of a pigmentation polymorphism in natural populations of a fascinating study system with well-studied ecology. The paper has the potential to be of general interest to biologists curious about the genetic basis of adaptive variation, which is especially relevant to evolutionary biologists and ecologists. The study reports substantial data and makes a strong case for the contribution of a duplication-derived gene acquiring a morph-specific function. Further information is required to implicate valkea in pigmentation morph formation and for diagnosing the duplicated segment as a supergene (associated with low recombination).

eLife assessment

This manuscript describes a valuable method to study the mechanism of action of essential genes and novel putative drug targets. Evidence for the effectiveness of the system, which is based on engineering pre-validated targets for RNA-mediated knockdown into genes of interest, is compelling, though some questions remain about the ease with which it can be put into general use.

eLife assessment

This study presents valuable findings from a study of identical twin pairs discordant and concordant for smoking to assess whether smoking has a direct effect on DNA methylation. The results are a valuable contribution as the study confirms the reported association between smoking and epigenetic profile is indeed due to the direct effects of constituents of tobacco smoke. The study design and methods applied by the authors are solid and provide a starting point for larger studies with rigorous laboratory approaches, as well as for assessing clinical impact. The work will be of broad interest to addiction researchers, genetic epidemiologists, and environmental scientists.

eLife assessment

This is an interesting and potentially significant study that adds important new information to our understanding of the mechanisms of lung epithelial repair after tissue injury. The authors have delineated a novel and non redundant role for the hippo pathway and the down stream regulators Yap/Taz in regulating repair of lung injury. These studies will inform future investigations into the mechanisms of repair of lung injury

eLife assessment

This study presents important results on the predicted impact of cancer screening disruptions in Australia during the COVID-19 pandemic based on consultation with public health stakeholders. The evidence presented is solid, as simulations were based on several previously validated breast, cervical, and bowel cancer screening decision models, though the scenarios were based on hypothetical disruptions that do not always match experienced disruptions. The work will be of interest to local policy-makers, public health specialists, and cancer epidemiologists.

eLife assessment

This work shows that higher socioeconomic status is associated with a higher risk of obesity, which should inform China's obesity public health programs and policies, and also be of interest to other countries and communities. The evidence supporting the conclusions is strong, but the data analysis is incomplete and would benefit from more rigorous approaches.

eLife assessment

This is important work that addresses a long-standing (but rarely acknowledged) question: given that multi-peaked tuning curves optimize Fisher information, why do early sensory areas typically have single-peaked tuning curves? This paper shows clearly, and convincingly, that multi-peaked tuning curves are likely to produce catastrophic errors at short times, so if speed is important, multi-peaked tuning curves should be avoided. This work should encourage neuroscientists to take into account the importance of stimulus encoding time in their formulations of models of neural coding.

eLife assessment

Endothelial cells mediate the growth of the vascular system, but they also need to prevent vascular leakage, which involves interactions with neighboring endothelial cells through junctional protein complexes. This important study provides a full mechanistic insight into how Sun1 is achieving its function, which supports the concept that nuclear anchoring is critical for proper mechanosensing and junctional organization. Although the evidence supporting the claims of the authors is solid and there are several merits and strengths in this study, a weakness is that some important controls are missing. The work will be of broad interest to cell biologists and vascular biologists.

eLife assessment

This manuscript presents a useful meta-analysis of genes with parent-specific expression from mouse published RNA-seq datasets, focusing on genes with weak allelic bias. A combination of systematic bioinformatic analysis and experimental validation convincingly shows that the number of parentally biased genes has been overestimated and the few novel ones lie at the periphery of known imprinted loci. The work will be of interest to genomicists with an interest in imprinting and its mechanisms.

eLife assessment

This study will be of interest to scientists within the field of hematopoiesis and ribosome biology. The paper provides evidence that haploinsufficiency of the mouse ribosomal protein gene Rps12 results in a number of phenotypes including defects in the production of specific blood cells and loss of hematopoietic stem cell quiescence. This work adds to the growing body of evidence that specific cell populations are particularly sensitive to disruption of mRNA translation machinery.

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 manuscript describes an approach for efficiently integrating diverse libraries into the C. elegans genome. The method 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 relative 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

The study has some significance for the field of dementia research and neurodegenerative diseases more broadly. Using the brain-age paradigm, the main findings are that having an older-appearing brain is associated with more advanced stages of amyloid and tau pathology, higher white matter hyperintensities, higher plasma NfL and carrying the APOE 34 allele. Findings were broadly similar in cognitively normal people and people with mild cognitive impairment and the evidence for these findings is convincing. Although sex differences are emphasized, the evidence for this is generally incomplete.

eLife assessment

This study presents important new findings regarding prenatal thalamocortical development. The authors present convincing evidence to overcome substantial methodological challenges in charting prenatal brain development in vivo. This work will be of interest to pediatric and developmental neuroscientists and neuroradiologists.

eLife assessment

The authors present valuable findings regarding the mechanism of high mannose induced cellular toxicity in cancer cells. The evidence supporting genomic instability as the anti-cancer activity of mannose is convincing with multiple orthogonal approaches showing consistent results, but the conclusions related to metabolic remodeling could be further strengthened by additional metabolomics data. While the findings are limited to genetically modified cancer cell lines cultured in vitro, this work will be of interest to cell biologists working on cancer metabolism.

eLife assessment

This potentially important study examines brain age based on resting state functional connectivity (RSFC) following an 18-month lifestyle intervention. The design of the intervention study is generally solid; the randomized controlled trial includes three intervention groups and assessments at two-time points of numerous health markers, however, the methodology for brain age prediction appears somewhat incomplete and would benefit from more rigorous approaches. The lack of control groups also prevents firm conclusions about the extent to which the observed RSFC changes are linked to the intervention. With these parts strengthened, the paper would be of broad interest to neuroscientists and biologists working on obesity, lifestyle interventions, and brain health.

eLife assessment

This paper reports a valuable new method for creating localized damage to candidate brain regions for functional and behavioral studies. The authors present solid support for their ability to create long-term local lesions with mm spatial resolution, although data supporting the extension to primates was incomplete. If the authors can demonstrate that the technique is applicable beyond the specific technical setup they employ, the paper is likely to be of broad interest to brain researchers working to establish causal links between neural circuits and behavior.

eLife assessment

This useful work proposes a framework inspired by chemotaxis for understanding how the brain might implement behaviours related to navigating towards a goal. The evidence supporting the conceptual claim is convincing, but some technical aspects are incomplete. The manuscript proposes a hypothesis that would be of interest to the broad systems neuroscience community, but the reviewers noted the relationship to existing similar hypotheses was not made sufficiently clear.

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 simple 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 paper presents valuable information 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 authors have used an extensive database to study associations between biphosphanate use and COVID-19. Using careful statistical analyses biphosphonate use appeared strongly associated with a lower risk of COVID-19. If these findings are confirmed in well-designed prospective studies biphosphanate use could be an attractive drug to prevent COVID-19.

eLife assessment

This paper provides a valuable systematic analysis of proteomic profiles associated with a particular murine Ryanodine receptor abnormality. Its analysis technique provides a solid and systematic set of data summarising the differences in different muscle types. The work emerges with insights into pathological mechanism of congenital muscle diseases linked to mutations in a range of other genes related to excitation contraction coupling in workers within the skeletal muscle field.

eLife assessment

This is a rigorous and compelling extension of previous normative modeling work that demonstrates that normative models incorporating lifespan trajectories of structural and functional connectivity provide a strong basis for brain imaging studies across a range of tasks including, univariate group difference assessment, classification, and building regression models. The work is important, rigorous and a valuable contribution to the field.

eLife assessment

This study presents a useful identification of an herbal drug combination for the treatment of plasma cell mastitis (PCM), a breast inflammation with severe and intense clinical symptoms. The data were collected and analyzed using a solid and in clinical trial of 160 patients (NCT05530226) and can be used as a starting point for understanding how herbal drug combinations could be helpful in the management of PCM patients.

eLife assessment

This paper presents an analysis of both contact tracing and whole-genome sequence data to track the elimination of dog-mediated rabies in Pemba Island, Tanzania. The work is a valuable contribution to the literature as it will have practical implications for the elimination of dog-mediated rabies in other regions/contexts. The main claims made are largely supported, but the strength of evidence for the cost-effectiveness is limited.

eLife assessment

This important study presents the idea of "Skeletal Age", defined as the age of one's skeleton as a consequence of fragility fracture, as a potential new tool to raise awareness about the increased risk of mortality following a fracture (particularly hip fractures) and thus improve the medical management of osteoporosis. The evidence is convincing and is derived from a very large database from the Danish National Hospital Discharge Registry. The proposed approach might represent a starting point for making doctor-patient communication about the health risks of an osteoporotic fracture more intuitive and possibly more effective.

eLife assessment

This study presents an important finding on the cause of the widely reported disruption of the excitation to inhibition (E-I) ratio change in Autism Spectrum Disorder (ASD) mouse models. The evidence supporting the main conclusions is solid and well-sampled. These results can be a starting point for studies that assess the functional role of daily oscillations of the E-I ratio in the pathophysiology of ASD, and possibly, reshape our understanding of the nature of the E/I balance alterations that contribute to normal and diseased circuits.

eLife assessment

Understanding specific tau-tau interactions that play key roles in Alzheimer's disease and tauopathies will enable the elucidation of the toxic tau species involved in the pathogenesis of these diseases and therapeutic development in this area. In this paper, the authors developed a series of NanoBiT complementation-based tau biosensors to monitor tau intramolecular and intermolecular interactions. This paper will be of high interest to a broad target audience including researchers in the field of biophysics, biochemistry, cell biology, neuroscience, neuropathology, and drug discovery as well as physicians.

eLife assessment

This important study reveals that slow plasticity in the neocortex is essential to prevent memory interference. The method of artificially increasing plasticity in the prefrontal cortex of rats during learning and its effect on sleep physiology, when memories are believed to be reprocessed, is solid. The work will be of interest to neuroscientists interested in learning and memory.

eLife assessment

Alamia and colleagues investigate the direction of traveling waves in the alpha frequency band during visual spatial attention. The authors' novel perspective adopted here is valuable to understanding the functional relevance of alpha oscillations for spatial attention. The observed pattern of results is consistent with distinct roles for travelling alpha waves in spatially opposite directions and makes a solid case for considering this new perspective on alpha rhythms in human cognitive function.

eLife assessment

Silva and colleagues present useful findings related to the isolation of an anti-S2 antibody that recognizes a previously uncharacterized SARS-CoV2 Spike (S) epitope, adding to the growing repertoire of anti-S antibodies that broadly cross-react against human and zoonotic coronaviruses. The evidence supporting the claims of the authors is solid, although antibody effectiveness as a prophylactic or therapeutic reagent in an animal model would have strengthened the study. The work will be of interest to biologists working to develop pan-coronavirus therapies.

eLife assessment

Germline inactivation of NPHP2, which encodes a protein that localizes to the transition zone at the base of the primary cilium, results in infantile kidney cysts and fibrosis. In this study, the authors provide solid evidence that increased cell proliferation and fibrosis precede cyst formation in Nphp-2 mouse models, that mutant renal epithelial cells are responsible for the phenotype, and that genetic inhibition of ciliogenesis in this model reduces disease severity. They also show that valproic acid, a drug that affects a number of cellular targets and is used to treat other human conditions, slows disease progression. One limitation of the study is that it provides limited insights into the mechanisms responsible for any of its interesting observations.

eLife assessment

This fundamental work substantially advances our understanding of how neighboring genes on a chromosome can be separately controlled in time and space. The evidence supporting the conclusions is compelling, with state-of-the-art genetic perturbations and imaging. The work will be of broad interest to geneticists and cell biologists.

eLife assessment

This study presents a useful tool called Phantasus, a web application to analyze gene expression data generated by microarray or RNA-seq technologies. The web application will help biologists end users, and non-bioinformatics experts to analyze new data or replicate transcriptomic studies. Local use of the Phantasus through its Bioconductor package reveals an incomplete functionality concerning the current best practices in analyzing bulk RNA-seq data.

eLife assessment

In this important work, the authors present a sequence-based approach using transfer learning and Restricted Boltzmann Machines to predict antigen immunogenicity and specificity. The evidence and methodology are compelling. This work should be of interest to immunologists, computational biologists, and biophysicists.

eLife assessment

This important study demonstrates a non-canonical, cancer-cell intrinsic role of the ectonucleotidase CD73 in the regulation of cancer cell metabolism. The evidence supporting the claims is solid, although further experimental details and conditions would strengthen the evidence provided.

eLife assessment

This important study by Bonnet et al addresses the question of how AMPA receptor numbers at the synapse are regulated during basal conditions and during chemically induced Long Term Potentiation. Specifically, the study aims to determine the molecular mechanisms that contribute to the intracellular trafficking of AMPA receptors and determine their insertion into the synaptic plasma membrane. Using compelling methodology, the authors dissect the distinct roles of two proteins that bind to the C-terminal domain of the AMPA receptor subunit GluA1: 4.1N and SAP97. The findings will be of interest to anyone trying to understand molecular events contributing to synaptic plasticity in health and disease, and more broadly, the method could be adapted for tracking intracellular movements of a wide range of proteins.

eLife assessment

This manuscript significantly advances our understanding of the development of drug resistance in the HIV-1 protease. The paper addresses the fundamental relationship between resistance mutations and inhibitor structure and will be useful in the design and development of the next generation of inhibitors.

eLife assessment

This important study evaluates the immunogenicity of 3rd and 4th doses of SARS-CoV2 vaccinations in patients with cancer. Their study is notable in that neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose. With the definitions and patient population better described, this paper would be of interest to those studying the effects of repeated COVID boosters on Omicron immunity.

eLife assessment

This paper proposes a new computational model for replay that is biologically realistic and accounts for a number of important phenomena in hippocampal replay. This is an important study with implications for multiple subfields. Whilst the majority of claims are convincingly supported by the data, simulation analyses for some crucial aspects of replay literature are currently incomplete.

eLife assessment

The authors developed a two-photon fluorescence microscope coupled with adaptive optics (AO-2PFM), allowing in vivo imaging of the mouse retinal structure and function. This new imaging system will be important for exploring normal retinal physiology and pathological alterations in retinal disease models.

eLife assessment

The overarching question of the manuscript is important and the findings inform the patterns and mechanisms of phage-mediated bacterial competition, with implications for microbial evolution and antimicrobial resistance. The evidence in the manuscript is, however, still incomplete and some of the conclusions made are not supported by the data. This manuscript would additionally be strengthened by a clearer narrative, to enable readers to more easily extract the key message this paper wants to convey.

eLife assessment

This is a well-done study to understand how Rab27 and its effectors regulate insulin secretion. The present work examines the relative hierarchy of exophilin-8 and melanophilin using single vs double knockouts and rescue experiments to show that melanophilin functions downstream of and potentially redundantly from Exo8. Imaging and protein co-localization studies were done in a rigorous way. The data are solid, and some additional data will make the work fully compelling. Overall this is an important study that sheds new light on the regulation of insulin granule exocytosis.

eLife assessment

This study presents a valuable finding on the role and function of the Gaq axis on the inflammatory response during decidualization essential for early pregnancy. The evidence supporting the claims of the authors is solid, although some of the methodology and data interpretation require further clarification and justification. The work will be of interest to reproductive biologists and clinicians.

eLife assessment

This important study reports Foxc2+ cells in the testis might be the true spermatogonial stem cells (SSCs). The data supporting this claim are solid and the finding, if proven true, would have a great impact on reproductive biology and stem cell biology as the genes responsible for maintaining the quiescent state of SSCs during spermatogenesis remain elusive.

eLife assessment

This paper reports valuable data on a classic model for cell fate specification in the C. elegans gonad. The data, though extensive, provide so far incomplete support for the major claims of the paper, especially regarding the functional significance of their conclusions. The paper will be of interest to developmental biologists studying transcriptional control of cell fate specification in animals, especially once issues around the functional significance of the condensates are resolved.

eLife assessment:

This manuscript describes development of a new algorithm for integrative analysis of multi-omics data. This work should be of potential interest to scientists performing bioinformatic pathway discovery in multi-omic datasets especially those that relate to signaling.

eLife assessment

This manuscript presents valuable findings that bring together two important topics in cell biology: the function of membrane contact sites and cell migration. The authors describe a role of the ER tether protein VAP-A in focal adhesion dynamics and cell motility. Although the authors present solid evidence to support some of the main claims of the paper, some of the other claims would benefit from stronger experimental support. Nonetheless, this paper will be of interest to those cell biologists and biophysicists working on adhesion, migration, and membrane contact site biology.

eLife assessment

This paper is of interest for skeletal biologists studying bone marrow stem/progenitor cells and bone remodeling. Using Adipoq-Cre-driven conditional deletion of Csf1 that encodes M-CSF and reanalyzing publicly available scRNAseq data, the authors recognize a subpopulation of bone marrow cells (i.e. AdipoQ-lineage progenitors) as an important source of M-CSF. The authors found that M-CSF production from these bone marrow cells influences the development of macrophages and osteoclasts as well as bone mass, including the bone loss associated with estrogen deficiency. This is a clearly written and nicely presented study that has potential to offer important new information regarding the source of M-CSF in the bone marrow.

eLife assessment

This study provides a valuable data resource to study the systemic effects of severe COVID-19. It shows compelling evidence that the transcriptional response to COVID-19 is coordinated across the body, and it highlights cell interactions between macrophages and endothelial cells in COVID-19. This analysis and the associated resource will be valuable to understand the pathogenic mechanism of long-COVID.

eLife assessment

This important study develops a new technical advancement in ex vivo live imaging of hematopoietic tissues to monitor blood cells in their native microenvironment. The new method for live imaging and tracking is compelling, and the strength and breadth of hematopoietic analysis are convincing. This work provides a very useful new system for immunologists and cell biologists, which will supply new perspectives on the system-level mechanisms of cell differentiation and innate immunity.

eLife assessment

This paper is of interest to immunologists conducting single-cell analyses of T-cell recognition. It provides a means of curating datasets to ensure T cell-antigen pairs are identified. The data generated through this method often suffers from a relatively high background, so the authors present a computational approach to enhance the signal-to-noise of this type of analysis. At this stage, it is unclear if the thresholds and filtering steps described by the authors can be generally applied to other datasets of different qualities than the one used here.

eLife assessment

This study presents a valuable mathematical model for the adaptive dynamics of cancer evolution in response to immune recognition. The mathematical analysis is rigorous and convincing, and overall the framework presented could be used in the future as a solid base for analytically tracking tumor evasion strategies. However additional discussion is needed to clarify certain gaps between the theory and cancer evolution in real systems. The work will be of interest to evolutionary cancer biologists and potentially it may also have implications for the design of clinical interventions.

eLife assessment

This study presents a valuable finding on the critical features and patterns of m1A modification and in neurons and OGD/R-treated neurons. Moreover, the authors identified m1A modifications on different RNAs and explored the possible effects of m1A modification on the functions of different RNAs via an integrated approach of omics and bioinformatics. The evidence supporting the claims of the authors is solid, although inclusion of more in-depth studies to analyze the transcription factors for the upstream regulation would have strengthened the study. The work will be of interest to neurobiologist and scientists in the field of RNAs.

eLife assessment

Scott et al use Drosophila as a model to study the sialylation pathway and its role in nervous system function. Surprisingly, they find that the critical substrate for sialylation, CMP-Neu5Ac, is 'outsourced' to glia. This significant study presents a new twist in mechanisms underlying protein glycosylation and uncovers a new layer in the complex interplay of neurons and glia.

eLife assessment

This work is an attempt to establish conditions that accurately and efficiently mimic a drought response in Arabidopsis grown on defined agar-solidified media – an admirable goal as a reliable experimental system is key to conducting successful low water potential experiments and would enable high-throughput genetic screening (and GWAS) to assess the impacts of environmental perturbations on various genetic backgrounds. The authors compare transcriptome patterns of plants subjected to water limitation imposed using different experimental systems. The work is valuable in that it lays out the challenges of such an endeavor and points out shortcomings of previous attempts. However, a lack of water relations measurements, incomplete experimental design, and a lack of critical evaluation of these methods in light of previous results render the proposed new methodology inadequate.

eLife assessment

This study links chromatin remodeling with antifungal drug resistance in Cryptococcus neoformans. The work is important because it reveals a new facet of how drug resistance can emerge and associates. The work presented is well done but the story is incomplete since there are questions about methods and association that need to be addressed. Establishing a link between chromatin remodeling and antifungal resistance is a finding that would be of interest to infectious disease researchers, cell biologists, and drug developers.

eLife assessment

This study uses a combination of compelling biochemical and genetic approaches to identify a highly mutagenic DNA polymerase, which drives a wide spectrum of mutations when overexpressed. The important findings advance the understanding of mutagenesis in mycobacteria. The work will be of interest to bacteriologists interested in mutagenesis and the emergence of drug resistance.

eLife assessment

There are many strengths in this paper that examines patterns of epididymal blood and lymphatic vasculature, supported by quantitative methods, and well-conducted 3D imaging studies (graphics and videos). Minor weaknesses include the lack of higher magnification images and the organization of image panels in some figures. Overall, this is a very important contribution to the epididymis research field.

eLife assessment

This study, of interest to population geneticists and evolutionary biologists alike, aims at investigating temporal variation in patterns of germline mutation during the evolution of human populations. The authors suggest that shifts in mutation spectra occur frequently, over a few thousands of generations, possibly as a consequence of changes in environmental exposure, or of genetic modifiers. There are several important aspects of methodology that need to be clarified, and several additional tests have to be done to confirm that the reported observations are not the result of methodological artifacts. The paper also overstates certain weaknesses of previously published papers on mutation spectrum evolution as well as the generation time hypothesis; correcting these oversimplifications would more accurately capture what the paper's new analyses add to the state of knowledge in these areas.

eLife assessment

This manuscript provides compelling evidence that macrophages transfer mitochondria to cancer cells and that transferred mitochondria stimulate proliferation in recipient cells. The usage an array of clever cell biology-based tools provides compelling evidence for these claims despite the difficulties associated with studying a relatively low probability event. Solid evidence supports the proposed model that transferred mitochondria induce proliferation by stimulating ERK signaling in a ROS dependent manner, although at present some aspects of the proposed model are incomplete. The work has broad significance for both mitochondrial biology and cancer biology as the authors show clear evidence of mitochondrial transfer in mouse models of human tumors.

eLife assessment

Opioid-induced respiratory depression is one of the side effects of opioid drugs. Although opioid overdose deaths are highly prevalent, our knowledge of the neural circuits underlying respiratory depression in the brainstem is far from complete. The present study used a variety of sophisticated experimental techniques to convincingly reveal the identity of brainstem components that are part of the neural circuits involved in the mediation of opioid respiratory effects, together with defining potential synaptic underlying mechanisms. They focused on two regions of the brainstem, namely the Kolliker-Fuse and the preBötzinger Complex, and proposed a combination of three complementary processes at pre- and post-synaptic sites in both KF and preBötC regions to explain respiratory depression linked to opioid exposure. This study provides very important findings on the circuitry involved in opioid-induced respiratory depression, and the present results are of broad interest to the respiratory control research community, as well as medically relevant.

eLife assessment

Candida morphogenesis is important for virulence. This study provides important new information as to how C. albicans regulates the switch from budding to hyphal morphology. Their results identify transcription factors involved in the process of hyphal morphogenesis in the host. The results are convincing and will be interesting to scientists in the fields of medical mycology and cell biology.

eLife assessment

This manuscript analyzes large-scale Neuropixels recordings from visual areas and hippocampus of mice passively viewing repeated clips of a movie and reports that neurons respond with elevated firing activities to specific, continuous sequences of movie frames. The important results support a role of rodent hippocampal neurons in general episode encoding and advance understanding of visual information processing across different brain regions. The strength of evidence for the primary conclusion is solid, but some technical limitations of the study were identified that merit further analyses.

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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. If more thorough statistical analysis of the response of neuronal populations supports the claims, the paper will be of interest to a broad audience of neuroscientists interested in reward processing in the brain.

eLife assessment

This study examines the inflammatory and immune response to live E. coli bacterial infection in neonatal and juvenile mice. Important information is described on the roles of Class II MHC and interferon responsive genes in regulating the host response to infection. This study will inform future efforts to further elucidate the impact of bacterial infections on lung development.

eLife assessment

This is a valuable study showing that fast, but transient, modifications of the synaptic efficacies, alone, can support the integration of information over time. Convincing supportive evidence is provided by showing that feed-forward networks, when equipped with such short-term synaptic modulations, can successfully perform a variety of temporal integration tasks at a performance level comparable with that of recurrent networks. These results will be of interest to both neuroscientists and researchers in machine learning.

eLife assessment:

Bone marrow stromal cells (BMSCs) can differentiate into a variety of cell types such as osteoblasts, chondrocytes, and adipocytes. The authors of this important study provide compelling and strong evidence that ablating O-GlcNAc transferase (OGT) in BMSCs impairs bone formation but promotes marrow adiposity. The results show that the balance of osteogenic and adipogenic differentiation of BMSCs is controlled by reciprocal O-GlcNAc regulation of lineage-specifying transcription factors, and highlights the importance of an intracellular glycosylation process of specific proteins in bone formation and bone marrow adipocytes.

eLife assessment

This theoretical work deals with the problem of homeostasis of protein density within cells, relying on the Pump and Leak model.  The model makes predictions both for growing and senescent cells, which they compare to experimental data on budding yeast. The work extends previous works and makes biologically-relevant predictions, which will be of interest to both theorists and experimentalists interested in cell physiology.

eLife assessment

The analysis of 89,000 independent somatic mtDNA mutations provides compelling evidence that allows the authors to refute the idea that reactive oxygen species (ROS) are a main driver of mtDNA mutagenesis, although ROS effects may still be tissue-dependent. These are fundamental results with convincing evidence, and they should appeal to a broad audience. The discovery of transversion mutations (C>A/G>T and C>G/G>C), which previously were assumed to be almost nonexistent, will nevertheless require additional validation.

eLife assessment

The study presents analyses linking cell-types to monogenic disorders using over-expression of known disease-associated genes in single-cell data to identify 110 disease-affected cell types for 714 Mendelian diseases. Overall this important study combines multiple data analyses to quantify the connection between cell types and human disorders. While some of the analyses are compelling, updates to the method are needed to ensure that statistical inference is appropriately stringent and rigorous.

eLife assessment

This important study demonstrates that the Drosophila FUS protein, the human homolog of which is implicated in amyotrophic lateral sclerosis (ALS) and related conditions, interacts with RNAs containing GGGGCC repeats and can regulate their translation by altering three-dimensional structures caused by these repeats. The study is carefully executed and the data provide convincing evidence for its major claims. This work will likely be of interest to researchers studying RNA-binding proteins, and to those working on ALS and related diseases.

eLife assessment

This paper presents a valuable advance in the ability to manipulate the integrity of the barrier between endothelial cells. A wide range of data are presented, offering solid support for the effectiveness of the method. This work is likely to attract a diverse audience of both cell biologists and researchers developing tools to manipulate cell and tissue function.

eLife assessment

This important study investigates the dynamic activation mechanism of a key mitotic kinase complex, Aurora B/INCENP. The method of generating specifically phosphorylated forms of the complex is elegant, supporting a compelling biochemical analysis of how these sites synergistically activate Aurora B. However, the limitations of the molecular dynamics approach and how these models compare to previous structural studies are incompletely addressed. This work will be of interest to cell biologists and biochemists studying cell division and kinase regulation.

eLife assessment

This important study advances our understanding of the composition and circuit organization of the preBötzinger complex (preBötC)-the brainstem region that generates the respiratory rhythm and coordinates breathing with different motor and physiological behaviors in mammals. The reviewers agreed that the evidence supporting the conclusion that the preBötC is composed of a segregated subgroup of output neurons that modulates orofacial muscle activity is compelling and based on technically elegant, state-of-the-art combinatorial dual viral transgenic and optogenetic approaches in rats. After the cytoarchitectonic analyses are strengthened, the work will be of interest to neuroscientists and physiologists working on the neural control of breathing and other motor systems.

eLife assessment

This study on snapping shrimp morphological weaponry presents important findings on trade-offs in investment in costly weaponry traits as related to body size and reproduction. Convincing evidence is based on the collection of an exceptional number of fields samples, the inclusion of three shrimp species, and the measurement of numerous morphological and behavioral traits. The evidence shows that there are size-dependent trade-offs, where males and females differ in weapon investment, as weapons are beneficial to males but expensive for females. The findings will be of broad interest to evolutionary biologists and researchers working in the field of animal behavior.

eLife assessment

This valuable study carried out a genetic screening of Drosophila lines expressing wild-type or ALS/FTD mutations of ubiquilin 2, and identified several suppressors and enhancers of ubiquilin 2 phenotypes. The study particularly focused on two genes involved in axon guidance pathways, unc5 and beat-1b. The evidence supporting the conclusions is solid, although some of the presented data are unrelated to the main findings, which detracts from the focus of the work. This work will be of interest to a broad audience studying ALS/FTD and neurodegenerative diseases.

eLife assessment

This fundamental study describes the structure-based design of novel hybrid inhibitors targeting a human sodium channel which is a pain target. Exceptionally strong evidence for key claims was produced with a structural biological pipeline for iterative structural determination of drugs complexed with an engineered sodium channel. This work is expected to be of interest to biophysicists, drug developers, neurobiologist, and pain researchers.

eLife assessment

This valuable study provides a synthesis of sector models for cellular resource partitioning in microbes, and shows how a simple flux balance model can quantitatively explain growth phenomena from numerous published experimental datasets. The study is overall convincing, although there are a few incomplete points regarding parameter values (justification and discussion of robustness). This work should be of interest to the microbial physiology community.

eLife assessment

In this useful and potentially important manuscript, Mazanek and colleagues combine computational analysis and in vitro experiments to develop a comprehensive analysis of the ability of pyrin-only proteins (POPs) to inhibit inflammasome assembly. The results lead the authors to propose that a mixture of favorable and unfavorable interaction surfaces is required for a POP to inhibit a given inflammasome component. The results presented are solid, but additional experimentation is required to fully justify the authors' model.

eLife assessment

Mutations in mitochondrial genes can lead to deafness but the mitochondrial biology of sensory hair cells is not well understood. In this study, high-resolution imaging of mitochondrial development in sensory hair cells of normal and mutant zebrafish lateral line systems was described. The authors provide evidence that the formation of the mitochondrial architecture requires normal hair cell activity. This paper is of potential interest to researchers interested in metabolic homeostasis and sensory hair cell biology.

eLife assessment

This important work presented is of interest to the electron microscopy community, which expanding to more and more cell biologists. The field has long searched for a suitable method to combine the pristine preservation of vitrified samples with a volumetric imaging modality that reveals subcellular architecture at sufficient contrast for ultrastructural analyses, and the authors describe here the use of novel ion beams for imaging cellular samples in three dimensions, concluding that one of the four plasma sources tested produces the highest quality images. This allows them to provide several recommendations for imaging along with software for improving collected images. This approach should be very useful for addressing many biological questions.

eLife assessment

This manuscript reports important and valuable new data about the intriguing role of the lncRNA Charme during cardiac development. Whilst the majority of claims are convincingly supported by the data, the evidence for the cardiac phenotype and the mechanism by which Charme/MATR3 interacts is currently incomplete and requires additional experimental support. This paper is of general interest to cardiac developmental biologists as well as to anyone studying non-coding RNAs.

eLife assessment

This valuable work provides insight into how Plasmodium falciparum optimises the balance between infection of the human host and investment in onward transmission to the mosquito. Based on the appropriate and validated methodology most of the results are convincing, nonetheless, some conclusions are incomplete and require further support.

eLife assessment

A small proportion of the genomes of humans whose ancestors lived outside Africa traces back to an interbreeding event with Neanderthals. While we know that selection has generally acted to remove Neanderthal ancestry, intense interest has focused on understanding the contribution to current human phenotypic variation. This paper uses a new set of approaches to carefully quantify this contribution, taking into account various complicating factors. The work will be of interest to colleagues in human evolution and evolutionary biology more generally.

eLife assessment

This manuscript will be of interest to centrosome and cilia cell biologists. It evaluates the in vivo and in vitro role of PCM1, and by extension, centriole satellites in ciliogenesis. The major strength of this study is the detailed characterisation of Pcm1-/- mutant mice, which reveals a role for PCM1 in biogenesis of specific types of cilia, such as motile cilia on ependymal cells. The claims are generally well supported by the data, but the mechanistic basis for the cell-type specific requirement for PCM1 in ciliogenesis remains to be fully clarified.

eLife assessment

In the present study, the authors discovered the inhibitory neurons that are potentiated during the repetitive visual stimuli and control neurons that transmit looming information to evoke escape responses. Thus, the study elucidated a principle of habituation using a model vertebrate zebrafish.

eLife assessment

The RNA-binding protein Tristetraprolin (TPP) regulates the abundance of mRNAs encoding proinflammatory cytokines. The study by Scinicariello and collaborators examined mechanisms regulating the turnover of TTP in cultured cells and identified the ubiquitin E3 ligase HUWE1 as a regulator of TPP degradation. The conclusions are largely supported by the cellular and biochemical experiments. This paper thus implicates the HUWE1-TPP axis in regulating macrophage inflammatory responses at the post-transcriptional steps.

eLife assessment

This manuscript reports valuable findings regarding the evolution of nitrogenases through ancestral sequence reconstruction and resurrection. The results are solid and support the conclusions of the study, and highlight the historical constraints that have been acting on this enzyme. The findings will be of interest for people interested in enzyme evolution in general and particularly for those interested in the evolution of nitrogenases.

eLife assessment

This is an important paper that combines comparative analysis and experimental assays to investigate the role of protein-coding and regulatory changes at TRNP1 in mammalian brain evolution. The evidence supporting a contribution of TRNP1 is convincing, although the link between protein-coding changes and trait evolution is stronger and more readily interpretable than the data on gene regulation. The work will be of interest to researchers in the areas of mammalian evolution, brain evolution, and evolutionary genetics.