eLife assessment

This important study by Yogesh and Keller provides a set of results describing the response properties of cholinergic input and its functional impacts in the mouse visual cortex. They found that cholinergic inputs are elevated by locomotion in a binary manner regardless of locomotor speeds, and activation of cholinergic input differently modulated the activity of Later 2/3 and Layer 5 visual cortex neurons induced by bottom-up (visual stimuli) and top-down (visuomotor mismatch) inputs. The reviewers found that the experiments are cutting-edge and well executed, and the results to be mostly convincing.

eLife assessment

This important study examined the mechanisms underlying reduced excitability of ventral tegmental area dopamine neurons in mice that underwent a chronic mild unpredictable stress treatment. The authors identify NALCN and TRPC6 channels as key mechanisms that regulate spontaneous firing of ventral tegmental area dopamine neurons and examined their roles in reduced firing in mice that underwent a chronic mild unpredictable stress treatment. The authors' conclusions on neurophysiological data are supported by multiple approaches and convincing, although the relevance of the behavioral results to human depression remains unclear.

eLife assessment

Using state-of-the-art single-nucleus RNA sequencing, Yao et al. investigate the transcriptomic features of neural stem cells (NSCs) in the human hippocampus to address how they vary across different age groups and stroke conditions. The authors report alterations in NSC subtype proportions and gene expression profiles after stroke and an exemplary gene elevated in NSCs and reactive astrocytes in stroke patients. Although the study is valuable, the significance is restricted by technical limitations and the incomplete evidence supporting the main conclusions.

eLife assessment

This important multicenter study provides convincing evidence that the auditory noise emitted during online transcranial ultrasound stimulation (TUS) protocols can pose a considerable confound and is able to explain corticospinal excitability changes as measured with Motor Evoked Potentials (MEP). The findings lay the ground for future studies optimising protocols and control conditions to leverage TUS as a meaningful experimental and clinical tool. A clear strength of the study is the multitude of control conditions (i.e., control sites, acoustic masking, acoustic stimulation). These findings will be of interest to neuroscience researchers using brain stimulation approaches.

eLife assessment

This important study utilizes a virus-mediated short hairpin RNA (shRNA) approach to investigate in a novel way the role of the wild-type PHOX2B transcription factor in critical chemosensory neurons in the brainstem retrotrapezoid nucleus (RTN) region for maintaining normal CO2 chemoreflex control of breathing in adult rats. The solid results presented show blunted ventilation during elevated inhaled CO2 (hypercapnia) with knockdown of PHOX2B, accompanied by a reduction in expression of Gpr4 and Task2 mRNA for the proposed RTN neuron proton sensor proteins GPR4 and TASK2. These results suggest that maintained expression of wild-type PHOX2B affects respiratory control in adult animals, which complements previous studies showing that PHOX2B-expressing RTN neurons may be critical for chemosensory control throughout the lifespan and with implications for neurological disorders involving the RTN. When some methodological, data interpretation, and prior literature reference issues further highlighting novelty are adequately addressed, this study will be of interest to neuroscientists studying respiratory neurobiology as well as the neurodevelopmental control of motor behavior.

eLife assessment

This study on the effects of fasting on safety learning rests on basic premises and concepts that both reviewers found difficult to follow. If these can be clarified, the findings may well be useful and of some utility for the field of emotional learning as well as experimental clinical psychology. However, the main claims of the study are only partially supported and are therefore incomplete.

eLife assessment

This potentially valuable study uses classic neuroanatomical techniques and synchrotron X-ray tomography to investigate the mapping of the trunk within the brainstem nuclei of the elephant brain. Given its unique specializations, understanding the somatosensory projections from the elephant trunk would be of general interest to evolutionary neurobiologists, comparative neuroscientists, and animal behavior scientists. However, the anatomical analysis is inadequate to support the authors' conclusion that they have identified the elephant trigeminal sensory nuclei rather than a different brain region, specifically the inferior olive.

eLife assessment

This study investigated the role of specific proteins in a mouse model of developmental epilepsy. The significance of the work is important because a new mouse model was used to simulate a type of developmental epilepsy. The work is also significant because the deletion of two proteins together, but not separately, improved the symptoms, and data were convincing.

eLife assessment

The authors used an innovative modified 10X genomic sequencing method to detect cPCDHg is-forms in pyramidal neurons. With solid electrophysiological recordings, they showed that neurons expressing the same sets of cPCDHg isoforms are less likely to form synapses with each other. These valuable findings confirms previous results and extend our understanding of cPCDHg diversity and neuronal connectivity.

eLife assessment

This important study tests the hypothesis that a high autism quotient in neurotypical adults is strongly associated with suboptimal motor planning and visual updating after eye movements, which in turn, is related to a disrupted efference copy mechanism. The implication is that such abnormal behavior would be exaggerated in those with ASD and may contribute to sensory overload - a key symptom in this condition. The evidence presented is convincing, with significant effects in both visual and motor domains, adequate sample sizes, and consideration of alternatives. However, the study would be strengthened with minor but necessary corrections to methods and statistics, as well as a moderation of claims regarding direct application to ASD in the absence of testing such patients.

eLife assessment

This study provides a valuable contribution to understanding the neural mechanisms underlying age-related changes in attention and speech understanding. The large dataset (N=105) provides convincing evidence for how speech recognition behaviour and neural tracking of speech separately evolve in about 2 years. The work would be of interest to psychologists, neuroscientists, and audiologists.

eLife assessment

This paper explores the relationships among evolutionary and epidemiological quantities in influenza, and presents fundamental findings that substantially advance our understanding of the drivers of influenza epidemics. The authors use a rich set of data sources to gather and analyze compelling evidence on the roles of genetic distance, other influenza dynamics and epidemiological indicators in predicting influenza epidemics. The central findings highlight the significant influence of genetic distance on A(H3N2) virus epidemiology and emphasize the role of A(H1N1) virus incidence in shaping A(H3N2) epidemics, suggesting subtype interference as a key factor. This paper also makes relevant data available to the research community.

eLife assessment

In this important study, the authors develop a promising experimental approach to a central question in ecology: What are the contributions of resource use and interactions in the shaping of an ecosystem? For this, they develop a synthetic ecosystem set-up, a variant of SELEX that allows very detailed control over ecological variables. The evidence is convincing, and the work should be of broad interest to the ecology community, leading to further quantitative studies.

eLife assessment

This valuable study describes mice with a knock out of the IQ motif-containing H (IQCH) gene, to model a human loss-of-function mutation in IQCH associated with male sterility. The infertility is reproduced in the mouse, making it a compelling model, but some of the mechanistic experiments provide only indirect and thus incomplete evidence for interaction between IQCH and potential RNA binding proteins. With more rigorous approaches, the paper should be of interest to cell biologists and male reproductive biologists working on the sperm flagellar cytoskeleton and mitochondrial structure.

eLife assessment

This study presents a valuable examination into the role Notch-RBP-J signalling in regulating monocyte subset homeostasis. The data were collected and analysed using solid and validated methodology and can be used as a starting point for exploring the mechanisms involved in RBP-J signalling in non-classical monocytes. The data presented strongly confirm the authors conclusions. However, this paper primarily focuses on providing a description, and additional studies are necessary to fully elucidate the mechanisms through which RBP-J deficiency contributes to the specific increase in Ly6Clo monocyte numbers in both the blood and lungs.

eLife assessment

This study provides an important finding that the local abundance of metabolites impacts the biology of the tumor microenvironment by utilizing kidney tumors from patients and adjacent normal tissues. The evidence supporting the claims of the authors is convincing although certain caveats need to be taken into consideration as the authors acknowledged in the paper. The work will be of interest to the research community working on metabolism and on kidney cancer especially.

eLife assessment

This study is useful as it provides further analysis of previously published data to address which specific genes are part of the masculinizing actions of E2 on female zebra finches, and where these key genes are expressed in the brain. However the data supporting the conclusion of masculinizing the song system are incomplete as the current manuscript is a re-analysis of differential gene expression modulated by E2 treatment between male/female zebra finches without manipulation of gene expression. The conclusions (and title) regarding song learning are not completely supported, with no gene manipulation or song analysis. The use of WGCNA for a question of sex-chromosome expression in species without dosage compensation is considered inadequate. As the experimental design did not include groups to directly test for song learning, and there was also no analysis of song performance, these data were also considered inadequate in that regard.

eLife assessment

This landmark study presents MetaPathPredict, a method that uses a stacked ensemble of neural networks to predict the presence or absence of KEGG modules based on annotated features in the genome. The evidence supporting the conclusions is compelling, with a tool that allows for prediction of KEGG modules in sparse gene sequence datasets.

eLife assessment

In this important study, the authors explore the importance of developmental changes in cortico-DRN innervation in the balance of behavioral control in a foraging task. The authors report somewhat convincing evidence that while juvenile mice and adult mice both perform the task, juveniles exhibit more impulsive behavior due to reduced efficacy of cortico-DRN projections. The authors conclude that the development of cortico-DRN (esp mPFC) projections allows 5HT input to promote perseveration (or exploitation) in the balance of behavioral control. However, reviewers raised issues regarding the strength of the evidence without further experiments.

eLife assessment

Using single-cell sequencing, high-resolution imaging, and inducible genetic deletion of yolk-sac (YS) derived macrophages, the authors present a useful map of fetal liver macrophage subpopulations and provide important data demonstrating that heterogeneous fetal liver macrophages regulate erythrocyte enucleation, interact physically with fetal HSCs, and may regulate neutrophil accumulation in the fetal liver. These novel findings, although yet incomplete, might provide a solid foundation for further investigating the effects of macrophages on HSC function during fetal hematopoiesis and into adulthood and will be useful for the field of macrophage biology and developmental hematopoiesis.

eLife assessment

This manuscript addresses a non-canonical function of the Class 2 ribonuclease III Drosha in the regulation of adult neural stem cell fate, important for understanding how these cells generate neurons or oligodendrocytic cells.<br /> Overall, this manuscript has many strengths. The authors identify 165 proteins, several of them enriched in neural stem cells, and potentially specific for miRNA dependent or independent Drosha macromolecular complexes.<br /> While the authors provide systematic and convincing evidence on the biochemical interactions among the key players in this cascade, the significance of these interactions for neural stem cell fate determination in vivo remains unclear, as the in vitro cellular systems used to document most of the data reported in the paper may not (fully) represent resident neural stem cells in the adult hippocampus. The in vivo function mediated by Drosha/ Safb1 needs to be substantiated by more evidence and/or complementary approaches.

eLife assessment

The authors observed a positive correlation between FSH and fat mass, as well as a negative association with the appendicular lean mass/fat mass ratio. These valuable findings in male subjects within a hypogonadal setting following Degarelix treatment imply that FSH might function as a predictor, similar to observations in women. However, it's important to note that the analysis is incomplete, as other major confounding factors such as testosterone were not included.

eLife assessment

The findings are important and would potentially have theoretical and practical implications outside the field. However the strength of evidence presented was assessed as being incomplete in several respects. Major strengths are (1) genetic factors in facial appearance are of broad interest, and the potential influence of possibly identical factors in a serious congenital disorder (cleft lip/palate) heightens that interest further; (2) proving which single nucleotide variants influence phenotypes, and by what mechanisms, is a major challenge for the field as a whole. The weakness, as assessed, was that in its present form the experimental approach was not sufficiently rigorous to support the conclusions unambiguously.

eLife assessment

This important study presents data suggesting that HFD-induced histone epimutations in sperm may impact the transcriptome of the placenta, thereby contributing to the paternal transmission of paternal metabolic disorders to offspring. Although the hypothesis is interesting and the evidence presented is compelling, more careful statistical analyses and functional validation experiments are needed to further strengthen the conclusion.

eLife assessment

In their short technical report, Verma et al. describe how endogenously-tagged dynein and dynactin molecules localize to growing microtubule plus-ends and move processively along microtubules in cells. The authors present solid evidence that cytoplasmic dynein is a processive motor that takes long excursions prior to dissociating from microtubules. However, there are concerns about the robustness of the imaging and analysis protocols, which should be more clearly defined. This is a useful study that will be of interest to cell biologists and biochemists in the motor protein field.

eLife assessment

The important study uses a new experimental method to provide compelling evidence on how sense- and anti-sense transcription is differentially regulated. The method described here can generally be used to study the alterations in transcription. This paper will be of interest to scientists working in the gene regulation community.

eLife assessment

Benner et al. identify OVO as a transcriptional factor instrumental in promoting the expression of hundreds of genes essential for female germline identity and early embryo development. While they provide the dataset that supports their model, the major evidence for the model proposed in this manuscript comes from a separate manuscript by the same group, making the contribution of this manuscript somewhat unclear - that is, the evidence provided in this paper is incomplete to support the proposal of this paper. Overall, the study provides useful information that will help understand the function of ovo during oogenesis and early embryonic development.

eLife assessment

This study combines molecular genetics and target validation to discover genes involved in obesity and determine their role. It was unanimously agreed that the work is important in terms of significance as it has conceptual and practical implications beyond metabolism, including embryonic and placental development. The strength of evidence is convincing from the use of their forward genetic screen in mice.

eLife assessment

The authors report a previously published method ReplicaDock to improve predictions from AlphaFold-multimer (AFm) for protein docking studies. The level of improvement is modest for cases where AFm is successful; for cases where AFm is not as successful, the improvement is more significant, although the accuracy of prediction is also notably lower. Therefore, the evidence for the ReplicaDock approach being more predictive than AFm is solid for some cases (e.g., the antibody-antigen test case) but incomplete for the more extensive test sets (e.g., those presented in Figure 6). Overall, the study makes a valuable contribution by combining data- and physics-driven approaches.

eLife assessment

This important study provides compelling evidence that the low-cost and open-hardware UC2 microscopy framework can be expanded to enable single-molecule localization microscopy. The authors managed to fit the instrumentation and control thereof in a unit that can be placed in a small stage-top-incubator. Together with providing adapted software for data acquisition and data analysis, the UC.STORM setup can rival the capabilities of comparable commercial instruments at a fraction of the costs.

eLife assessment

This important collection of over 800 new cell type-specific driver lines will be an invaluable resource for researchers studying associative learning in Drosophila. Thoroughly characterized and well documented, this collection will permit researchers to selectively target neurons that deliver information to, or receive it from, the memory center of the fly brain called the Mushroom Body. Given the wealth of new drivers and the genetic access they provide to over 300 cell types, this compelling work will be of interest not only to researchers studying the mechanisms of associative learning but more generally to those dissecting sensorimotor circuits in the fly nervous system.

eLife assessment

This study presents valuable intracranial findings on how two types of natural auditory stimuli – speech and music – are processed in the human brain, and demonstrates that speech and music largely share network-level brain activities, thus challenging the domain-specific processing view. The evidence supporting the claims of the authors is solid but somewhat incomplete: although the data analysis is thorough, the results are robust and the stimuli have ecological validity, considerations such as low-level acoustics control, limitations of experimental design, and in-depth analysis, are lacking. The work will be of broad interest to speech and music researchers as well as cognitive scientists in general.

eLife assessment

In this study, the authors provide compelling evidence for dysgranular insular involvement in top-down and bottom-up interoceptive processing. Its translational application in ADE patients corroborates the assumption that the mid-insula may indeed be a locus of 'interoceptive disruption' in psychiatric disorders, which underscores the study's high relevance for both body-brain as well as clinical research. The authors' findings are fundamental and substantially advance our understanding of the neural basis of interoception and its putative disruption in psychiatric disorders.

eLife assessment

This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. While the strength of the evidence supporting these claims is compelling, the authors do not discuss how their results affect our understanding of insect nest construction or animal-built structures more broadly.

eLife assessment

This valuable study substantially advances our understanding of molecular mechanisms driving the phase separation behavior of HP1 paralogs. The evidence supporting the conclusions is convincing, with rigorous and well-designed computational simulations. The work will be of broad interest to biophysicists and biochemists.

eLife assessment

In this valuable study, the authors aimed to identify and characterize intrinsic factors that govern the aging process of bone marrow mesenchymal stromal cells (BMSCs), which are believed to be related to osteoporosis. The authors conclude that PCBP2 is an intrinsic aging factor, the decrease of its expression during aging results in cell proliferation activity decrease and cell senescence. The study provides convincing evidence in support of its conclusions.

eLife assessment

This valuable study describes an investigation of the properties of two heterologously-expressed Nav1.4 channels, with mutations close to the selectivity filter found in tetrodotoxin(TTX)-resistant snakes. The authors studied these mutants by electrophysiological methods, assessed the muscle properties of two types of snakes bearing these mutations, and built homology models of the channels to hypothesize a molecular explanation of the altered channel properties. The methods employed and the results are generally solid, although some aspects would benefit from additional experiments and a more nuanced discussion.

eLife assessment

The authors provide solid data on a functional investigation of potential nucleoid-associated proteins and the modulation of chromosomal conformation in a model cyanobacterium. While the experiments presented are convincing, the manuscript could benefit from restructuring towards the precise findings; alternatively, additional data buttressing the claims made would significantly enhance the study. These valuable findings will be of interest to the chromosome and microbiology fields.

eLife assessment

The manuscript describes a valuable method to boost WNT signaling in a tissue-specific manner. The work extends previous data from the authors based on fusing an RSPO2 mutant protein to an antibody that binds ASGR1/2. In the current manuscript, two new antibodies with similar effects are described, that expand this solid approach and provide alternatives for potential future clinical applications. This manuscript will be of interest to all scientists studying protein engineering and cellular targeting.

eLife assessment

The authors examined in detail the epigenetic changes and alterations in the subnuclear arrangement of a unique var gene associated with Plasmodium falciparum placental malaria. Although the observations are mainly confirmatory, the findings are valuable for theoretical considerations and practical applications. Applying the latest methods for the analysis of histone marks, transcriptomics, DNA methylation, and chromosome conformation, the authors provide observations that are convincing, thus making their claims appropriate.

eLife assessment

This important work significantly advances the field of computational modelling of genome organisation through the development of OpenNucleome. The evidence supporting the tool's effectiveness is compelling, as the authors compare their predictions with experimental data. It is anticipated that OpenNucleome will attract significant interest from the biophysics and genomics communities. Providing comprehensive tutorials and documentation is highly encouraged.

eLife assessment

The authors identify a new role for C1ql2 at moss fiber synapses in the hippocampus and find that C1ql2, whose expression is controlled by Bcl11b, controls the recruitment of synaptic vesicles to active zones and is necessary for synaptic plasticity. The data implicating C1ql2 involvement, using numerous viral/genetic rescue approaches, are largely convincing, while the experimental evidence supporting the role of the specific Nrxn3 splice variant is less complete. These data are valuable, building on prior discoveries of how Bcl11b, a disease-relevant molecule, contributes to our understanding of mossy-fiber synaptic development.

eLife assessment

The authors identify a new role for C1ql2 at mossy fiber synapses in the hippocampus and convincingly find that C1ql2, whose expression is controlled by Bcl11b, controls the recruitment of synaptic vesicles to active zones and is necessary for synaptic plasticity. These important results build upon prior discoveries of how Bcl11b, a disease-relevant molecule, contributes to our understanding of mossy-fiber synaptic development.

eLife assessment

This study presents a useful strategy in which the authors devised a simple method to attenuate Candida albicans and deliver a live whole-cell vaccine in a mouse model of systemic candidiasis. While a robust candidiasis vaccine will be critical for the field, the study in its current form is incomplete. The strength of the evidence could be augmented with additional experiments to more fully characterize vaccine efficacy and host immune responses.

eLife assessment

This useful study tackles the well-established overflow metabolism issue by applying a coarse-grained metabolic flux model to predict how individual cells execute various energy strategies, such as respiration versus fermentation. While the model's population average is convincing enough to align with experimental observations on overflow metabolism, the overall assertions to enhance our comprehension of this biological phenomenon are incomplete.

eLife assessment

This study presents a valuable finding on the relationship between neuronal dynamics in the thalamus and brain state modulation. The evidence supporting the claims of the authors is incomplete, as additional analyses and better presentation of the data are needed to support the specific role of the mediodorsal nucleus in this phenomenon. The work will be of interest to systems neuroscientists interested in brain dynamics and behavioural states.

eLife assessment

The manuscript by Agha et al. provides a fundamental understanding regarding the participation of V2a interneurons in generating and patterning the locomotor rhythm. The authors provide convincing and solid evidence regarding the heterogeneity of V2a neurons in their intrinsic and synaptic properties and how these shape their outputs. The manuscript could be much improved by the inclusion of statistical analysis of some of the key data currently presented qualitatively.

eLife assessment

This study presents an important set of results illuminating how movement sequences are planned. Using several different behavioural manipulations and analysis methods, the authors present compelling evidence that multiple future movements are planned simultaneously with execution, and that these future movement plans influence each other. The work will be of great interest to those studying motor control.

eLife assessment

This valuable study, of interest for students of the biology of genomes, uses simulations in combination with published data to examine how many TADs remain after cohesin depletion. The authors suggest that a significant subset of chromosome conformations do not require cohesin, and that knowledge of specific epigenetic states can be used to identify regions of the genome that still interact in the absence of cohesin. The theoretical approaches and quantitative analysis are state-of-the-art, and the data quality and strength of the conclusions are convincing, but it is unfortunately still unclear whether physical boundaries (of domains?) in the model appear to be a consequence of preserved TADs, or whether preserved TADs are caused by the physical boundaries.

eLife assessment

This useful study uses a microfluidic method to evaluate the ability of single human white blood cells to produce combinations of cytokines and the evidence that this takes place is solid. The paper highlights polyfunctionality using data that are similar to a prior dataset from the same group. The authors comment that, in analysis of larger panels, single cells rarely make more than 2 or 3 cytokines so that investigation of 3 cytokines at a time is sufficient to investigate this phenomenon. Coupling this approach to other modes of single cell analysis may provide greater insight into what limits simultaneous production of multiple cytokines.

eLife assessment

This important study indicates a significant role for individual let-7 miRNA clusters in regulating generation of Tc17 CD8 cells and emphysema severity in a mouse model. The authors provide convincing evidence for let-7-mediated repression of the transcription factor RORgt and consequent modulation of IL-17-producing CD8 T cells, with correlated data from human emphysema material, though the most effective let-7 cluster/s is/are yet to be tested for its/their ability to modulate disease. The findings, which substantially advance the understanding of roles that let-7 miRNA clusters play in modulating both T cell responses and emphysematous lung disease, will be of interest to T cell and lung disease researchers.

eLife assessment

In this useful study, the authors analyze droplet size distributions of multiple protein condensates and their fit to a scaling ansatz, highlighting that they exhibit features of first- and second-order phase transitions. The experimental evidence is still incomplete as the measurements were apparently done only at one time point, neglecting the possibility that droplet size distribution can evolve with time. The text would benefit from a connection to and contextualization with the well-understood expectations from the coupling of percolation and phase separation in protein condensates - a phenomenon that is increasingly gaining consensus amongst the community and that emphasizes "liquid-gas" criticality.

eLife assessment

This fundamental study explores the relationship between guanine-quadruplex structures and pathogenicity islands in 89 bacterial strains representing a range of pathogens. Guanine-quadruplex structures were found to be non-randomly distributed within pathogenicity islands and conserved within the same strains. These compelling findings shed light on the molecular mechanisms of Guanine-quadruplex structure-pathogenicity island interactions and will be of interest to all microbiologists.

eLife assessment

This valuable study advances our understanding of spatial-temporal cell dynamics both in vivo and in vitro. The authors provide solid evidence for their innovative deep learning-based apoptosis detection system, ADeS, which utilizes the principle of activity recognition. This work will be of broad interest to cell biologists and neuroscientists.

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 the histone tails in the complex based on molecular dynamics simulations. While similar structures have recently been published elsewhere, this solid study supports the conclusions of those papers and also includes new insights into the potential dynamics of Sirt6 bound to a nucleosome, insights that help explain its substrate specificity.

eLife assessment

This manuscript presents potentially valuable results indicating a plastic enhancement in the vasomotion response of pial cortical arterioles to external stimulation in awake mice using a wide range of external visual stimulation paradigms. The evidence for this interesting effect, with broad potential applications, is, however, incomplete because it is unclear whether the effect is a modulation of vasomotion rather than stimulus-driven hyperaemia and whether it is reversible. These results are relevant for scientists and clinicians interested in the regulation of blood flow in the brain.

eLife assessment

This valuable study from Zaman et al. demonstrates that the cKit-Kit ligand complex is necessary for the formation and/or maintenance of molecular layer interneuron synapses in cerebellar Purkinje cells. The evidence presented is solid; in particular, the use of cell-type specific knockout of cKit in molecular layer interneurons and knockout of Kit ligand in Purkinje cells provides robust evidence. This work will be of particular relevance to those interested in inhibitory synapse formation or the role of inhibition in Purkinje cell behavior.

eLife assessment

This valuable study from Zaman et al. demonstrates that the cKit-Kit ligand complex is necessary for the formation and/or maintenance of molecular layer interneuron synapses in cerebellar Purkinje cells. The evidence presented is convincing; in particular, the use of cell-type specific knockout of cKit in molecular layer interneurons and knockout of Kit ligand in Purkinje cells provides robust evidence. This work will be of particular relevance to those interested in inhibitory synapse formation or the role of inhibition in Purkinje cell behavior.

eLife assessment

This manuscript presents a generally convincing set of experiments to address the question of whether the lateral parafacial area (pFL) is active in controlling active expiration, which is particularly relevant in patient populations that rely on active exhalation to maintain breathing (eg, COPD, ALS, muscular dystrophy). This study presents a valuable finding by pharmacologically mapping the core medullary region that contributes to active expiration and addresses the question of where these regions lie anatomically. Results from these experiments will be of value to those interested in the neural control of breathing and other neuroscientists as a framework for how to perform pharmacological mapping experiments in the future.

eLife assessment

This study presents important findings for understanding cortical processing of color, binocular disparity, and naturalistic textures in the human visual cortex at the spatial scale of cortical layers and columns using state-of-the-art high-resolution fMRI methods at ultra-high magnetic field strength (7 T). Solid evidence supports an interesting layer-specific informational connectivity analysis to infer information flow across early visual areas for processing disparity and color signals. While the question of how the modularity of representation relates to cortical hierarchical processing is interesting, the findings that texture does not map onto previously established columnar architecture in V2 are suggestive but would benefit from further controls. The successful application of high-resolution fMRI methods to study the functional organization along cortical columns and layers is relevant to a broad readership interested in general neuroscience.

eLife assessment

This manuscript describes a model to estimate what fraction of DNA from specific human tissues becomes cell-free DNA in plasma. This fundamental study, supported by convincing evidence, will be of great interest to the community, as the amount of DNA from a certain tissue (for example, a tumor) that becomes available for detection in the blood has significant implications for disease detection.

eLife assessment

This fundamental study identifies the homeodomain transcription factor Meis2 as a transcriptional regulator of maturation and end-organ innervation of low-threshold mechanoreceptors (LTMRs) in the dorsal root ganglia (DRG) of mice. The authors use histology, behavioral tests, RNA-sequencing, and electrophysiological recordings to provide evidence that conditional deletion of Meis2 in postmitotic DRG neurons causes gene expression changes together with targeting errors and altered sensory neuron responses, ultimately resulting in reduced sensitivity to light touch in mutant animals. The data presented are convincing, the discussion comprehensive, and the conclusions drawn justified.

eLife assessment

This is an important follow-up study to a previous paper in which the authors reconstituted CO2 metabolism (autotrophy) in Escherichia coli. Here, the authors define a set of just three mutations that promote autotrophy, highlighting the malleability of E. coli metabolism. The authors make a convincing case that mutations in pgi are loss-of-function mutations that prevent metabolic efflux from the reductive pentose phosphate autocatalytic cycle, and their data suggest possible roles of mutations in two other genes - crp and rpoB. This research will be particularly interesting to synthetic biologists, systems biologists, and metabolic engineers aiming to develop synthetic autotrophic microorganisms.

eLife assessment

Yang et al. investigate whether distinct sources of conflict are represented in a common cognitive space. The study uses an interesting task that mixes different sources of difficulty and reports that the brain appears to represent these sources as a mixture on a continuum in prefrontal areas. While the findings could be valuable to theory in this area, there are some concerns with the design and results, that raise uncertainty regarding the main conclusion of a shared cognitive space. The authors appropriately acknowledge these limitations while also highlighting the valid contributions that the study makes. Thus, while solid evidence is reported here, consistent with the central hypothesis, further experiments are required to support the strictest interpretation.

eLife assessment

SCARF1 is a scavenger membrane-bound receptor that binds modified versions of lipoproteins and has a major role in maintaining lipid homeostasis. This useful study reports the crystal structure of SCARF1 and identifies putative binding sites for modified lipoproteins. While some aspects of the analysis are incomplete, others are solid, and overall, the study advances our knowledge of how scavenger receptors clear modified lipoproteins to maintain lipid homeostasis.

eLife assessment

This important work describes a compelling analysis of DNA damage-induced changes in nascent RNA transcripts, and a genome-wide screening effort to identify the responsible proteins. A significant discovery is the inability of arrested cells to undergo DNA damage-induced gene silencing, which, is attributed to an inability to mediate ATM-induced transcriptional repression. Revisions are suggested that would significantly enhance and support the central claims of the study. This work will be of general interest to the DNA damage, repair, and transcription fields, with a potential impact on the cancer field.

eLife assessment

This study is partly useful as it corroborates what is already known about the elevated proliferation capacity of mid lobular hepatocytes in liver regeneration. Lineage tracing and scRNAseq studies are powerful for the investigation of such heterogeneous hepatocyte proliferation capacity. Nevertheless, based on experimental limitations, incomplete method description and inadequate data analyses the presented data are insufficient to support the proposed conclusions of a mesenchymal-hepatocyte hybrid population in the murine liver.

eLife assessment

This important study identifies a role for triglycerides and lipid droplets in spermatogenesis, with data supporting relevance of this finding across phyla. The work shows with convincing data that a triglyceride lipase is required cell-autonomously for germline differentiation into meiotic stages and haploid spermatids and that an increase in triglycerides is detrimental to spermatogenesis. This paper would be of interest to developmental and cell biologists working on gametogenesis.

eLife assessment

This valuable study investigates likely molecular mechanisms underlying the increasingly common deletions of the hrp2 and hrp3 genes of the human malaria parasite Plasmodium falciparum, that render parasites undetectable by widely used rapid diagnostic tests. The generation of additional long-read data, alongside a new analysis of 19,000 public short-read sequenced genomes, makes this the most detailed investigation currently available on this topic. The authors provide solid evidence for chromosomal breakage with subsequent telomere healing as the mechanism for hrp2 deletion, with more complex patterns for hrp3 deletion, but further methodological details would bolster confidence in the conclusions and enable replication of the results.

eLife assessment

This article provides a review and test of image-analysis methods for bacteria growing in the 'mother-machine' microfluidic device, introduceing also a new graphical user interface for the computational analysis of mother-machine movies based on the 'Napari' environment. The tool allows users to segment cells based on two previously published methods (classical image transformation and thresholding as well as UNet-based analysis), with solid evidence for their robust performance based on comparison with other methods and use of datasets from other labs. While it was difficult to assess the user-friendliness of the new GUI, it appears to be valuable and promising for the field.

eLife assessment

This study provides an important advancement of knowledge by showing neural functional compensation in the brains of healthy older adults completing a fluid-intelligence task. Validated whole-brain voxel-wide analyses and multivariate Bayesian approaches provide compelling evidence that supports the claims of the authors. The work delivers methods for quantifying reserve and compensation in future studies and will be of interest to researchers in the field of the neuroscience of healthy aging.

eLife assessment

This fundamental study addresses the question of how certain zooplankton achieve barotaxis, directed locomotion in response to changes in hydraulic pressure. The authors provide compelling evidence that the response involves ciliary photoreceptors interacting with motoneurons. This work should be of broad interest to scientists working on mechanosensation, cilia, locomotion, and photoreceptors.

eLife assessment

This important study provides a new way to enhance organ preservation. The authors provide solid evidence that an existing drug, SNC80, can rapidly and reversibly slow biochemical and metabolic activities while preserving cell and tissue viability. This study will be of interest to a broad set of readers interested in organ transplantation, tissue engineering, regenerative medicine organoids, and organ-on-a-chip engineering.

eLife assessment

This study provides insights into the developmental origin of endothelial cells found in blood vessels called pial collaterals. The work is important, as collateral capacity can strongly influence the trajectory of outcomes with vascular blockage, and the approaches are novel and overall convincing; however, some mechanistic claims are only partially supported, and collateral characterization is incomplete. Given the clear positive correlation between pial collateral flow and improved stroke outcome, this study will be of interest to vascular biologists and clinicians caring for stroke patients.

This sentence summarizes a growth mindset. They believe that intelligence can be grew and cultivated through hard work and education. They don't believe everyone has uncapped potential, but are more focused on the growth rather then the end goal.

This sentence summarizes a fixed mindset very clearly. It shows that a fixed mindset entails each person having their own set amount of intelligence and its hard set on that

reasons for german conformity - fear of nazi retaliation - maintaining appearances with other germans - pressure to conform - new opportunities in nazi society - disliked nazis but liked german unity - in search of national community - agreed w nazis socially and politically

eLife assessment

The present study offers valuable insights into the emergence of oscillations in neural networks. It underscores the importance of achieving a delicate balance between excitatory and inhibitory links, and deals with the topological conditions for oscillations. The study provides solid evidence in simple networks based on formal mathematical theory and advanced simulations, but the wider implications to biological networks would require a more detailed investigation into delays and nonlinearities.

eLife assessment

This study uses carefully designed experiments to generate a useful behavioural and neuroimaging dataset on visual cognition. The results provide solid evidence for the involvement of higher-order visual cortex in processing visual oddballs and asymmetry. However, the evidence provided for the very strong claims of homogeneity as a novel concept in vision science, separable from existing concepts such as target saliency, is inadequate.

eLife assessment

This study presents useful findings that describe how activity in the corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons) modulates sevoflurane anesthesia, as well as a phenomenon the authors term a "sevoflurane general anesthetic-elicited stress response". The technical approaches are solid, and the data presented is largely clear. However, the primary conclusion, that the PVHCRH neurons are critical for the mechanisms of sevoflurane anesthesia, is incompletely supported by the data.

eLife assessment

This useful study provides incomplete evidence for the functional roles of the human DCP1 paralogs in regulating RNA decay by DCP2. Using a combination of cellular-based assays and in vitro assays, the authors conclude that DCP1a/b plays a role in regulating DCP2 activity. This study makes a number of interesting and potentially relevant observations; however, a number of outstanding questions remain to be addressed. These results will be of interest to the RNA community.

eLife assessment

In their valuable study, Chen et al. aim to define the neuronal role of HMMR, a microtubule-associated protein typically associated with cell division. Their findings suggest that HMMR is necessary for proper neuronal morphology and the generation of polymerizing microtubules within neurites, potentially by promoting the function of TPX2. While the study is recognized as a first step in deciphering the influence of HMMR on microtubule organization in neurons, the reviewers note the current work is incomplete, with significant gaps and it would benefit from further exploration of the mechanism of microtubule stability by HMMR, the link between HMMR-mediated microtubule generation and morphogenesis, and the physiological implications of disrupting HMMR during neuronal morphogenesis.

eLife assessment

This manuscript presents a useful presentation of a new method for assessing the adhesion strength of axons with the use of a laser-induced shock wave. However, the strength of the evidence is incomplete as critical controls for calibration and time course are lacking.

eLife assessment

This useful study explores the phenomenon of glucose-induced mitochondrial repression, known as the Crabtree effect, in cells cultured under high glucose conditions. The study uses a variety of well-designed assays to support the authors' hypothesis, shedding light on inorganic phosphate-mediated metabolic regulation. The analysis and conclusions could benefit from a more rigorous approach, given the limited replication on a single yeast strain background and inadequacies in the normalization methods, leaving the evidence in parts incomplete.

eLife assessment

This important study highlights how a single protein transporter dysfunction can significantly alter brain biochemistry, potentially playing a crucial role in the intellectual disability in creatine transporter deficiency (CTD) patients. The evidence is compelling that the new in vitro CTD model using CTD patient's brain organoid cultures will be widely applicable. Despite minor areas for further exploration, the study significantly enhances our understanding of CTD, offering potential therapeutic targets and a robust foundation for continued research in the field.

eLife assessment

The solid study addresses the role of extracellular matrix (ECM) in neuronal migration. The authors showed that the interaction between the ternary complex formed by tenascin-C, the chondroitin sulfate proteoglycan neurocan, and hyaluronic acid is important for the multipolar to bipolar transition in the intermediate zone (IZ) of the developing cortex.

eLife assessment

The study presents valuable findings concerning how a highly conserved signal transduction pathway helps budding yeast cells adapt their growth to nitrogen sources of differing qualities. However, the evidence is incomplete for the authors' main claim that the pathway adopts three distinct states depending on the nitrogen source. The presented data, particularly phospho-proteomic datasets, will be of interest to the cell growth signaling community.

eLife assessment

This valuable work investigates the role of boundary elements in the formation of 3D genome architecture. The authors established a specific model system that allowed them to manipulate boundary elements and examine the resulting genome topology. The work yielded the first demonstration of the existence of stem and circle loops in a genome and confirms a model which had been posited based on extensive prior genetic work, providing valuable insights into how 3D genome topologies affect enhancer-promoter communication. The evidence is solid, although the degree of generalization remains uncertain.

eLife assessment

This valuable work presents elegant experimental data from the Drosophila embryo supporting the notion that interactions among specific loci, called boundary elements, contribute to topologically associated domain (TAD) formation and gene regulation. Although the evidence supporting boundary elements as determinants of 3D structures is compelling, the evidence rejecting loop extrusion is incomplete. This study will be of interest to the nuclear structure community, particularly those using Drosophila as a model.

eLife assessment

The work is a fundamental contribution towards understanding the role of archaeal and plant D-aminoacyl-tRNA deacylase 2 (DTD2) in deacylation and detoxification of D-Tyr-tRNATyr modified by various aldehydes produced as metabolic byproducts in plants. It integrates convincing results from both in vitro and in vivo experiments to address the long-standing puzzle of why plants outperform bacteria in handling reactive aldehydes and suggests a new strategy for stress-tolerant crops. A limitation of the study is the lack of evidence for accumulation of toxic D-aminoacyl tRNAs and impairment of translation in plant cells lacking DTD2.

eLife assessment

In this valuable study, the authors investigate the role of the UFD-1/NPL-4 complex in the response of C. elegans to infection. While the work is of interest to the field, several pieces of evidence are incomplete, including a lack of validation of the inferences from the RNAi experiments with mutant analyses. There is also the question whether the UFD-1/NPL-4 complex might be better described as regulating "tolerance" to infection instead of inflammation.

eLife assessment

This manuscript describes an important NMR investigation of allosteric interactions within Abl kinase. The authors identify helix I as a major element that couples the Abl active site with the myristate-binding pocket. The convincing findings have implications for understanding Abl kinase activation and how to target Abl kinase in diseases.

eLife assessment

This paper provides a simple example of a neural-like system that displays criticality, but not for any deep reason; it's just because a population of neurons are driven (independently!) by a slowly varying latent variable, something that is common in the brain. Moreover, criticality does not imply optimal information transmission (one of its proposed functions). The work is likely to have an important impact on the study of criticality in neural systems and is convincingly supported by the experiments presented.

eLife assessment

This paper provides a simple example of a neural-like system that displays signatures of criticality, but not for any deep reason; it's just because a population of neurons are driven (independently!) by a slowly varying latent variable, something that could easily arise in neural systems. In this model, criticality does not imply optimal information transmission (one of its proposed functions). This is an important finding backed up by compelling evidence, and it should be influential in how people think about criticality in the brain.

eLife assessment

This valuable study advances our understanding of the forces that shape the genomic landscape of transposable elements. By exploiting both long-read sequencing of mutation accumulation lines and in vivo transposition assays, the authors offer compelling evidence that structural variation rather than transposition largely shapes transposable element copy number evolution in budding yeast. The work will be of interest to the transposable element and genome evolution communities.

eLife assessment

This work presents convincing evidence for the presence of wooly mammoth/rhinoceros ancient environmental DNA (aeDNA) far from the time likely to host living individuals: what is effectively a genetic version of a geological inclusion. These are important findings that will have ramifications for the interpretation and conclusions extracted from aeDNA more generally.

eLife assessment

This work presents important findings on the cellular and ultrastructural organization of the nervous system in the freshwater polyp Hydra. The authors present outstanding imaging data with convincing evidence to support their claims. The manuscript provides a starting point for further functional in vivo studies. The work will be of interest to developmental biologists and neurobiologists.

eLife assessment

This manuscript provides important information on the calcification process, especially the properties and formation of freshly formed tests (the foraminiferan shells), in the miliolid foraminiferan species Pseudolachlanella eburnea. The evidence from the high-quality SEM images is solid, but the evidence is incomplete when it comes to the specificity of the auto-fluorescent signals for calcified structures, or the presence of photosynthetic (living) symbionts, which are not verified experimentally. The conclusions based on fluorescent imagery therefore do not have strong support.

eLife assessment

This study showing how the Circle of Willis acquires smooth muscle coverage during development in the zebrafish model is important, and the evidence provided is solid, with only minor weaknesses. The work is of interest to researchers working on cerebral circulation, angiogenesis, and developmental vascular stabilization.

eLife assessment

This paper marks a fundamental advance in our understanding of prokaryotic Type IV restriction systems. The authors provide an encyclopedic overview of a hitherto uncharacterized branch of these systems, which they name CoCoNuTs, for coiled-coil nuclease tandems. They provide compelling evidence that these nucleases target RNA and are part of an echeloned defense response following viral infection. This article will be of great interest to scientists studying prokaryotic immunity mechanisms, as well as broadly to protein scientists engaged in the analysis, classification, and functional annotation of the proteome of life.

eLife assessment

This study presents a useful tool for predicting TCR specificity with compelling evidence for improvements over prior art. This work/tool will be broadly relevant to computational biologists and immunologists.

eLife assessment

This important study conducts genetic analyses utilizing zebrafish, mouse, and mouse embryonic stem cell models to elucidate the role of Rtf1, a component of the PAF1 complex, in early cardiac development. By combining marker gene expression analysis, single-cell transcriptomics, ChIP-seq, and chemical inhibition, the study provides convincing evidence that Rtf1-mediated RNAPII (Pol2) transcriptional pausing is required for early cardiac development and that attenuation of pause release by pharmacological inhibition of Cdk9, a component of the PTEF-b complex that regulates the transition between the pausing and elongation phases of transcription, can partially restore transcriptional pausing and cardiogenesis in zebrafish rtf1 mutants. The work will be of broad interest to developmental biologists.

eLife assessment

The current manuscript re-examines an established claim in the literature that human PANX-1 is regulated by Src kinase phosphorylation at two tyrosine residues, Y199 and Y309. This issue is important for our understanding of Pannexin channel regulation. The authors present an extensive series of experiments that fail to detect PANX-1 phosphorylation at these sites. Although the authors' approach is more rigorous than the previous studies, this work relies primarily on negative results that are not unambiguously definitive; the work nonetheless provides a compelling reason for the field to reexamine conclusions drawn in earlier studies.

eLife assessment

This valuable study describes the molecular mechanism of daptomycin insertion into bacterial membranes. The authors provide solid in vitro evidence for the early events of daptomycin interaction with phospholipid headgroups and stronger, specific interaction with phosphatidylglycerol. This work will be of interest to bacterial membrane biologists and biochemists working in the antimicrobial resistance field.

eLife assessment

The manuscript constitutes an important contribution to antimalarial drug discovery, employing diverse systems biology methodologies; with a focus on an improved M1 metalloprotease inhibitor, the study provides convincing evidence of the utility of chemoproteomics in elucidating the preferential targeting of PfA-M1. Additionally, metabolomic analysis effectively documents specific alterations in the final steps of hemoglobin breakdown. These findings underscore the potential of the developed methodology, not only in understanding PfA-M1 targeting but also in its broader applicability to diverse malarial proteins or pathways. Revisions are needed to further enhance overall clarity and detail the scope of these implications.

eLife assessment

This manuscript describes structures of HER4 homo- and HER4/HER2 hetero-dimer complexes using single particle cryo-EM. This important work describes convincingly new structural details of these complexes that expand our understanding of their function. This work will be of interest to researchers working on cell surface signalling and kinase activity.

eLife assessment

This interesting and important work shows that diacety, a volatile organic compound released by yeast in fermenting fruit, can act as a histone deacetylase (HDAC) inhibitor and trigger wide changes in gene expression, together with suppression neurotoxicity in a Drosophila model of Huntington's disease. While the effects on gene expression changes and degenerative phenotypes are convincingly shown, further studies are required to determine whether and how olfactory sensory neurons and odorant receptors mediate the effects of diacetyl described by the authors.

eLife assessment

This study presents a useful method for the extraction of behaviour-related activity from neural population recordings based on a specific deep learning architecture - a variational autoencoder. However, the evidence supporting the scientific claims resulting from the application of this method is incomplete as the results may stem, in part, from its properties. The main limitations are: (1) benchmarking against comparable methods is limited; and (2) some observations may be a byproduct of their method, and may not constitute new scientific observations.

eLife assessment

The study makes a valuable empirical contribution to our understanding of visual processing in primates and deep neural networks, with a specific focus on the concept of factorization. The analyses provide solid evidence that high factorization scores are correlated with neural predictivity, yet more evidence would be needed to show that neural responses show factorization. Consequently, while several aspects require further clarification, in its current form this work is interesting to systems neuroscientists studying vision and could inspire further research that ultimately may lead to better models of or a better understanding of the brain.

eLife assessment

This paper provides valuable insights into the neural substrates of human working memory. Through clever experimental design and rigorous analyses, the paper provides compelling evidence that the working memory representation of stimulus orientation is a reformatted version of the presented stimulus, reflecting the content that is of importance to the task. This work will be of broad interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife assessment

Based on analyses of retinae from genetically modified mice, and from wild-type ground squirrel and macaque employing microscopic imaging, electrophysiology, and pharmacological manipulations, this useful study on the role of Cav1.4 calcium channels in cone photoreceptor cells (i) shows that the expression of a Cav1.4 variant lacking calcium conductivity supports the development of cone synapses beyond what is observed in the complete absence of Cav1.4, and (ii) indicates that the cone pathway can partially operate even without calcium flux through Cav1.4 channels, thus preserving behavioral responses under bright light. The evidence for the function of Cav1.4 protein in synapse development is convincing, and in agreement with a closely related earlier study by the same authors on rod photoreceptors, but the evidential support for the notion of a homeostatic compensation of Cav1.4 loss by Cav3 is incomplete. As congenital Cav1.4 dysfunction can cause stationary night blindness, this work relates to a wide range of neuroscience topics, from synapse biology to neuro-ophthalmology.

eLife assessment

This paper provides a valuable method that uses a computational model to predict photoreceptor currents in mammalian photoreceptors. By inverting the model, visual stimuli can be constructed to produce desired photoreceptor current responses. The authors provide convincing evidence that this approach can disentangle the effects of photoreceptor nonlinearities including light adaptation from downstream nonlinear processing, thus facilitating future studies of the higher visual system.

eLife assessment

In this important work, authors show that brain activity thought to be a travelling wave may just be a series of sequentially activated sources at the neuron spiking level. They support this with convincing results from a turtle cortex preparation and relevant simulations. This work will be of interest to neuroscientists interested in understanding how cortical computations are made.

eLife assessment

This fundamental study advances our understanding of nitrogen metabolism by identifying a new type of guanidine-forming enzyme in eukaryotes. The key claims of the article are convincingly supported by the data, with meticulous biochemical, cellular, and in vivo studies on guanidine production. The work will stimulate interest in the cellular roles of homoarginine, and, more generally, in the biochemistry and metabolism of guanidine derivatives.

eLife assessment

This study presents a valuable finding on a new role of Foxp3+ regulatory T cells in sensory perception, which may have an impact on our understanding of somatosensory perception. The authors identified a previously unappreciated action of enkephalins released by immune cells in the resolution of pain and several upstream signals that can regulate the expression of the proenkephalin gene PENK in Foxp3+ Tregs. However, whereas the generation of transgenic mice with conditional deletion of PENK in Foxp3+ cells and PENK fate-mapping is novel and generates compelling data, they show an incomplete analysis of Tregs in the control and transgenic mice, proper tamoxifen controls nor the role of PENK+ skin T cells to further support their hypothesis. Nonetheless, the study would be of interest to the biologists working in the field of neuroimmunology and inflammation.

eLife assessment

In this important study, Lui and colleagues examine whether the locus coeruleus is involved in extinction of an appetitive conditioned response. Using a set of optogenetic approaches aimed at manipulating the activity of locus coeruleus cells, the authors provide solid evidence that these neurons regulate the extinction of conditioned responses. Overall this study further highlights the key role of noradrenaline in cognitive processes and will be of interest to those interested in associative learning, extinction, noradrenaline, associated brain systems and translational endpoints.

eLife assessment

The current manuscript presents a cryo-EM structure of a tripartite ATP-independent periplasmic (TRAP) transporter that contributes to Haemophilus influenzae virulence. Convincing biophysical and cryo-EM experiments yield a valuable molecular model, but the functional importance of some of the molecular features identified remains to be demonstrated.

eLife assessment

ROCO proteins are evolutionarily conserved GTPases characterized by the presence of a tandem "COR" domain, sometimes accompanied by a kinase domain as in the LRRK2 protein that is linked to neurodegeneration. Previously the authors have shown that two conformational nanobodies can be used to trap a ROCO protein CtRoco in a monomer-GTPyS-bound state. The high-resolution structural data here provides convincing insights into the active state conformation of CtRoco, an important initial advance towards a broader mechanistic understanding of these cryptic tandem-domain proteins.