eLife assessment

This work presents valuable new information on the microtubule-binding mode of the microtubule kinesin-13, MCAK. The authors use quantitative single-molecule studies to propose that MCAK preferentially binds to a GDP-Pi-tubulin portion of the microtubule end. However, the evidence provided to support this claim remains incomplete and would benefit from a more rigorous methodology. Additionally, the physiological relevance of the proposed binding mode remains speculative.

eLife assessment

This study by Sheng and colleagues provides valuable insights into the mechanism of competitive inhibitors of P2X receptors. The structural and functional evidence supporting the subtype specificity of pyridoxal-5'-phosphate derivatives is solid and provides information for designing drugs that selectively target different subtypes of P2X receptor channels. The written presentation could be improved for clarity. The work will be of interest to biochemists, structural biologists, and pharmacologists.

eLife assessment

This important manuscript details the characterization of ClpL from L. monocytogenes as an effective and autonomous AAA+ disaggregase that provides enhanced heat resistance to this food-borne pathogen. The authors convincingly demonstrate that ClpL has DnaK-independent disaggregase activity towards a variety of aggregated model substrates, which is more potent than that observed with the endogenous canonical DnaK/ClpB bi-chaperone system. The work will be of broad interest to microbiologists and biochemists.

eLife assessment

This study is valuable and contains results that are supported by convincing evidence. In the future, the observations could be further strengthened by independent validation, and by looking at larger numbers of patients, as well as by determining whether patient heterogeneity is either contributing to or obscuring certain patterns. The work will be of interest to a broad audience in the oncology and immunology fields as it is on a cancer type that does not respond well to immune checkpoint therapeutics.

eLife assessment

The intrinsic chirality of actin filaments (F-actin) is implicated in the chiral arrangement and movement of cellular structures, but it was unknown how opposite chiralities can arise when the chirality of F-actin is invariant. Kwong et al. present evidence that two actin filament-based cytoskeletal structures, transverse actin arcs and radial stress fibers, drive clockwise and anti-clockwise rotation, respectively. This fundamental work, which has broad implications for cell biology, is supported by solid data, although the effect of the perturbations should be interpreted with caution.

eLife assessment

This important, well-conducted study in a large data set - the UK BioBank population - reports that both circulating omega-6 and omega-3 PUFAs as well as the ratio of omega-6 to omega-3 PUFAs are associated with lower all-cause, cancer and cardiovascular mortality. The study is convincing and these findings will be of broad interest to epidemiologists, nutritionists, medical practitioners and the general population.

eLife assessment

This study presents a valuable finding on the optimal prioritization in different malaria transmission settings for the distribution of insecticide-treated nets to reduce the malaria burden. The evidence supporting the claims of the authors is solid. The work will be of interest from a global funder perspective, though somewhat less relevant for individual countries.

eLife assessment

This valuable study underscores the significance of PfMORC in shaping chromatin and guiding transitions in the malaria parasite, Plasmodium falciparum, that are essential for its survival. Solid evidence reveals PfMORC's influence on genes related to antigenic variation and the parasite's lifecycle, marking PfMORC as a key regulator of parasite heterochromatin.

eLife assessment

Using a variety of methods including mutant analyses, the authors study chromatin structure during spermatogenesis in Drosophila and transcriptional profiling in single cells/nuclei. This description of the dramatic changes in chromatin structure during spermatogenesis leads to some new observations, with convincing evidence, and it is useful for the field.

eLife assessment

This study makes a valuable contribution by characterizing the role of the exocyst in secretory granule exocytosis in the Drosophila larval salivary gland. The results lead to the novel interpretation that the exocyst participates not only in exocytosis, but also in earlier steps of secretory granule biogenesis and maturation. Although these ideas are potentially of interest to a wide range of membrane traffic researchers, the evidence is incomplete, and the authors are urged to consider the possibility that inactivation of an essential exocytosis component might have indirect effects on other parts of the secretory pathway.

eLife assessment

Connelly and colleagues provide convincing genetic evidence that importation from mainland Tanzania is a major source of Plasmodium falciparum lineages currently circulating in Zanzibar. This study also reveals ongoing local malaria transmission and occasional near-clonal outbreaks in Zanzibar. Overall, this research highlights the role of human movements in maintaining residual malaria transmission in an area targeted for intensive control interventions over the past decades and provides valuable information for epidemiologists and public health professionals.

eLife assessment

This important study combines laboratory and field studies to quantify the force of human malaria parasite transmission. The methods of malaria parasite quantification in the mosquito midgut and salivary glands are compelling, but the statistical analyses seem to be biased by high infection loads of laboratory infections and would benefit from a more granular assessment of low parasite loads observed in the field. The study establishes a correlation between the sporozoite loads in the mosquito and the number of expelled parasites and would be of interest to vector biologists, parasitologists, immunologists, and mathematical modellers.

eLife assessment

In this important paper, Al-Hasani and colleagues provide the scientific community with a method to measure peptide concentrations in the brains of freely behaving animals. This support for this method is solid and expands upon previous methodological advances by this group by uncovering the role of these molecules during ongoing behavior. This solid contribution will be of broad interest to the neuroscientific community.

eLife assessment

This manuscript reports important results on the potential influence of maternally derived extracellular vesicles on embryo metabolism. The study combines convincing techniques for isolating different subtypes of EV, DNA sequencing, embryo culture, and respiration assays performed on human endometrial samples and mouse embryos. These findings set the stage for in-depth studies to elucidate the role of EV contents in embryo energetics and further enhance our understanding on maternal-fetal communication during peri-implantation development.

eLife assessment:

This important study combines a comparative approach in different synapses with experiments that show how synaptic vesicle endocytosis in nerve terminals regulates short-term plasticity. The data presented support the conclusions and make a convincing case for fast endocytosis as necessary for rapid vesicle recruitment to active zones. Some aspects of the description of the data and analysis are however incomplete and would benefit from a more rigorous approach. With more discussion of methods and analysis, this paper would be of great interest to neurobiologists and biophysicists working on synaptic vesicle recycling and short-term plasticity mechanisms.

eLife assessment

This study presents an important discovery that the RNA synthesis protein of SARS-CoV-2, the virus that is responsible for COVID 19, has fewer mutations and causes limited conformational changes. The evidence supporting the claims is convincing, with robust sequence alignment studies, state-of-the-art protein-protein interaction analysis, and molecular conformational analysis. This work has implications for drug design and will be of broad interest to the general biophysics and structural biology community.

eLife assessment

Through a combination of careful experimental designs and computational modelling, this study provides solid evidence highlighting the role of attention in shaping temporal binding. Overall, the findings of this paper are important, supporting the cognitive link between time perception, temporal binding, and spatial attention.

eLife assessment

In this useful study, Millard et al. assessed the effects of nicotine on pain sensitivity and peak alpha frequency (PAF). The evidence shown is incomplete to support the key claim that nicotine modulates PAF or pain sensitivity, considering the effect sizes observed. This raises the question of whether the chosen experimental intervention was the most suitable approach for investigating their research question. Nonetheless, the work can be incorporated into the literature investigating the relationship between nicotine and pain, and could be of broad interest to pain researchers.

eLife assessment

The ThermoMaze represents a valuable tool to control the rest/exploration states of an animal. The data, collected and analyzed using solid and validated methodology, demonstrate its use in addressing previously elusive questions. More in-depth analysis of place cell activity would provide better support for some of the claims.

eLife assessment

Building on previous toolboxes to distinguish 1/f noise from oscillatory activity, this study introduces an important advancement in neural signal analysis to identify oscillatory activity in electrophysiological data that refines the accuracy of identifying non-sinusoidal neural oscillations. Extensive validation, using synthetic and various empirical data, provides convincing evidence for the accuracy of the method and outlines practical implications for relevant scientific problems in the field.

eLife assessment

This important study advances our knowledge of Drosophila Bonus, the sole ortholog of the mammalian transcriptional regulator Tif1. Solid evidence, both in vivo and in vitro, shows how SUMOylation controls the function of the Bonus protein and what the impact of SUMOylation on the function of Bonus protein in the ovary is.

eLife assessment

This study represents a valuable addition to the understanding of the DNA replication origin selection process in the budding yeast. The authors provide convincing evidence that the number of possible origins of replication is much higher than previously appreciated, although many of the newly identified origins are likely to only direct replication initiation rarely. This work will be of interest to those studying DNA replication and investigating protein-DNA interactions across the genome.

eLife assessment

In this study, the authors present important tools for monitoring distinct tissue-specific patterns of agonist-induced Free Fatty Acid receptor 2 phosphorylation. The work includes several validation experiments, which provide convincing evidence that will be beneficial for the scientific community.

eLife assessment

This important study investigates the structural organization of a series of diblock elastin-like polypeptide condensates. The methodology is highly compelling, as it combines multiscale simulations and fluorescence lifetime imaging microscopy experiments. The results increase our understanding of model biomolecular condensates. The manuscript would benefit from more details for the concepts and terminology introduced, as well as the analysis of the simulations.

eLife assessment

In this technically advanced and important piece of work, the authors study the coordination of microtubule growth in kinetochore fibers using force spectroscopy and numerical simulations. With compelling evidence the authors address the question of how microtubules, which naturally exhibit variable growth rates, can coordinate their behavior by mechanical coupling so as to function as a single unit in generating forces during chromosome segregation.

eLife assessment

This fundamental study substantially advances our understanding of how the pseudokinase ULK4 interacts with an active member of the same kinase subfamily (STK36) to promote GLI phosphorylation and Hedgehog pathway activation. The evidence supporting the proposed mechanism is compelling, with rigorous biochemical assays and state-of-the-art cell based imaging techniques. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This valuable study reports on the structure and function of capsid size-determining external scaffolding protein encoded by a Vibrio phage satellite. The structural work is of high quality and the presented reconstructions are compelling. The paper offers a substantial advance in the field of phage and virus structure and assembly, with implications for understanding the evolution of phage satellites.

eLife assessment

This manuscript is a valuable study of the responses of GPi neurons to DBS stimulation in human PD and dystonia patients and it finds evidence for altered short-term and long-term plasticity in response to DBS between the two patient populations. This data set is of interest to both basic and clinical researchers working in the field of DBS and movement disorders. While there was enthusiasm for the potential significance of these findings, support for their conclusions was incomplete. Their data may be indicative of more interesting and complex interpretations than currently considered in the article.

eLife assessment

This study presents a valuable finding on the identification of tumor-reactive T lymphocytes (TRLs) using paired single-cell sequencing and PDX models for cell therapy and marker selection in uveal melanoma treatment. The evidence supporting the claims of the authors is convincing, although the inclusion of detailed explanations of the results for a broader audience would have strengthened the study. The work will be of interest to clinicians and medical biologists working on uveal melanoma (UM).

eLife assessment

This paper reports a useful finding on the impact of choices of quality control and differential analysis methods on the discovery of disease-associated gene expression signatures. The study provides a solid comparison of the data process by re-analysis of a large-scale snRNA-seq dataset for Alzheimer's Disease. This paper would be of interest to the community as to rigorous analyses for large-scale single cell datasets.

eLife assessment

This valuable manuscript attempts to identify the brain regions and cell types involved in habituation to dark flash stimuli in larval zebrafish. Habituation being a form of learning widespread in the animal kingdom, the investigation of neural mechanisms underlying it is a worthwhile endeavor. The authors use a combination of behavioral analysis, neural activity imaging, and pharmacological manipulation to investigate brain-wide mechanisms of habituation. While the data presented are solid, the authors conclude that there is no simple relationship between pharmacological intervention, neural activity patterns, and behavioral outcomes, and a robust causative link can therefore not be established.

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. Similar structures have recently been published, but this work provides solid support for the conclusions of those papers and also includes some novel insights into the potential dynamics of Sirt6 bound to a nucleosome that help explain its substrate specificity.

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 concerns with the analysis, design and results, that raise uncertainty regarding the main conclusion of a shared cognitive space. Thus, the evidence reported here remains incomplete.

eLife assessment

This study presents valuable observations on the role of creatine (Cr) in the context of synaptic transmission. Overall, the data are solid in support of the conclusion that Cr is present in synaptic vesicles, although the evidence for Cr release and Cr-dependent modulation of neuronal function was considered incomplete. The work will be of general interest to the field of neuroscience.

eLife assessment

This useful study provides a systematic mutational analysis to elucidate mechanisms involved in transcriptional activation by the murine DUX protein, DUX is a master transcription factor regulating mammalian early embryonic gene activation and its human homolog DUX4 is also involved in a muscular disease, fascioscapulohumeral dystrophy (FSHD). The data are solid and the interpretations of the findings are reasonable. The work will be of interest to colleagues studying early embryonic development or FSHD.

eLife assessment

This important study examined the use of dantrolene, a Ryanodine Receptor stabilizer, in slowing pathological progression of pressure-overload heart failure in a guinea pig model and reducing arrhythmias. Convincing data were collected and analyzed using validated methodology and can be used as a starting point for future studies of dantrolene in Ca2+ handling in ROS production and further deterioration of cardiac function in chronic heart failure.

eLife assessment

This is valuable study on the mechanistic relationship between two prominent events in post-stimulus EEG: alpha desynchronization and P300 that are known for their slow/relatively late build up. The sample size is substantial. The data are compelling, showing that the P300 can be explained by desynchronization of a non-zero mean alpha oscillations over posterior sites through the baseline-shift model, at least partially. This makes a significant contribution to understanding and interpreting P300 generation (and possibly other ERP components) from concurrent changes in brain oscillations, with links to cognition.

eLife assessment

This valuable work proposes a framework inspired by chemotaxis for understanding how the brain might implement behaviours related to navigating toward a goal. The evidence supporting the conceptual claim is convincing. The manuscript proposes a hypothesis that would be of interest to the broad systems neuroscience community, although it was noted the relationship to existing similar hypotheses could be clarified.

eLife assessment

This important study time elegantly demonstrates that ferroptotic stress may play critical roles in regulating tooth germ development. The evidence presented is compelling, based on an explant model and providing novel mechanistic insights into tooth development.

eLife assessment

This important paper provides solid evidence that the angular gyrus plays a role in insight-based memory updating. The study is well conducted, timely, and presents clear-cut behavioral results. Analyses of the EEG data leave open questions, and evidence for the strong claim of a causal contribution of the angular gyrus in particular - apart from other connected regions, including the hippocampus - is not conclusive.

eLife assessment

The authors performed a useful RNAi screen to identify epigenetic regulators involved in oxygen-glucose deprivation (OGD)-induced neuronal injury. PRMT5 was identified as a negative regulator of neuronal cell survival after OGD. Solid in vitro and in vivo data suggest that PRMT5 could be a novel therapeutic target for the treatment of ischemic stroke.

eLife assessment

The finding that Fusicoccin (FC-A) promotes locomotor recovery after spinal cord injury is useful, and the idea of harnessing small molecules that may affect protein-protein interactions to promote axon regeneration is interesting and worthy of study. However, the main methods, data, and analyses are inadequate to support the primary claim of the manuscript that a 14-3-3-Spastin complex is necessary for the observed FC-A effects.

eLife assessment

This valuable study extends the previous interesting work of this group to address the potentially differential control of movement and posture. Through experiments in which stroke participants used a robotic manipulandum, the authors provide evidence supporting a lack of a relation between the resting force postural bias they measure (closely related to the flexor synergy in stroke) and kinematic deficits during movement. Based on these results, the authors propose a conceptual framework that differentially weights the two main descending pathways (corticospinal tract and reticulospinal tract) for neurologically intact and stroke patients. The reviewers point out that some of the evidence supporting the authors' conclusions is incomplete, and that the study would benefit from considering alternative explanations involving other mechanisms, which could be addressed with additional experiments and analyses.

eLife assessment

This important paper sheds light on the role of expectations in perceptual decision-making. Sophisticated analyses of human EEG data provide convincing evidence that both motor preparation and sensory processing were affected by expectations, albeit with different time courses. These findings will be of interest to scientists interested in perception and decision-making.

eLife assessment

Peripheral neurons are capable of regeneration after injury, however it is not known if all of these neurons react in the same way. The results presented here are useful to the field and strongly indicate with solid evidence that different classes of neurons exhibit different speeds of regeneration. The reason for these key differences is explored by the finding of potential factors and genes that contribute to the regulation of regenerative capacity.

eLife assessment:

This comprehensive study presents valuable results that delineate the involvement of a small subset of (DL1) dopaminergic neurons in the Drosophila larva's aversive learning response to high salt. Systematic loss-of-functional and gain-of-function manipulations coupled with in-vivo calcium imaging offer compelling evidence for the pivotal roles of these neurons, thereby advancing our understanding of the cellular mechanisms underlying associative conditioning. Despite its report of notable similarities between the learning mechanisms of learning in flies and mammals, the work underscores the necessity to further elucidate the interplay between aversive and appetitive pathways in future work.

eLife assessment

This important work combines molecular genetics and behavioral analyses to identify neurons in the female mouse preoptic area that respond specifically to mating completion. These experiments are rigorous and well-performed. The data convincingly demonstrate a subpopulation of neurons in the medial preoptic area that are selectively activated following the completion of mating in females. But concerns around the timing of the labeling of neurons as being specific to mating completion make the some conclusions incomplete, in the manuscript's current form. Confounds around the mating satiety status of the male partners influencing the motivation of the females also result in a study that is not complete.

eLife assessment

This important study presents evidence to support the efficacy of oral administration of DNL343, an integrated stress response (ISR) suppressor, in two mouse models in which neurodegeneration is induced. This suggests a therapeutic potential for ISR-related neurodegenerative diseases based on DNL343. The results from the in vivo animal models are convincing. However, adequate analyses are needed to fully support the conclusion, as there is no evidence that DNL343 acts in vitro.

eLife assessment

This fundamental study has major implications that can be paradigm-shifting for our understanding of how the phage lambda DNA motor works and what the precise roles of the TerS and TerL proteins in the motor complex are. The experiments are exceptionally well done, providing compelling evidence for the conclusion of the authors.

eLife assessment

This fundamental work by Cao et al. advances our understanding of the role of senescent osteoclasts (SnOCs) in the pathogenesis of spine instability. The authors provide compelling evidence for the SnOCs to induce sensory nerve innervation. Subsequently, reduction of SnOCs by the senolytic drug Navitoclax markedly reduces spinal pain sensitivity. This work will be of broad interest to regenerative biologists working on spinal pain.

eLife assessment

The findings of this article provide valuable information on the changes of cell clusters induced by chronic periodontitis. The observation of a new fibroblast subpopulation, named AG fibroblasts, is interesting, and the strength of evidence presented is solid.

eLife assessment

This is a valuable comparative study of adaptation across multiple species. The results provide a solid example of the application of genotype-environment associations to demonstrate that local adaptation is repeatable.

eLife assessment

Multimodal experiences that for example contain both visual and tactile components are encoded as associative memories. This manuscript is a valuable contribution supporting structural and functional brain plasticity following associative training protocols that pair together different types of sensory stimuli. The results provide solid support for this plasticity being a basis for cross-modal associative memories.

eLife Assessment

This valuable paper presents a new protocol for quantifying tRNA aminoacylation levels by deep sequencing. The improved methods for discrimination of aminoacyl-tRNAs from non-acylated tRNAs, more efficient splint-assisted ligation to modify the tRNAs' ends for the following RT-PCR reaction, and the use of an error-tolerating mapping algorithm to map the tRNA sequencing reads provide new tools for anyone interested in tRNA concentrations and functional states in different cells and organisms. The results and conclusions are solid with well-designed tests to optimize the protocol under different conditions.

eLife assessment

This valuable study reports on the potential of neural networks to emulate simulations of human ventricular cardiomyocyte action potentials for various ion channel parameters with the advantage of saving simulation time in certain conditions. The evidence supporting the claims of the authors is solid, although the inclusion of open analysis of drop-off accuracy and validation of the neural network emulators against experimental data would have strengthened the study. The work will be of interest to scientists working in cardiac simulation and quantitative pharmacology.

eLife assessment

This is an important study highlighting a distinct role of WASP dependent actin foci in B cell antigen receptor signalling. The evidence supporting the conclusions is compelling. The proposal of higher molecular density in B cell receptor clustering leading to kinase exclusion and attenuated signalling is provocative as it contrasts with models for other antigen receptors.

eLife assessment

O'Brien and co-authors addressed how statins reduce levels of aldosterone in humans and provide important data demonstrating that tissue-resident macrophages can exert physiological functions and influence endocrine systems. However, the strength of evidence, as of now, is incomplete, as the sole description of the phenotype of MARCO-deficient mice is insufficient to claim that MARCO in alveolar macrophages can negatively regulate ACE expression and aldosterone production at steady-state. The work will be of broad interest to cell biologists and immunologists.

eLife assessment

This study presents a useful inventory of the joint effects of genetic and environmental factors on psychotic-like experiences and identifies cognitive ability as a potential underlying mediating pathway. The data were analyzed using a solid and validated methodology based on a large, multi-center dataset. The claim that these findings are of relevance to psychosis risk and have implications for policy changes is partially supported by the results.

eLife assessment

This study presents a valuable finding on relationship between high protein diet and resistance exercise on fat accumulation and glucose homeostasis. The evidence supporting the claims of the authors is solid, although inclusion of mechanistic insight would have strengthened the study. The work will be of interest to dietician and exercise biologists working to understand the synergy between diet and physical activity.

eLife assessment

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

eLife assessment

This manuscript reports important findings, demonstrating a critical role for a cysteine-containing dimerization interface in the secretion of FGF2 through an unconventional pathway. The authors provide compelling evidence, combining in vitro biochemical assays with structural simulation. The work will be of interest to researchers working on protein trafficking and secretion.

eLife assessment

This important study describes the coordinated regulation of cellular size and protein translation in response to chronic stress as an adaptive mechanism, termed the 'rewiring stress response' regulated by the heat shock response. The evidence supporting this conclusion is solid, utilizing diverse methods to monitor and manipulate cell size and evaluate stress resistance. The study could be strengthened by the inclusion of more experiments focused on defining the mechanistic basis of this coordination and broadening the scope of the specific role of the 'rewiring stress response' across different chronic cellular stresses. This work will be of broad interest to researchers interested in diverse fields including cellular proteostasis, stress-responsive signaling, and aging and senescence.

eLife assessment

This is an important contribution to the origins and translational consequences of the relatively low rate of translation elongation in the first ∼30-50 codons of genes in most organisms. The authors provide convincing evidence that the prevalence of rare codons in the first ~40 codons in yeast is due to the relatively recent evolution of these coding sequences, or of lower purifying selection operating on them, and that a preponderance of codons encoded by rare tRNAs near the N-terminus is not associated with higher translational efficiency in the manner proposed by the "translational ramp" hypothesis. The work is incomplete in that the results of reporter assays may have been confounded by alterations of mRNA sequence or structure that could have influenced their translation or mRNA stability; that the work cannot fully account for a greater enrichment of slowly translated codons in N-terminal vs. C-terminal regions; and that the work does not resolve whether translation elongation through N-terminal coding is truly slow.

eLife assessment

This manuscript provides important insights into the degradation of a host tRNA modification enzyme TRMT1 by SARS-CoV-2 protease nsp5. The data convincingly support the main conclusions of the paper. These results will be of interest to virologists interested in studying the alterations in tRNA modifications, host methyltransferases, and viral infections.

eLife assessment

This study reports biochemical and structural analysis of two PLP decarboxylase enzymes from plants. The findings are useful due to the utility of these enzymes in industrial theanine production. While certain aspects of the study are solid, other components elucidating the role of a Zn(II)-binding motif are incomplete. In addition, some of the finding could be presented more clearly, including the connections between the structural findings and the reaction mechanism. The work will be of interest to enzymologists studying PLP enzymes and those interested in enzyme engineering in plants.

eLife assessment

This manuscript provides important structural insights into the recognition and degradation of the host tRNA methyltransferase by SARS-CoV-2 protease nsp5 (Mpro). The data convincingly support the main conclusions of the paper. These results will be of interest to researchers studying structures and substrate recognition and specificity of viral proteases.

eLife assessment

This comprehensive study provides valuable information on the cooperation of Ikaros with Foxp3 to establish and regulate a major portion of the epigenome and transcriptome of T-regulatory cells. However, the characterization is incomplete in that incontrovertible evidence that these are intrinsic features regulating biological function and not outcomes of the inflammatory micro-environment of the genetically manipulated mice is missing.

eLife assessment

This valuable study advances our understanding of the relationship between different mammalian ligands and receptors of the Notch signaling pathway. The authors systematically evaluate the effects of different combinations of ligands and receptors on levels of pathway activation. The convincing though not always complete data uncover interesting and unexpected differences, which provide a foundation for interpreting Notch signaling events in normal and disease contexts where this pathway operates.

eLife assessment

In this valuable study the authors propose a new regulatory role for one the most abundant circRNAs, circHIPK3, mediated by the RNA binding protein IGF2BP2. While the study presents interesting and largely solid evidence, part of the work is incomplete, requiring additional controls to more robustly support the major claims. The work would also benefit from further discussion addressing the apparently contradictory effects of circHIPK3 and STAT3 depletion in cancer progression.

eLife assessment

This is an important study describing the function of Laminin γ1-dependent basement membranes in the development of the olfactory placode, including morphogenesis of the placode, boundary formation, and olfactory axonal pathfinding. The study uses elegant live imaging approaches, and detailed mutant analyses to provide a convincing description of the role of Laminin in olfactory placode development, although the mechanisms by which Laminin γ1 regulates these processes are not conclusive. In addition to the contributions this study makes to understanding olfactory placode development, it will also be of broader interest to individuals interested in extracellular matrix regulation of tissue morphogenesis, and neural development including neuronal pathfinding.

eLife assessment

In a valuable study that will be of interest to the mechanistic membrane transport community, the authors capture the first cryo-EM structure of the inward facing melbiose transporter MelB, a well-studied model transporter from the major facilitator (MFS) superfamily. Cryo-EM experiments and supporting biophysical experiments provide solid evidence for transporter conformational changes. The supporting evidence is incomplete in that the maps were not provided for review.

eLife assessment

This important study convincingly shows that the less common D-serine stereoisomer is transported in the kidney by the neutral amino acid transporter ASCT2 and that it is a non-canonical substrate for sodium-coupled monocarboxylate transporter SMCTs. With a multi-hierarchical approach, this important study further shows that Ischemia-Reperfusion Injury in the kidney causes a specific increment in renal reabsorption carried out, in part, by ASCT2.

eLife assessment

This is a useful study that investigates neural circuits mediating behavioral responses to cold in Drosophila larvae. Using a combination of behavioral analysis, neuronal manipulation, EM connectomics, and reporters of calcium activity, the authors convincingly show that cold-induced body contraction is mediated by specific central neurons. However, the strength of evidence is incomplete due to the concern that larval contraction is a result of chilling the nervous system and muscles, which causes spreading depolarization and mechanical contraction of the body, rather than an active sensorimotor response to cold. With these concerns addressed, this paper would be of interest to neuroscientists interested in temperature sensing.

eLife assessment

Antibodies are some of the most critical tools in biomedical research. However, their quality and specificity vary significantly. This fundamental study provides guidelines for how the quality of an antibody should be assessed and recorded and provides compelling data on the selected antibodies. This paper will be of interest to researchers working in experimental cell biology.

eLife assessment

This is an important study on how behavioral context affects decision making in the nematode C. elegans. Behavioral analyses at multiple time scales combined with genetic and neuronal manipulations revealed how arousal states affect decision making. The results and interpretations are convincing. This work will be of interest to both neuroscientists and ecologists.

eLife assessment

In this valuable study, the authors characterize the role of splicing factor SRSF1 during spermatogenesis with a conditional knockout for Srsf1 in male mouse germ cells. The requirement of SRSF1 for maturation of postnatal gonocytes into spermatogonia, and the molecular role of SRSF1 in regulating alternative splicing in juvenile testes are convincingly supported. The paper also provides strong evidence that the mRNA encoding Tial, a factor relevant for spermatogonial maintenance and male fertility, is alternatively spliced in testis and that this splicing is regulated by SRSF1. The work will be of interest to reproductive biologists and stem cell biologists.

eLife assessment

This valuable study provides extensive high-quality imaging data and new insights into the process of the endothelial-to-hematopoietic transition (EHT), which generates nascent hematopoietic stem cells from the ventral wall of the dorsal aorta. This study provides strong evidence that, based on apicobasal cell polarity, different morphologies exist for emergent hematopoietic stem cells. The study is incomplete at present in that it does not yet support the additional claim that there are functional consequences, as altered cell fate related to these different morphologies has not been definitively shown.

eLife assessment

Studies of synaptic development and plasticity in the nematode C. elegans have been limited by the difficulty of rapid, accurate assessments of synaptic structure. In this valuable work, the authors convincingly introduce and validate a computational pipeline, "WormPsyQi," that allows rapid, reproducible quantitation of fluorescent synaptic puncta while minimizing human error and bias. The authors also describe a new set of strains carrying synaptic markers. Together, these tools should provide many groups studying this model system with the ability to quantitatively characterize chemical and electrical synapses, even in densely packed regions in 3D space such as the nerve ring.

eLife assessment

Using the continuum theory of elastic solids, the authors suggest that periodic muscle contraction leads to elongation of C. elegans embryos by storing elastic energy that is subsequently released by extending the embryo's long axis. This important finding could apply to other developmental processes and be exploited in soft robotics. While the presented evidence is in principle convincing, features of the the theory are not explained in sufficient detail.

eLife assessment

This is an important demonstration of how the false-positive rate of high-resolution 2D template matching to find particles of a given target structure in 2D cryo-EM images (2DTM) relates to overfitting the data towards the template. The authors present new methods to measure the amount of model bias that gets introduced in high-resolution features of such maps, with compelling evidence that high-resolution features that are not present in the template can still be reconstructed in 3D from images obtained by 2DTM.

eLife assessment

This study presents a useful new approach for efficient computation of statistics on correlations between genetic variants (linkage disequilibrium, or LD), which the authors apply to quantify the extent of LD across chromosomes. The method and its derivation are solid. The authors document that cross-chromosome LD can be substantial, which has implications for geneticists who are interested in population structure and its impact on genetic association studies.

eLife assessment

This important proof-of-concept study strongly supports the utility of functional ultrasound imaging for evaluating cerebral hemodynamics in rat models of brain injury. Functional ultrasound affords a distinct coverage/spatial/temporal resolution tradeoff when compared to other modalities for studying brain hemodynamics. The solid data presented indicate high fidelity of the recordings, a particular feat given that the rats were awake. On the other hand, single slice imaging and complexity of registration of subsequent imaging sessions limit the usefulness of the approach, particularly for quantitative imaging, and the small sample size will need to be followed up with and verified by future studies. This work will be of interest to researchers working in functional neuroimaging and more precisely with preclinical models of stroke in rodents.

eLife assessment

This important study shows that pharmacologically enhanced catecholamine levels and increased voluntary spatial attention have overlapping as well as dissociable effects on performance on a visuospatial attention task and corresponding EEG markers. The findings provide solid evidence regarding how neuromodulatory arousal and selective spatial attention jointly shape perceptional decision-making.

eLife assessment

This study presents valuable findings about synaptic connectivity among subsets of unipolar brush cells (UBCs), a specialized interneuron primarily located in the vestibular lobules of the cerebellar cortex. The evidence supporting the claims are interesting although incomplete in some areas. The work will be of interest to cerebellar neuroscientists as well as those focussed on synaptic properties and mechanisms. Although several compelling pieces of data were presented, substantial work remains to be conducted in order for the hypothesis and predictions of the manuscript to confirm how these factors play out in the actual brain circuit and how it would impact the processing of feedback or feedforward activity that would be required to promote behavior.

eLife assessment

This manuscript provides valuable insights to the underlying mechanism for Spinocerebellar ataxia 6 (SCA6) due to defective endolysosomal trafficking of BDNF and its receptor TrkB. The findings are compelling and significant in understanding the underlying pathology of SCA6. The authors have acknowledged the experimental weaknesses and recognize there may be multiple mechanisms to explain the findings.

eLife assessment

This valuable study illuminates molecular movements of acid-sensing ion channels by combining advanced chemical biology and biophysical techniques. The evidence for the main claim, lack of interaction of molecular termini, is compelling and challenges prior models. This work is expected to pique interest in the ion channel signaling field, providing a fresh perspective.

eLife assessment

Miyano et al. study the impact of RIM-BP2 deletion at mossy fiber synapses, using direct electrophysiological recordings from mossy terminals and STED super-resolution microscopy. The paper addresses an important question in the field of synaptic transmission and provides compelling evidence demonstrating reduced calcium channel abundance in mossy terminals upon RIM-BP2 removal.

eLife assessment

This manuscript provides a useful demonstration that distractor effects in multi-attribute decision-making correlate with the form of attribute integration (additive vs. multiplicative). The evidence supporting the conclusions is generally solid, but there are concerns regarding the robustness of the statistical analyses. In addition, the lack of a clear theoretical motivation complicates the interpretation. The manuscript will be interesting to decision-making researchers in neuroscience, psychology, and related fields.

eLife assessment

The study by Ghafari et al. addresses a question that is highly relevant for the field of attention as it connects structural differences in subcortical regions with oscillatory modulations during attention allocation. Using a combination of magnetoencephalography (MEG) and magnetic resonance imaging (MRI) data in human subjects, inter-individual differences in the lateralization of alpha oscillations are explained by asymmetry of subcortical brain regions. The results are important, and the strength of the evidence is convincing. Yet, clarifying the rationale, reporting the data in full, a more comprehensive analysis, and a more detailed discussion of the implications will strengthen the manuscript further.

eLife assessment

Richevaux and colleagues conducted a valuable study that investigated the integration of thalamic and retrosplenial inputs in the dorsal presubiculum, an essential hippocampal region involved in spatial navigation and memory. Through ex vivo optogenetic electrophysiological experiments, they discovered that many presubicular pyramidal cells receive convergent inputs from both the anterior thalamus and the retrosplenial cortex. These solid findings provide a potential cellular mechanism for anchoring the brain's internal compass to external landmarks, shedding light on how the brain integrates spatial information with an animal's sense of its position in space.

eLife assessment

The authors present a software package called osl-dynamics that uses generative models (Hidden Markov Model and Dynamic Network Modes) that can be adapted to the data, and the latent states and transition across states obtained through the model can be used to describe spectro-temporal characteristics of the brain signals, as well as for oscillatory burst detection. This approach is important and adds to the repertoire of techniques that can be used to study high-dimensional data and having access to this software (with tutorials and examples) will help other researchers test the usefulness of their approach. The evidence is convincing, but could further benefit from an objective way by which the output of their model can be compared/judged or through results from synthetic data with known properties.

eLife assessment

This paper by Aitchison and colleagues describes nanobody neutralizing and binding activity against various SARS-CoV-2 variants of concern. The findings are important in that the described nanobodies may have broad therapeutic relevance against current and future variants of concern and may be able to avoid significant resistance. The claims are incomplete: while the study is well-executed and uses a nice balance of biochemical and cellular assays, the efficacy of the proposed nanobody library against VOCs is not completely supported as IC50 values appear to increase against newer variants and are higher than previously used therapeutic bNAbs, animal data showing in vivo efficacy is lacking, and protection against future possible variants is not proven.

eLife assessment

This study presents a useful differentiation method that produces syndetome-like cells from human induced pluripotent stem cells as determined through single-cell RNA sequencing analysis. Nevertheless, it is essential to note that the authors' assertion that the efficiency of syndetome differentiation can be enhanced by inhibiting BMP and Wnt requires further substantiation, as the evidence provided remains incomplete. The major weaknesses of the manuscript center on issues related to data representation in figures and their subsequent interpretation. The work holds relevance for scholars in the field of musculoskeletal research who are dedicated to advancing translational medicine for the benefit of patients.

eLife assessment

This study presents valuable structural data for the bacterial adhesin PrgB, an atypical microbial cell surface-anchored polypeptide that binds DNA. There is convincing support for the claims regarding the overall function and importance of individual domains, which integrate a wide range of new and previously published experimental data. The structure-based model of PrgB molecular activity will be impactful in the field of bacterial adhesins, conjugation, and biofilm formation, especially because it focuses on a clinically relevant Gram-positive pathogen, whereas most work in the field has been focused on Gram-negative model systems.

eLife assessment

This paper describes innovative force measurements of the bending modulus of gliding cyanobacteria, along with measurements of the critical buckling length of the cells, which combined lead to valuable insight into how these cells produce the force necessary to move. The major findings are well supported by the data; however, the evidence that the results favor an adhesion-based mechanism is currently incomplete.

eLife assessment

This fundamental study identifies the homeodomain transcription factor and suspected autism-candidate gene Meis2 as transcriptional regulators of maturation and end-organ innervation of low-threshold mechanoreceptors (LTMRs) in the dorsal root ganglia (DRG) of mice. For a few years, the view on autism spectrum disorders (ASD) has shifted from a disorder that exclusively affects the brain to a condition that also includes the peripheral somatosensory system, even though our knowledge about the genes involved is not complete. The study by Desiderio and colleagues is therefore not only scientifically interesting but may also have clinical relevance. The work is convincing, with appropriate and validated methodology in line with current state-of-the-art and the findings contribute both to understanding and potential application.

eLife assessment

This paper presents a new method called MINT that is simple yet effective at BCI-style decoding tasks in stereotyped settings. While the reviewers raise caveats, overall they believe the work is a valuable study for the field of motor control, and the evidence to support their claims is solid.

eLife assessment

What makes one member of the species behave differently from another is a core problem in behavioral neuroscience. The authors studied the specific case of odor preference behavior in fruit flies, and searched for links to activity in the first and second stages of the olfactory system. This is a valuable study, but the results are overstated and the evidence incomplete. It is difficult to discern robust links between neural structure/function and behavior in the data set as presented here.

eLife assessment

In zebrafish, primary motor neurons (PMNs) control escape movements, and a more heterogeneous population of secondary motor neurons (SMNs) regulate the speed of rhythmic swimming. Using single cell RNA sequencing (scRNAseq), the authors have obtained compelling evidence that PMNs, and two types of interneurons innervating them, express a set of three genes encoding voltage-gated ion channels enabling rapid firing. The PMNs also express high transcript levels of proteins involved in exocytosis, which would be expected to support rapid neurotransmitter release. These results will be important for those working on spinal cord function and zebrafish genomics/transcriptomics.

eLife assessment

This study presents a valuable set of experiments to test whether Bombus terrestris bumblebees can detect lethal-level doses of a series of pesticides in nectar-mimicking sugary solutions. Behavioural essays were coupled with electrophysiological measurements to show that B. terrestris mouthparts cannot detect high levels of the tested pesticides. If confirmed using pesticide formulas, and other bumblebee species, the study will be of general interest in environmental science research. Most experimental data are compelling, and the conclusions are sound, but the write-up would benefit from a broader ecological context.

eLife assessment

Müller glial cells of the zebrafish retina can differentiate into all neural cell classes following injury, providing full regenerative capabilities of the zebrafish retina. This valuable study presents a description of transcriptional changes of Müller glia cells in the adult and regenerating retina using single-cell RNA sequencing. The overall evidence supporting the main claims of the authors is solid.

eLife assessment

This important study identifies the gustatory receptors for sugar sensing in the larval and adult forms of the cotton bollworm, which is responsible for the destruction of many food crops world-wide. The authors find that the larval and adult forms utilise different receptors to sense sugars. The data are convincing and will be of interest neuroscientists working in sensory coding of sugars and to the pest management field.

eLife assessment

This manuscript will provide a valuable method to evaluate the safety of MR in patients with orthopaedic implants, which is required in clinics. A strength of the work is that the in-silicon testbed is solid, based on the widely available human project, and validated. In addition, the toolbox will be open for clinical practice.

eLife assessment

This important work by Hann et al. advances our understanding of the role of the survival motor neuron (SMN) protein in coordinating pathogenesis of the spinal muscular atrophy (SMA). The authors provide convincing but, nevertheless, incomplete evidence in terms of skeletal analyses not being able to satisfactorily elucidate SMN regulation of bone development. The paper appears to be descriptive and will benefit from additional experiments to justify the hypothesis. With amendments, this work will be of broad interest to biologists especially those working on the SMA.

eLife assessment

This study presents valuable data on how HSCs are expanded under PVA cultures. The functional evidence supporting the claims of the authors is solid, although an extended multi-omic data analysis could have strengthened the study. The work will be of interest to individuals within this HSC field.

eLife assessment

This study presents valuable new insights into HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, and delineates the kidney cell types that express HIV genes and are injured in these HIV-transgenic mice. A series of compelling experiments demonstrated that PKR inhibition can ameliorate HIVAN with reversal of mitochondrial dysfunction (mainly confined to endothelial cells), a prominent feature shared in other kidney diseases. Although there are concerns regarding the specificity of C16 to PKR inhibition, as well as with the in situ hybridization studies, the data suggests that inhibition of PKR and mitochondrial dysfunction has potential clinical significance for HIVAN.

eLife assessment

This valuable study examines the effects of NFKB2 mutations on pituitary gland development through hypothalamic-pituitary organoids. The evidence supporting the main conclusions is solid, although analysis of additional clones to exclude inter-clone variability would strengthen the conclusions. Insight into the mechanism of action of NFKB2 during pituitary development is incomplete. This work will be of interest to endocrinologists and biologists working on pituitary gland development and disease.

eLife assessment

This useful article reports the possible roles of the natural product TRPV1 activator Eugenol on muscle performance and remodeling. It provides as yet incomplete evidence for eugenol, through TRPV1, but nevertheless merits future investigation.

eLife assessment

This study presents a valuable report on the first warm autopsy case of a metastatic prostate cancer patient and the follow-up genomic and epigenomic analysis. The evidence supporting the claims of the authors is solid, although inclusion of more discussion of the study limitation and elaboration of mechanistic link for TP53, CDK12, and CDKN1B mutations would have strengthened the study. The work will be of interest to medical biologists working on prostate cancer.

eLife assessment

This compelling and novel mathematical method assesses drug pro-arrhythmic cardiotoxicity by examining the electrophysiology of untreated cardiac cells. It will be valuable for future drug safety design.

eLife assessment

This study presents valuable findings on diabetogenic risk from colorectal cancer (CRC) treatment. The authors claim that postoperative screening for type 2 diabetes should be prioritized in CRC survivors with overweight/obesity, irrespective of the oncological treatment received. The evidence supporting the claims is solid but requires confirmation in different populations. These results have theoretical or practical implications and will be of interest to endocrinologists, oncologists, general practitioners, gastrointestinal surgeons, and policymakers working on CRC and diabetes.

eLife assessment

Trypanosoma brucei evades mammalian humoral immunity through the expression of different variant surface glycoprotein genes. In this fundamental paper, the authors extend previous observations that TbRAP1 both interacts with PIP5Pase and binds PI(3,4,5)P3, indicating a role for PI(3,4,5)P3 binding. They therefore suggest that antigen switching might have a signal-dependent component. The evidence is mostly compelling, but with some caveats because tagged proteins were used.

eLife assessment

This important study demonstrates widespread introgression between species of cyanobacteria in hot springs in Yellowstone National Park. Using single cell sequencing of hundreds of genomes, the authors provide one of the most convincing demonstrations to date of the importance of selection and hybridization in shaping polymorphism within a natural community. The strong enthusiasm for the paper is only dampened slightly by the methods not being described in the clearest possible manner.

eLife assessment

This work provides valuable insights into mucosal antibody responses against SARS-CoV-2 following intranasal immunization by characterizing a large number of monoclonal antibodies at both mucosal and non-mucosal sites. The evidence supporting the claims is overall solid, although the flow cytometric assessment of antibody-expressing cells would benefit from more rigorous controls. The demonstrated in vitro antiviral activity of antibodies characterized provides a rationale for developing mucosal vaccines, especially if confirmed in vivo and benchmarked against antibodies generated following intramuscular vaccination.

eLife assessment

While decades of research findings have supported the idea that action attenuates predicted touch, recent work has countered this, proposing that action actually enhances predicted touch and the previously observed attenuation is due to tactile contact. This present study resolves these contradictory claims regarding the role of prediction in perception of self-action. This important work provides compelling evidence that self-generated touch is attenuated compared to the same touch externally-generated, and a clear explanation for recent high-profile results that appeared to support the opposite view.

eLife assessment

This work presents useful and potentially valuable findings on how food signals may influence reproduction in the nematode C. elegans. In the current manuscript, the evidence in support of the authors' model is incomplete, and additional experimental data is needed to buttress the authors' conclusions.