eLife assessment

This important study sheds light on the role of sphingolipids on the maturation of Parkinson's disease-associated Synphilin-1 inclusion bodies (SY1 IBs) on the mitochondrial surface in a yeast model using Synthetic Genetic Array (SGA) and state-of-the-art imaging techniques. The authors provide solid evidence that downregulating the sphingolipid biosynthesis pathway leads to defective maturation and enhanced toxicity of SY1 IBs in both yeast and mammalian cells. However, these data neither explain the role of mitochondrial surface sphingolipids in SY1 IB maturation (the cellular site of maturation of smaller toxic aggregates to bigger less toxic IBs), nor the requirement of mitochondrial activity in IB maturation.

eLife assessment

This study presents a valuable finding on the cell composition in mouse spleen depleted for the CD47 receptor and its signaling ligand Thrombospondin in hematopoietic differentiation. The supporting evidence is convincing with analytical improvements on the individual contributions of the signaling components and with functional studies. This work has implications for the role of CD47/Thsp in extramedullary erythropoiesis in mouse spleen and will be of interest to researchers in cell signaling, transfusion medicine, and cell therapy.

eLife assessment

This valuable work deals with mathematical modeling of centrosome maturation, building on the insight that autocatalytic assembly of the centrosome leads to size inequality. To remedy this, the authors propose a catalytic growth model with a shared enzyme pool that is able to reproduce various experimental results such as centrosome size scaling with cell size and centrosome growth curves in C. elegans. While finding the work of interest, the strength of the evidence presented in favor of the model is incomplete.

eLife assessment

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

eLife assessment

This study provides a valuable finding on the mechanistic connections between epithelial-mesenchymal transition (EMT) and lipid metabolism. The authors identified the ZEB2/ACSL4 axis as a newly discovered metastatic metabolic pathway that promotes both lipogenesis and fatty acid oxidation. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on cancer.

eLife assessment

This paper reports important findings on a potent activator of the YAP pathway, demonstrating its mechanism through alternative splicing changes. The authors provide convincing evidence to support their claims. This research is of interest to biologists studying alternative splicing or the Hippo pathway, with significant implications for medical research.

eLife assessment

This valuable study advances our understanding of the evolution of protein complexes and their functions. Through convincing experimental and computational methodologies, the authors show that the specialization of protein function following gene duplication can be reversible. The work will be of interest to investigators working in biochemical evolution and those working on heat shock proteins.

eLife assessment

This valuable paper characterizes a murine model for congenital cystic airway abnormalities (CPAM). In contrast to previous assumptions that only epithelial cells are involved in the formation of pulmonary cysts, the authors provide compelling new evidence that defective BMP signaling in lung mesenchymal cells can disrupt airway development. Knowing that proper BMP signaling in mesenchymal cells is required for normal cyst-free lungs could potentially pave the way to understanding and preventing CPAM in infants at risk for this common disorder, which can be fatal if untreated. The relevance of the murine model could be enhanced by providing further histological details in comparison with human cysts, as well as interrogation of datasets such as GWAS whether genetic changes in human cysts are related to abnormal BMP signaling.

eLife assessment

This valuable study identifies an uncharacterized yeast gene regulating chronological lifespan in a mitochondrial-dependent pathway. The approach to identify and characterise this new gene is compelling, but the evidence is incomplete in supporting the major conclusions. With a stronger focus on the relevance of replicative in addition to chronological lifespan, and stronger data linking to mitochondrial function, this paper would be interesting to the yeast biologists working in metabolism and aging.

eLife assessment

This is a useful contribution to our understanding of how different cell stressors (ethanol or heat-shock) might elicit unique responses at the genomic and topographical level under the regulation of yeast transcription factor Hsf1, and of the temporal coupling (or lack thereof) between Hsf1 aggregation and long-range communication among co-regulated heat-shock loci versus chromatin remodeling and transcriptional activation. A particular strength is the combination of genomic and imaging-based experimental approaches applied to genetically engineered in vivo systems. While much of the data is convincing, the work is incomplete in not providing strong evidence supporting (i) a similar rate and extent of proteotoxic stress under the two chosen stress conditions, (ii) relatively greater bulk chromatin compaction elicited by ethanol, (iii) reproducible levels of interactions between chromosomal loci, and (iv) phase-separated condensates versus other types of Hsf1 clusters.

eLife assessment

This important work shows compelling evidence that Chandelier cells in the visual cortex receive inputs most prominently from local layer 5 pyramidal neurons, only mildly inhibit L2/3 pyramidal neurons, and respond massively to visuomotor mismatch. It also indicates that visual experience in the virtual tunnel activates a plasticity mechanism in Chandelier cells which could be due to the particular visuo-motor coupling experienced in this setting, although a specific control is lacking for this conclusion. This study will be of interest to neuroscientists involved in cortical circuits, visual processing, and predictive coding research.

• for: Horizon Canada - strategic foresight think tank

• summary

  • Horizon Canada still makes the biggest assumption of all, an intact modernity

eLife assessment

This study reports useful information on the limits of the organotypic culture of neonatal mouse testes, which has been regarded as an experimental strategy that can be extended to humans in the clinical setting for the conservation and subsequent re-use of testicular tissue. The evidence that the culture of testicular fragments of 6.5-day-old mouse testes does not allow optimal differentiation of steroidogenic cells is compelling and should enable further optimizations in the future.

eLife assessment

This study presents valuable observations on a potential role of creatine (Cr) as a novel neurotransmitter. The data provide solid evidence that Cr is present in synaptic vesicles. If, in the future, a receptor can be described, it will support the claim that Cr is synaptically released and binds to a post-synaptic receptor. This would be of wide interest to the field of neuroscience.

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 valuable study focuses on the role of the Gr28 family of insect chemoreceptors. Using the Drosophila larva, the authors show that taste neurons expressing different members of this family of bitter taste receptors trigger opposite behavior – attraction and repulsion. They establish the minimal bitter taste receptor subunit composition needed in these neurons to mediate the repulsion of bitter tastants. The evidence presented is convincing, using well-validated and controlled tools and experiments.

eLife assessment

This important study presents findings regarding the role of Juvenile Hormone in development and cell differentiation in the ametabolous insect Thermobia domestica, providing an in-depth analysis of JH's roles in a member of this basally branching group. The evidence supporting the claims of the authors is convincing, drawing on a broad range of approaches and variety of experimental techniques. While the interpretation of this work in the wider context regarding its relevance for the evolution of metamorphosis is in some places overly speculative, the work will be of interest to evolutionary developmental biologists studying hormonal control of development and to entomologists studying the evolution of metamorphosis.

eLife assessment

This potentially important paper compares cross-species cortical folding patterns in human and non-human primates, showing that most gyral peaks shared across species are in lower-order cortical regions. The supporting evidence is currently incomplete, requiring the addition of multiple comparison corrections and further clarification and elaboration upon the statistical procedures used.

eLife assessment

This valuable study has practical and possibly theoretical implications for rhythm perception and production by showing individual differences in frequency preferences, and a deterioration in frequency adaptation with age. As it stands, the evidence for the main claims regarding the entrainment of internal oscillators is incomplete and requires further consideration. Regardless, the findings may inform existing models of rhythm perception and production, and the effects of age may have clinical implications.

eLife assessment

These important findings stand out from other similar studies via solid demonstration of behavioural and neural relationships between two helping tasks - one focusing more on social perception, one more on its influence on social behaviour - that were performed more than 300 days apart. The claims however would be enhanced with a larger sample size and greater consideration of the fact that merit and need are signalled via quite different cues - such that differences between them may have multiple origins.

eLife assessment

This work describes new validated conditional double KO (cDKO) mice for LRRK1 and LRRK2 that will be useful for the field, given that LRRK2 is widely expressed in the brain and periphery, and many divergent phenotypes have been attributed previously to LRRK2 expression. The manuscript presents solid data demonstrating that it is the loss of LRRK1 and LRRK2 expression within the SNpc DA cells that is not well tolerated, as it was previously unclear from past work whether neurodegeneration in the LRRK double Knock Out (DKO) was cell autonomous or the result of loss of LRRK1/LRRK2 expression in other types of cells. Future studies may pursue the biochemical mechanisms underlying the reason for the apoptotic cells noted in this study, as here, the LRRK1/LRRK2 KO mice did not replicate the dramatic increase in the number of autophagic vacuoles previously noted in germline global LRRK1/LRRK2 KO mice.

eLife assessment

This study provides useful information on the function of a ciliary and flagellar-associated protein, CFAP52, in the assembly of sperm head-tail connecting apparatus (HTCA) and tail formation in humans and mice. The significance is to identify CFAP52 as a genetic factor for asthenoteratozoospermia with a mixed acephalic spermatozoa syndrome (ASS) and multiple morphological abnormalities of the sperm flagella (MMAF) phenotype. The strength of the study is that the experimental evidence using CFAP52 loss-of-function in mice is solid to support that CFAP52 is essential for sperm motility and male fertility by contributing to HTCA and 9+2 axoneme, corroborating the sperm phenotypes of human patients with compound heterozygous mutations in CFAP52.

eLife assessment

This study reports an important physiological function of a conserved meiosis factor in spermatogenesis in mice. The genetic and cell biological evidence supporting the conclusion is convincing. This work will be of broad interest to cell biologists, geneticists, and reproductive biologists.

eLife assessment

This study provides useful datasets on gene expression and chromatin accessibility profiles in spermatogonial cells at different postnatal ages in mice. Overall, the technical aspects of the sequencing analyses and computational/bioinformatics are solid. However, there are concerns with the identity of the isolated cells and the lack of acknowledgment for previous studies that have also performed ATAC-sequencing on spermatogonia of mouse and human testes. The limitations call into question the validity of the interpretations and reduce the potential merit of the findings.

eLife assessment

This study provides a valuable survey of SMAD1/5 direct transcriptional events at the time of uterine receptivity to pregnancy in the mouse. The evidence supporting the authors' claims is solid, although functional validation, a more thorough genome-wide bioinformatic analysis, and better provision of methodological details would strengthen the study. The work will be of interest to reproductive biologists.

eLife assessment

This study presents valuable insights into the evolution of the gasdermin family, making a strong case that a GSDMA-like gasdermin was already present in early land vertebrates and was activated by caspase-1 cleavage. Convincing biochemical evidence is provided that extant avian, reptile, and amphibian GSDMA proteins can still be activated by caspase-1 and upon cleavage induce pyroptosis-like cell death - at least in human cell lines. The caspase-1 cleavage site is only lost in mammals, which use the more recently evolved GSDMD as a caspase-1 cleavable pyroptosis inducer. The presented work will be of considerable interest to scientists working on the evolution of cell death pathways, or on cell death regulation in non-mammalian vertebrates.

eLife assessment

Using extensive atomistic molecular dynamics simulations, the authors analyzed the TCR/pMHC interface with different peptide sequences and protein constructs. The results provide important insights into the catch-bond phenomenon in the context of T-cell activation. In particular, the analysis points to convincing evidence that supports the role of force in further discriminating different peptides during the activation process beyond structural considerations.

eLife assessment

This study presents a valuable inventory of immune responses to the BTN162b2 mRNA COVID-19 vaccination in 20 hemodialyses (HD) patients and controls at different time courses. The transcriptomic sequencing data were collected and analyzed using a solid and validated methodology. The data analysis and clinical predictors to predict anti-Spike IgG titers in HD can be a starting point for further studies characterizing the immune dysregulation seen in ESRD.

eLife assessment

This work is a valuable presentation of sharp-wave-ripple reactivation of hippocampal neural ensemble activity recorded as animals explored two different environments. It attempts to use the fact that the ensemble code remaps between the two mazes to identify the best replay-detection procedures for analyzing this type of data. The reviewers found the evidence for a prescriptive conclusion inadequate, while still appreciating the concept of comparing maze-identity discrimination with replay.

eLife assessment

This work is a valuable presentation of sharp-wave-ripple reactivation of hippocampal neural ensemble activity recorded as animals explored two different environments. It attempts to use the fact that the ensemble code remaps between the two mazes to identify the best replay-detection procedures for analyzing this type of data. The reviewers found the evidence for a prescriptive conclusion inadequate, while still appreciating the concept of comparing maze-identity discrimination with replay.

Editors Assessment:

The hairy vetch Vicia villosa is an annual legume widely used as a cover crop due to its ability to withstand harsh winters. Here a new a 2.03GB reference-quality genome is presented, assembled from PacBio HiFi long-sequence reads and Hi-C scaffolding. After adding some more methodological details and long-terminal repeat (LTR) assembly index (LAI) analysis the assembly quality and metrics look quite convincing as a chromosome-scale assembly. This resource hopefully providing the foundation for a genetic improvement program for this important cover crop and forage species.

This evaluation refers to version 1 of the preprint

Editors Assessment: Aedes mosquito spread Arbovirus epidemics (e.g. Chikungunya, dengue, West Nile, Yellow Fever, and Zika), are a growing threat in Africa but a lack of vector data limits our ability to understand their propagation dynamics. This work describes the geographical distribution of Ae. aegypti and Ae. albopictus in Kinshasa, Democratic Republic of Congo between 2020 and 2022. Sharing 6,943 observations under a CC0 waiver as a Darwin Core archive in the University of Kinshasa GBIF database. Review improved the metadata by adding more accurate date information, and this data can provide important information for further basic and advanced studies on the ecology and phenology of these vectors in West Africa.

This evaluation refers to version 1 of the preprint

eLife assessment

This study in budding yeast (S. cerevisiae) presents important findings demonstrating that the exonuclease Xrn1 regulates autophagy in response to methionine deprivation through effects on TORC1. There is solid evidence that the impact of Xrn1 on TORC1 is contingent on its catalytic activity rather than the degradation of any specific category of mRNAs. A major strength is the novel mechanism, in which Xrn1 modulates the nucleotide-binding state of the Gtr1/2 complex.

eLife assessment

This potentially important study examines patterns of diversity and divergence in two closely related sub-species of Zea mays, patterns that have bearings on local adaptation in maize and teosinte at intermediate geographic scales. The authors suggest that convergent evolution has been facilitated by both standing variation and gene flow, with independent selective sweeps in the two species. Limitations concerning population sampling, false positive rates in sweep detection and integration of phenotypic data at this stage only inadequately support the major conclusions. The work should in principle be of broad interest to colleagues studying the relationship between domesticated species and their progenitors, as well as those studying instances of parallel evolution.

eLife assessment

This work provides a valuable contribution and assessment of what it means to replicate a null study finding, and what are the appropriate methods for doing so (apart from a rote p-value assessment). Through a convincing re-analysis of results from the Reproducibility Project: Cancer Biology using frequentist equivalence testing and Bayes factors, the authors demonstrate that even when reducing 'replicability success' to a single criterion, how precisely replication is measured may yield differing results. Less focus is directed to appropriate replication of non-null findings.

eLife assessment

In their fundamental study, the authors employ a combination of cryo-electron microscopy, molecular dynamics, and mass spectrometry to elucidate the impact of α-tubulin acetylation at the lumenal lysine 40 residue (αK40) on the structure and stability of doublet microtubules in cilia. While the work provides compelling evidence for the role of αK40 acetylation in the cilium, the current version could benefit from additional statistical analyses and clarification of its conclusions regarding the effects of acetylation on microtubule inner proteins (MIPs).

eLife assessment

This landmark study sheds light on a long-standing puzzle of Protein kinase A activation in Trypanosoma. Extensive experimental work provides compelling evidence for the conclusions of the manuscript. It represents a significant advancement in our understanding of the molecular mechanism of Cyclic Nucleotide Binding domains and will be of interest to researchers with interest in kinases and mechanistic studies.

eLife assessment

This important study revises the evolutionary history of Heliconius butterflies, a well-established model system for understanding speciation in the presence of gene flow between species. Using a convincing statistical phylogenetic approach that relies on the multispecies coalescent, the authors reconstruct the evolution of the lineage, including the timing of speciation events and the history of gene flow. The new phylogeny will be of interest to all researchers working on Heliconius butterflies, and the phylogenetic approach to investigators aiming to understand the history of lineages that have experienced extensive gene flow.

eLife assessment

This study illuminates the effects of ultrasound-induced extracellular vesicle interactions with macrophages. It provides solid data offering insights that will be potentially useful in exploring therapeutic approaches to inflammation modulation, by suggesting that ultrasound-treated myotube vesicles can suppress macrophage inflammatory responses.

eLife assessment

This valuable study examines the evolution of the pillars in the shell architecture of organo-phosphatic brachiopods. The phylogenetic implications of this shell structure in relation to other early Cambrian brachiopod families are interpreted based on solid evidence. As such, this paper with interesting ideas regarding the evolution of brachiopod shell structure contributes to our understanding of the ecology and evolution of brachiopods as a whole.

eLife assessment

This important study offers new insight into how floral and reproductive phenotypes and gene expression evolve in allopolyploids. The authors marshal compelling evidence, using well-constructed genetic lines, RNA sequencing, and phenotypic analyses to distinguish the roles of hybridization, whole genome duplication, and subsequent evolution in phenotypes associated with the selfing syndrome and in gene expression. The work will be of interest to researchers working in plant speciation and genomics, as well as those more broadly interested in the effects of genome copy number on phenotypic and expression evolution.

eLife assessment

This important study highlights a potential connection between fatty acid intrusion into myocytes and increases in mitochondrial ceramide that cause deficits in coenzyme Q and consequent insulin resistance. The authors primarily use the L6 myocyte model, which may not fully recapitulate in vivo conditions, however, the manuscript shows compelling data in mice that substantially supports the L6 cell results. Overall, this study provides a strong framework for a compelling pathway of myocyte dysfunction and for continued efforts to test the important hypotheses that are presented.

eLife assessment

This study provides valuable findings on a causative relationship between LRRC23 mutations and male infertility due to asthenozoospermia. The evidence supporting the conclusions is solid. This work will be of interest to biomedical researchers who work on sperm biology and non-hormonal male contraceptive development.

eLife assessment

This study has uncovered some interesting findings about the fungal composition and its interaction with bacteria in Caesarean section scar diverticulum (CSD). While the study's findings are valuable and with translation possibilities, the strength of the conclusions obtained is incomplete due to the small sample size and methodological issues indicated by the reviewers such as the lack of controls and the location of samples analyzed.

eLife assessment

This manuscript reports an important series of results showing the relationship between oscillatory zinc and calcium fluctuations during egg activation and fertilization. Compelling evidence using several complimentary approaches provides further insight into the signals for proper egg activation that underpin successful fertilization and embryo development. The findings are significant because they may lead to improvements in assisted reproduction methods.

eLife assessment

The study presents valuable findings demonstrating that physiologically relevant concentrations delta-9-tetrahydrocannabinol, which is found in cannabis, have metabolic effects on early mouse embryonic cell types. The evidence supporting the claims is convincing. The work will be of interest to researchers in stem cell and epigenetics fields.

eLife assessment

This study provides valuable insight into the role of FBXO24, a member of the less characterized F-Box protein subfamily (F-box only protein) in controlling mRNA expression during spermiogenesis using loss-of-function and HA-tagged knock-in mouse models. The major strengths of the study are the rigorous phenotypic and molecular analysis by using two complementary animal models (knock-out mouse model but also HA-tagged transgenic mouse model) to determine protein levels and localization in time and space during normal spermatogenesis and in the absence of the protein. Overall, this solid study highlights the relevance and importance of FBXO24 in male fertility and provides a better understanding of the MIWI/piRNA pathway, mitochondrial organization, and chromatin condensation in mouse spermatozoa during spermiogenesis.

eLife assessment

This important study assesses anatomical, behavioral, physiological, and neurochemical effects of early-life seizures in rats, describing a striking astrogliosis and deficits in cognition and electrophysiological parameters. The convincing aspects of the paper are the wide range of convergent techniques used to understand the effects of early-life seizures on behavior as well as hippocampal prefrontal cortical dynamics. While reviewers thought that the scope was impressive, there was criticism of the statistical robustness and number of animals used per study arm, as well as the lack of causal manipulations to determine cause-and-effect relationships. This paper will be of interest to neurobiologists, epileptologists, and behavioral scientists.

eLife assessment

The current manuscript offers important updates to qFit , the state-of-the art tool for modeling alternative conformations of protein molecules based on high resolution X-ray diffraction or Cryo-EM data. While the authors provide convincing examples of qFit's performance, these are restricted to selected test cases. This manuscript will be of interest to structural biologists and protein biochemists more generally.

eLife assessment

This manuscript describes a potentially important theoretical framework to link predictive coding, error-based learning, and neuronal dynamics. The provided evidence is solid but would be made more robust if the different lines of argument were more directly connected. Improving the exposition of the manuscript would make it more accessible to a broader audience.

eLife assessment

This study reports important evidence that infants' internal factors guide children's attention and that caregivers respond to infants' attentional shifts during caregiver-infant interactions. The authors analyzed EEG data and multiple types of behaviors using solid methodologies that can guide future studies of neural responses during social interaction in infants. However, the analysis is incomplete, as several methodological choices need more adequate justification.

eLife assessment

This is a fundamental cell biological study of host responses during symbiotic microbial infection of plants. Compelling imaging-based approaches using genetically-encoded cell cycle markers show that in Medicago truncatula root cortex cells, early rhizobial infection events are associated with cell-cycle re-entry, but once the infection is established, host cells exit the cell cycle. The work will be of interest to a wide range of colleagues, from development and cell biology to plant-microbe interactions.

eLife assessment

Your study is based on exciting new tools that you have developed and is an important contribution to our understanding of the role of Calcium channels and their accessory subunits in synaptic biology The data are robust and provide compelling evidence for some of the proposed molecular mechanisms.

eLife assessment

This manuscript makes a valuable contribution to understanding the entanglement of homeostatic structural plasticity and synaptic scaling, yet only homeostasis after activity deprivation is studied in depth. The experimental and computational methods are solid but overall incomplete as the link between them remains qualitative. The conclusions drawn from the results are rather vague and their generality or relevance for other research fields is not made clear.

eLife assessment

This manuscript addresses infections of the parasite Taenia solium, which causes neurocysticercosis (NCC). NCC is a common parasitic infection that leads to severe neurological problems. It is a major cause of epilepsy, but little is known about how the infection causes epilepsy. The authors used neuronal recordings, imaging of calcium transients in neurons, and glutamate-sensing fluorescent reporters. A strength of the paper is the use of both rodent and human preparations. The results provide convincing evidence that the larvae secrete glutamate and this depolarizes neurons. Although it is still uncertain exactly how epilepsy is triggered, the results suggest that glutamate release contributes. Therefore, the paper is an important initial step towards understanding how Taenia solium infection leads to epilepsy.

eLife assessment

In this valuable manuscript Li & Jin record from the substantial nigra and dorsal striatum to identify subpopulations of neurons with activity that reflects different dynamics during action selection, and then use optogenetics in transgenic mice to selectively inhibit or excite D1- and D2- expressing spiny projection neurons in the striatum, demonstrating a causal role for each in action selection in an opposing manner. They provide solid evidence for the argument that their findings cannot be explained by current models and propose a new 'triple control' model instead, with one direct and two indirect pathways, although direct evidence for a second indirect pathway is still lacking. These findings will be of broad interest to neuroscientists across multiple subfields.

eLife assessment

This study provides a comprehensive whole genome transcriptomic analysis of three small mammals, including Peromyscus leucopus, after exposure to endotoxin lipopolysaccharide. The authors find that the inflammatory response of the three species is complex and that P. leucopus responds differently compared to mice and rats. The data are convincing and constitute an important advance in our understanding of inflammatory responses in animals that serve as reservoirs for relevant pathogens.

eLife assessment

This study presents important findings regarding the local dynamics at the anion binding site in the SLC26 transporter prestin that is responsible for electromotility in outer hair cells. The authors reveal critical differences to homologous proteins and thereby provide insight into prestin's unique function. The evidence is generally convincing, although the interpretations concerning the mechanistic basis for voltage sensitivity would benefit from orthogonal evidence.

eLife assessment

This important study provides data that challenges the standard model that binding of Type 2 Nuclear Receptors to chromatin is limited by the available pool of their common heterodimerization partner Retinoid X Receptor. The evidence supporting the conclusions is compelling, utilizing state-of-the-art single-molecule microscopy. This work will be of broad interest to cell biologists who wish to determine limiting factors in gene regulatory networks.

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 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.