eLife assessment

This is an important study that extends our understanding of how the medial prefrontal cortex regulates goal-directed action during threat. The authors provide convincing evidence that prefrontal cortex parvalbumin neurons suppress conditional freezing responses, permitting the initiation of active controlling responses over shock onset (termed 'avoidance'); also, this cell-type function does not generalize to appetitive situations or general locomotion. These findings are expected to be of great benefit to multiple neuroscience subfields interested in the mechanisms of adaptive behavior.

eLife assessment

This study provides an important contribution to understanding how parafoveal words are neurally processed. The study employs a state-of-the-art frequency tagging paradigm to study the MEG response to words during natural reading. It provides solid evidence that semantic information of parafoveal words can be extracted.

eLife assessment

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

eLife assessment

The aim of this valuable study is to uncover developmental roles of the neuropeptide prothoracicotropic hormone (PTTH) and ecdysone, which later regulate female receptivity of Drosophila melanogaster. The work combines spatially and temporally restricted genetic manipulation with behavior quantification to explore these molecular pathways and the neuronal substrates participating in the control of female sexual receptivity. At present, the implication of both signaling pathways in this process is convincing but the strength of the evidence is incomplete to support the main claim that PTTH pathway controls female sexual receptivity through the function of ecdysone in pC1 neurons.

eLife assessment

This important and elegant study makes a significant step towards harmonisation of two perspectives on synaptic plasticity in the brain: Bayesian inference and energy efficiency. Through a combination of analytical derivations and numerical simulations, the authors make a compelling case that the two perspectives, which on the surface seem very different, are in fact closely related. In addition, they provide moderate experimental evidence that corroborates predictions of their synaptic plasticity models.

eLife assessment

Winter months with short days are commonly associated with seasonal depression and hypersomnolence; the mechanisms behind this hypersomnolence however remain unclear. Chen and colleagues identify a genetic basis for this phenomenon in the fly Drosophila - mutations in the circadian photoreceptor cryptochrome resulted in increased sleep under short photoperiods. These findings are potentially valuable insights into the genetic mechanisms regulating sleep under short days. The data supporting the neurobiological basis of these effects is however incomplete.

eLife assessment

This study reports valuable findings that corticostriatal projections (specifically, from M1 and MCC ) target direct and indirect pathway striatal projection neurons in partially segregated ways. Moreover, this partial segregation is biased, implying that specific engagement of the direct pathway may be achieved through the selective activation of unique cortical neurons. The evidence for this conclusion is solid, though the key experiments (rabies tracing controls, etc.) are incomplete. Otherwise, the experiments are rigorously designed, and the results are solid. This work will be of interest to those interested in brain anatomy and/or circuitry, cortical and/or basal ganglia function, locomotor activity, reinforcement learning, or diseases related to these.

eLife assessment

This MEG study reports valuable new findings regarding the nature of memory reactivation during cued recall. It replicates previous work showing that such reactivation can be sequential or clustered, with sequential reactivation being more prevalent in low performers. It adds solid evidence, even though based on limited data, that item strengths during clustered reactivation vary with item distance in the learned graph structure. The study will be of interest to human and rodent neuroscientists working on memory replay.

eLife assessment

This valuable study provides molecular-level insights into the functional mechanism of bacterial ice-nucleating proteins, detailing electrostatic interactions in the domain architecture of multimeric assemblies. The evidence supporting the claims of the authors is solid, with results from protein engineering experiments, functional assays, and cryo-electron tomography, while the proposed structural model of protein self-assembly remains hypothetical. The work is of broad interest to researchers in the fields of protein structural biology, biochemistry, and biophysics, with implications in microbial ecology and atmospheric glaciation.

eLife assessment

This manuscript presents a useful analysis of allosteric communication in the CFTR protein using a coarse-grained dynamic model and characterized the role of disease-causing mutations. The results and analyses are generally solid and validated with available experimental observations. The findings provide comprehensive insights into the allosteric mechanism of this protein.

eLife assessment

This important paper reports major technical advances for in vivo intramuscular electrical recording from multiple motor units in behaving animals. The paper includes compelling demonstrations of the efficacy of this new technique in multiple animal species. This new muscle recording method has the potential to provide new insight into a wide range of questions in motor neuroscience.

eLife assessment

This is a valuable computational study that applies the machine learning method of bilinear modeling to the problem of relating gene expression to connectivity. Specifically, the author attempts to use transcriptomic data from mouse retinal neurons to predict their known connectivity. The results are promising, although the reviewers felt that demonstration of the general applicability of the approach required testing it against a second data set. Hence the present results were felt to provide borderline incomplete support for a key premise of the paper.

eLife assessment

In this paper, the authors introduce fundamental work on mathematical methods for inferring evolutionary parameters of interest from RNA data in healthy tissue and during hematopoiesis. By combining single cell and bulk sequencing analyses, the authors use a stochastic process to inform different aspects of genetic heterogeneity; the strength of evidence in support of the authors' claim is exceptional. The work will be of broad interest to cell biologists and theoretical biologists.

eLife assessment

This review examines seasonal dormancy in various species, including hibernating mammals (excluding bats and bears) and ectotherms. It tests hypotheses on dormancy timing, considering energetic constraints and life history as alternative drivers. While the review is valuable, ecological differences between males and females can drive differences in energy balance, hence the idea that sex differences in dormancy timing are associated with non-energy constraints. Evidence supporting a life-history hypothesis is therefore somewhat incomplete. Nonetheless, examining these alternative hypotheses is of interest to evolutionary biologists, and including a diverse range of species, population-level traits, and some ecological context would enhance the value of the review.

eLife assessment

This study presents fundamental findings on the evolution of extremely elongated mandibular symphysis and tusks in longirostrine gomphotheres from the Early and Middle Miocene of northern China. The integration of multiple methods provides compelling results in the eco-morphology, behavioral ecology, and co-evolutionary biology of these taxa. In doing so, the authors elucidate the diversification of fossil proboscideans and their likely evolutionary responses to late Cenozoic global climatic changes.

eLife assessment

This valuable manuscript reports on the relationship between GTP hydrolysis parameters and kinase activity of LRRK2, which is associated with Parkinson's disease. The authors provide a detailed accounting of the catalytic efficiency of the ROC GTPase domain of pathogenic variants of LRRK2, in comparison with the wild-type enzyme. The authors propose that phosphorylation of T1343 inhibits kinase activity and influences monomer-dimer transitions, but the experimental evidence is currently incomplete.

eLife assessment

This is a theoretical analysis that gives compelling evidence that length control of bundles of actin filaments undergoing assembly and disassembly emerges even in the absence of a length control mechanism at the individual filament level. Furthermore, the length distribution should exhibit a variance that grows quadratically with the average bundle length. The experimental data are compatible with these fundamental theoretical findings, but further investigations are necessary to make the work conclusive concerning the validity of the inferences for filamentous actin structures in cells.

eLife assessment

The authors present 16 new well-preserved specimens from the early Cambrian Chengjiang biota. These specimens potentially represent a new taxon which could be useful in sorting out the problematic topology of artiopodan arthropods - a topic of interest to specialists in Cambrian arthropods. Because the anatomic features in the new specimens were neither properly revealed nor correctly interpreted, the evidence for several conclusions is inadequate.

eLife assessment

This is a useful study examining the determinants and mechanisms of LRMP inhibition of cAMP regulation of HCN4 channel gating. The evidence provided to support the main conclusions is unfortunately incomplete, with discrepancies in the work that reduce the strength of mechanistic insights.

eLife assessment

This important study provides proof of the principle that C. elegans models can be used to accelerate the discovery of candidate treatments for human Mendelian diseases by detailed high-throughput phenotyping of strains harboring mutations in orthologs of human disease genes. The data presented are solid and would potentially be convincing if complete data sets were to be made available to the scientific community. This approach enables the potential rapid repurposing of FDA-approved drugs to treat rare diseases for which there are currently no effective treatments.

eLife assessment

This valuable study presents presents solid evidence that an anti-CTLA-4 antibody drug conjugate transiently depletes circulating B cells in a mouse model, showing how dysregulation of the T cell immune system can impact B cell homeostasis. The work will be of broad interest to immunologists and medical biologists, but a major limitation is that the mechanism of B-cell reduction remains unclear, as evidence of killing of B-cells by T-cells is not presented.

eLife assessment

This study presents valuable information that an anti-CTLA-4 antibody drug conjugate transiently depletes circulating B-lymphocytes in a mouse model. It shows how dysregulation of the T cell immune system can impact B cell homeostasis. The work will be of broad interest to immunologists and medical biologists, but the strength of evidence is incomplete at this time mainly because they only analyzed circulating B cells.

eLife assessment

This important study offers new and convincing support for the idea that about a third of mouse liver DNAse hypersensitivity sites (DHS) showing male-biased chromatin opening are sex-biased because of the male-specific cyclic action of growth hormone pulses to alter chromatin accessibility, as compared to the relative ineffectiveness of the more static pattern of growth hormone secretion in females. Supporting evidence is found in the impact of hypophysectomy and growth hormone treatment on chromatin accessibility, and the binding of specific transcription factors and epigenetic marks at STAT5-sensitive sites. This work uncovers mechanisms underlying sex differences in liver function and will be of broad interest to endocrinologists and hepatologists.

eLife assessment

This study defines the roles for two different missense mutations observed in patients in the Trabid/ZRANB1 gene associated in children with a range of congenital disorders including reduced brain size. The study is important because the findings have theoretical or practical implications beyond a single subfield, as the study of DUB and cytoskeletal alterations have implications for neurodevelopment broadly. The methods are convincing as they utilize appropriate and validated methodology in line with current state-of-the-art by incorporating knock-in mice of the patient mutations. Many of the reviewer comments were focused on potential next experiments, rather than on evaluation of the data at hand, and the authors have considered these as future studies. The work as presented suggests critical roles for Trabid in the STRIPAK complex mediating APC deubiquitylation.

eLife assessment

This work presents important findings regarding the use of soil environmental DNA for non-invasive monitoring of the endangered kākāpō parrot population in New Zealand. The approach based on sequence analysis is convincing but comparisons to established methods are lacking. The tools presented in this study are innovative and will be relevant to those working with environmental DNA and the conservation of biodiversity.

eLife assessment

This valuable data study presents convincing data that expression of the C. elegans transcription factor NHR-67 is sufficient to drive an invasive fate, and that the alternative proliferative fate is associated with NHR-67 transcriptional down-regulation. While the observation that NHR-67 forms punctae associated with transcriptional repressors in non-invasive cells is intriguing, the work does not yet established a clear link between the formation and dissolution of NHR-67 condensates with the activation of downstream genes that NHR-67 is actively repressing. The work will be of interest to developmental biologists studying transcriptional control of cell fate specification in animals, especially once issues around the functional significance of the NHR-67 contiaining punctae are resolved.

eLife assessment

This important study identifies the role of Caveolin1 and Cavin1 as regulators of TransEndothelial Macroaperture (TEM). The methodology used is rigorous and compelling, and further research can point to a more mechanistic understanding of the process.

eLife assessment

This fundamental work proposes a novel mechanism for memory consolidation where short-term memory provides a gating signal for memories to be consolidated into long-term storage. The work combines extensive analytical and numerical work applied to three different scenarios and provides a convincing analysis of the benefits of the proposed model, although some of the analyses are limited to the type of memory consolidation the authors consider (and don't consider), which limits the impact. The work could be revised to include a more thorough comparison to existing models of memory consolidation and a discussion of its limitations, and the revision could also streamline the technical terminology. The work will be of interest to neuroscientists and many other researchers interested in the mechanistic underpinnings of memory.

eLife assessment

This is a potentially important study that integrates QM/MM free energy simulations and experimental kinetic analyses to probe the nature of phosphoryl transfer transition state in adenylate kinase. The idea that the transition state ensemble encompasses conformations with substantially different structural features (including the breaking/forming bonds) is interesting and potentially applicable to many other enzyme systems. In the current form, however, the study is considered incomplete since the connection between the putative transition state ensemble from the computations and key experimental observables, such as the activation entropy, is not well established.

eLife assessment

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

eLife assessment

The work is a useful contribution towards understanding the role of archaeal and plant D-aminoacyl-tRNA deacylase 2 (DTD2) in deacylation and detoxification of D-Tyr-tRNATyr modified by various aldehydes produced as metabolic byproducts in plants. It integrates convincing results from both in vitro and in vivo experiments to address the long-standing puzzle of why plants outperform bacteria in handling reactive aldehydes and suggests a new strategy for stress-tolerant crops. The impact of the paper is limited by the fact that only one modified D-aminoacyl tRNA was examined, in lack of evidence that plant eEF1A mimics EF-Tu in protecting L-aminoacyl tRNAs from modification, and in failure to measure accumulation of toxic D-aminoacyl tRNAs or impairment of translation in plant cells lacking DTD2.

eLife assessment

The work by Johnson and co-workers has identified an important role of 2-Hydroxybutyrate in skeletal muscle oxidative capacity in the early stages of exercise. Mechanistically, they show convincing data to support a role of 2-Hydroxybutyrate in the regulation of BCAA metabolism via SIRT4, ADP-Ribosylation, and CEBP. However, whether this is the sole mechanism and if these translate to longer exercise training regimes requires future experiments.

eLife assessment

The manuscript "Structure Guided mutatgensis of OSCAs reveals differential activation to mechanical stimuli" seeks to dissect the molecular underpinnings of poke and stretch activation in OSCA channels. While the structural and functional experiments are well done, and the authors present some important data, the reviewers identified weaknesses in experimental design and interpretation that render the data incomplete in supporting some of the main conclusions of the paper. Nevertheless, this work will be of interest to those working in the fields of mechanosensation, sensory biology, and ion channels.

eLife assessment

This study reports valuable findings on the correlation between the positions of dendritic mitochondria and the orientation preference of calcium responses of individual spines. The conclusion about the biased localization of dendritic mitochondria near functional diverse spines is informative to understand the functions of dendritic mitochondria. The experimental evidence supporting the conclusion is compelling.

eLife assessment

This important paper exploits new cryo-EM tomography tools to examine the state of chromatin in situ. The experimental work is meticulously performed, with a vast amount of data collected, with convincing interpretation of possible nucleosomal structures in yeast. The majority of these nucleosomes appear not to possess stable octameric configurations. Although it cannot be excluded that there could be an unknown bias in class detection, we agree that the authors have gone as far as is possible, given constraints in current technology and analysis, to support their model. Despite the provocative nature of this report, it is our hope that such work will spark debate, and further the development of exciting new tools that can interrogate the dynamic nature of the nucleosome, and its associated functions in situ.

eLife assessment

This important paper exploits new cryo-EM tomography tools to examine the state of chromatin in situ. The experimental work is meticulously performed and convincing, with a vast amount of data collected. The main findings are interpreted by the authors to suggest that the majority of yeast nucleosomes lack a stable octameric conformation. Despite the possibly controversial nature of this report, it is our hope that such work will spark thought-provoking debate, and further the development of exciting new tools that can interrogate native chromatin shape and associated function in vivo.

eLife assessment

This important study evaluates the outcomes of a single-institution pilot program designed to provide graduate students and postdoctoral fellows with internship opportunities in areas representing diverse career paths in the life sciences. The data convincingly show the benefit of internships to students and postdocs, their research advisors, and potential employers, without adverse impacts on scientific productivity. This work will be of interest to multiple stakeholders in graduate and postgraduate life sciences education and should stimulate further research into how such programs can best be broadly implemented.

eLife assessment

This study presents a valuable 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 appears solid, although the presentation of equations needs clarification and improvement. 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 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 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 orthogonal evidence would be required to fully support the claims concerning the mechanistic basis for voltage sensitivity.

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 study presents valuable observations on a potential role of creatine (Cr) as a novel neurotransmitter. While the data provide compelling evidence that Cr is present in synaptic vesicles, the evidence that Cr is synaptically released and binds to a post-synaptic receptor is incomplete, as no receptor is described. With further evidence, these results will be of wide interest to the field of neuroscience.

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 is a valuable comparative study of local adaptation using gene-by-environment and gene-by-phenotype correlations. The analyses seemed still incomplete, as the biological take-home messages were obscured by the statistical approaches used, and it remains unclear how to best interpret the level of genome-wide convergence and in inversions. The repeatability of local adaptation across species, and the role of inversions in local adaptation, are questions of considerable empirical interest.

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

This is a valuable information-theoretic re-analysis of human intracranial recordings during reward and punishment learning. It provides solid evidence that reward and punishment learning is represented in overlapping regions of the brain while relying on specific inter-regional interactions. However, there are weaknesses in the analysis approach that raise concerns about the consistency of the effects across participants and the interpretation of the findings. This preprint will be interesting to researchers in systems and cognitive neuroscience.

eLife assessment

This fundamental study addresses the earliest events that enable plant roots to reorient growth in response to gravity. Compelling molecular and cell biological data establish that plasma membrane localization of the LAZY or NEGATIVE GRAVITROPIC RESPONSE OF ROOTS (NGR) protein family is required for rapid and polar redirection of D6 protein kinase, an activator of the PIN3 auxin transporter. This work complements recent publications on the NGR family in gravity sensing (Chen et al., PMID: 37741279 and Nishimura et al., PMID: 37561884). Collectively these papers advance our understanding of rapid plant gravity sensing and response.

eLife assessment

This manuscript provides a fundamental contribution to the understanding of the role of intrinsically disordered proteins in circadian clocks and the potential involvement of phase separation mechanisms. The authors convincingly report on the structural and biochemical aspects and the molecular interactions of the intrinsically disordered protein FRQ. This paper will be of interest to scientists focusing on circadian clock regulation, liquid-liquid phase separation, and phosphorylation.

eLife assessment

This manuscript describes fundamental single-molecule correlative force and fluorescence microscopy experiments to visualize the 1D diffusion dynamics and long-range nucleosome sliding activity of the yeast chromatin remodelers, RSC and ISW2. Compelling evidence shows that both remodelers exhibit 1D diffusion on bare DNA but utilize different mechanisms, with RSC primarily hopping and ISW2 mainly sliding on DNA. These results will be of interest to researchers working on chromatin remodeling.

eLife assessment

This manuscript describes useful information on the interactions of the BRAF N-terminal regulatory regions (CRD, RBD and BSR) with the C-terminal kinase domain and with the upstream regulators HRAS and KRAS. The authors provide solid evidence that the BRAF BSR domain may negatively regulate RAS binding and propose that the presence of the BSR domain in BRAF provides an additional layer of autoinhibitory constraints. The data will be of interest for researchers in the RAS/RAF and general kinase regulation fields.

eLife assessment

This important study examined whether the BMP signaling pathway has a role in H3.3K27M DMG tumors, regardless of the presence of ACRVR1 activating mutations. The authors show compelling evidence that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. Although this work could be further enhanced by the inclusion of additional models as well as further consideration of elements, such as the location of the tumor, in the datasets used, overall this work suggests that BMP2/7 could be considered as a target for future therapies in this deadly cancer.

eLife assessment

This study presents a useful finding on the role of GABRD and its downstream target CDK1 in the progression of breast cancer. The evidence supporting the claims of the authors is somewhat incomplete and the elaboration of the mechanistic details on GABARD/CDK1 regulation would have strengthened the study. The work will be of interest to clinicians and biologists working on breast cancer.

eLife assessment

This important study substantially advances our understanding of pediatric Crohn's disease, mapping the cellular make-up of this disease and how patients respond to treatment. The evidence supporting the conclusions is compelling, with thorough bioinformatic analyses, underpinned by rigorous methodology and data integration. The work will be of broad interest to pediatric clinicians, immunologists and bioinformaticians.

eLife assessment

The authors analyzed the causative association between circulating immune cells and periodontitis, and reported three risk immune cells related to periodontitis. The significance of the findings is fundamental, which substantially advances our understanding of periodontitis. The strength of evidence is convincing.

eLife assessment

This manuscript reports important in vitro biochemical and in planta experiments to study the receptor activation mechanism of plant membrane receptor kinase complexes with non-catalytic intracellular kinase domains. Several lines of evidence convincingly show that one such putative pseudokinase, the immune receptor EFR achieves an active conformation following phosphorylation by a co-receptor kinase, and then in turn activates the co-receptor kinase allosterically to enable it to phosphorylate down-stream signaling components. This manuscript will be of interest to scientists focusing on cell signalling and allosteric regulation.

eLife assessment

This useful manuscript reports mechanisms behind the increase in fecundity in response to sub-lethal doses of pesticides in the crop pest, the brown plant hopper. The authors hypothesize that the pesticide works by inducing the JH titer, which through the JH signaling pathway induces egg development. Evidence for this is, however, inadequate.

eLife assessment

This study describes important results from cardiac-specific overexpression of adenylyl cyclase type 8 (TGAC8) mice that was integrated with transcriptomic and proteomic evidence. The paper convincingly provides new insights into how one can interpret signals from visceral organs.

eLife assessment:

This valuable manuscript provides solid methodologies for utilizing SMALP nanodisks for oligomer characterization. The authors present a platform for capturing and studying native membrane protein oligomerization and subsequent cryoEM analysis. The specific application of the method to WbaP, a membrane-bound phosphoglycosyl transferase, adds to our understanding of glycoconjugate production in bacteria. This manuscript would be of interest to those focusing on native membrane protein studies and antimicrobial resistance.

eLife assessment

This important paper addresses the challenging problem of dating the origin of several groups of marine microorganisms. However, while much of the analyses are solid, the lack of robustness analysis in molecular dating component such as using alternative time calibrations, clock models, and input gene sets makes the study incomplete. Despite some concerns, this work is a commendable attempt at an extremely difficult problem and will be of broad interest to microbiologists, geologists, and evolutionary biologists.

eLife assessment

This important paper addresses the challenging problem of dating the origin of several groups of marine microorganisms. The analyses are solid, with various test of clock models and time calibrations used, however given the uncertainty of many of the dates used to anchor ancient geological events, further studies are needed to support or refute the hypotheses put forth in this paper. Despite some methodological concerns, this work is a commendable attempt at an extremely difficult problem and will be of broad interest to microbiologists, geologists, and evolutionary biologists.

eLife assessment

This paper identifies a subset of neurons within adult mouse myenteric ganglia that are not labeled via canonical neural-crest labeling, and argues, based on extensive lineage tracing, imaging and genomic data that these neurons are derived from mesoderm. There is convincing evidence for the existence of an unusual cell type in the gut that expresses neuronal markers, but which is derived from cells expressing markers of the mesoderm rather than the expected neural crest, which is an intriguing and important observation. While the data do not definitively establish the molecular taxonomy of this lineage, there is sufficient evidence to support the provocative and paradigm-shifting hypothesis of the non-ectodermal origin for enteric neurons to warrant further deeper investigation.

eLife assessment

The work is a valuable contribution to understanding the mechanism of nuclear export of tRNA in budding yeast. The authors present solid evidence that Dbp5 functions in parallel with Los1 and Msn5 in tRNA export, in a manner dependent on Gle1 for activation of its ATPase activity but independently of Mex67, Dbp5's partner in mRNA export. It further presents solid biochemical evidence that Dbp5 can bind tRNA but that Gle1 and InsP6 are required for activating ATP hydrolysis by the Dbp5-tRNA complex, suggesting a possible mechanism for tRNA export by Dbp5.

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 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 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.