eLife assessment

By developing a novel method for detecting genetic variants associated with germline mutation spectrum variation, this important study identifies a new "mutator" locus in a population of inbred mouse strains, although the causal gene(s) within this locus remains uncertain. The authors further demonstrate that this new mutator locus interacts epistatically with a previously identified mutator allele on C>A mutation rate, showcasing the complexity of the genetic basis underlying variation in mutation rate and spectrum. Evidence for major findings in this paper is convincing, but the power, statistical properties and limitations of the new method need to be further characterized to support its broader applicability to other systems.

eLife assessment

In this useful study, a solid machine learning approach based on a broad set of systems to predict the R2 relaxation rates of residues in intrinsically disordered proteins (IDPs) is described. The ability to predict the patterns of R2 will be helpful to guide experimental studies of IDPs. A potential weakness is that the predicted R2 values may include both fast and slow motions, thus the predictions provide only limited new physical insights into the nature of the relevant protein dynamics.

eLife assessment

This important study provides insights into the functions of different GNAI subunits, substantially advancing our understanding of their roles in the regulation of hair cell stereociliary bundle development. Convincing evidence is provided to support the findings and overall, the results of this study provide a thorough and careful examination of the roles of different GNAIs in the inner ear, with only minor weaknesses identified in review.

eLife assessment

This work is a valuable exploration of a new stability-guided fine-mapping method, which aims to identify causal genetic variations, by extending the previously proposed PICS method. While the results are empirically validated using functional annotations, their evaluation is incomplete and lacks extensive simulations where true causal variants are known. The approach to improving fine-mapping of causal variants presented will be of interest to geneticists and biomedical researchers using genetic data to guide their investigations.

eLife assessment

This study presents valuable findings on the symptoms and disease trajectories preceding a diagnosis of pancreatic cancer in Denmark. The evidence supporting the claims of the authors is solid, although an error analysis of the text mining evaluation results and a discussion on how the findings can be applied in practice would strengthen the study. The work will be of interest to public health researchers and clinicians working on pancreatic cancer.

eLife assessment

This article is of broad interest to public health researchers and to health policymakers in populations with national screening programs. It provides important knowledge on the impact of the COVID-19 pandemic on participation in mammography screening in Denmark by socio-economic indicators. The study provides convincing evidence for how the pandemic exacerbated disparities in breast cancer screening in Denmark.

eLife assessment

In this valuable report, the authors explore the connection between mTORC signaling and APA regulated by the CFIm complex. Using a combination of genetic and functional genomics approaches, the study reveals that a twin UGUA motif is a potent cis acting regulation of PAS usage that is recognized by CFIm. Overall, the evidence in general is convincing and supports the conclusions and provides the field with additional mechanistic insight of how signaling connects to APA regulatory machinery.

eLife assessment

This is an important study of the dimensionality and synchrony of calcium responses in Purkinje cells measured across a large region of the cerebellar cortex over the course of learning. This work has the potential to inform our understanding of the functional organization of the cerebellum and longstanding hypotheses about the role of cerebellar climbing fibers in the induction of learning and in the timing of movement, but the evidence provided for the many sweeping claims is incomplete. The paper would benefit from additional statistical analyses to more rigorously evaluate the central claims, with consideration of appropriate comparison groups and potential confounds.

eLife assessment

This important study uses mathematical modelling to demonstrate that conformational autoinhibition of the RAF kinase is an important feature of its paradoxical activation by pharmacological inhibitors. This part of the theoretical analysis is highly compelling but its extension to the investigation of how the binding of 14-3-3 adaptors additionally contributes to the paradoxical activation phenomenon is incomplete and would benefit from more rigorous experimental validation. With the experimental part addressing 14-3-3-dependent regulation strengthened or the 14-3-3 part completely removed, this paper would be of considerable interest to cell biologists and cancer biologists, ultimately paving the way for improved RAF therapeutics.

eLife assessment

This is a descriptive paper in the field of metascience, which documents levels of accessibility and reproducible research practices in the field of cardiovascular science. As such, it does not make a theoretical contribution, but it argues, first, that there is a problem for this field, and second, it provides a baseline against which the impact of future initiatives to improve reproducibility can be assessed. The study was pre-registered and the methods and data are clearly documented. This kind of study is extremely labour-intensive and represents a great deal of work.

eLife assessment

This study presents important evidence of the impact of the covid pandemic on breast cancer screening globally but with important variations by healthcare setting. The data analysis is comprehensive, using solid systematic review methods. The results will be of interest to public health policymakers and health care and cancer control practitioners and researchers across the globe.

eLife assessment

TP73 is a member of the p53 family of tumor suppressors. The authors provide compelling evidence that a TAp73-alpha to TAp73-gamma switch could be a frequent phenomenon in human cancers and provide novel evidence that TAp73-gamma has oncogenic functions via Leptin. The authors provide a substantial amount of high-quality data and convincingly demonstrate a novel function of this specific isoform of p73 in lipid metabolism and tumorigenesis.

eLife assessment

This is a valuable contribution to the effort to provide genetic access to and characterization of the major classes of interneurons in the mammalian neocortex. The authors develop an improved strategy for intersectionally targeting a fourth (and final) major category of diverse interneurons in the mouse, including the previously studied neurogliaform cells. They provide a detailed characterization of these cells and show convincingly that their genetic strategy can be used to identify and manipulate these cells, both in vitro and in vivo.

eLife assessment

In this important study, the authors present evidence for the novel involvement of a scavenger receptor in tubular morphogenesis. Using a convincing set of data, the authors propose that the Drosophila scavenger receptor Emp (homologous to human CD36 ) couples endocytosis of luminal molecules and regulates tube length via controlling Crumbs and Src. This work will be of broad interest to cell and development biologists as well as cancer biologists.

eLife assessment

This manuscript is important as it showed an establishment of a method for looking a neuronal activity in embryos which can support the previously reported laterality in chick thalamofugal system. However, the evidence the author provided was incomplete as no actual data was provided.

eLife assessment

This important study provides a substantial advance with a method by which a protein target resistant to therapeutic approaches can be uniquely modulated by a cellular protein kinase ferried by nanobodies to a precise molecular site of recruitment. Evidence for this major claim is compelling, but evidence for some of the minor claims seems incomplete. The work will be of broad interest to cell biologists, cardiovascular researchers, and drug developers.

eLife assessment

This important study provides a state-of-the-art framework to explore the coupling of complementary cerebral measures (neural, hemodynamic, and metabolic) during development by providing an interesting roadmap for multimodal neuroimaging in infants. The methodological contribution is compelling with an original setup for simultaneous EEG and NIRS recording and solid data analyses. However, the claims about functional specialization and the role of the temporal-parietal junction in social processing are only partially supported by the results. This work will be of interest to a broad audience of scientists interested in multimodal neuroimaging and cognitive development.

eLife assessment

Overall, this is an important study that characterizes human oral lichen planus via single-cell analysis. Although the work is descriptive, it can represent an important resource for future studies and highlights potentially relevant biology. However, the claims are a bit overstated and some of the analyses that lead to interpretations remain incomplete.

eLife assessment

This study is a valuable contribution to our understanding of vocal variation in acoustic displays of male baleen whales, part of a developing story about cultural change in songs in species other than the relatively well studied humpback whales. The authors present solid evidence of changes at various timescales in 20-Hz song note intervals and call center frequency over decadal time scales and large spatial scales.

eLife assessment

This is an important study demonstrating distinct roles for the nuclear receptor genes COUP-TFI and COUP-TFII in hippocampal development. The strength of evidence is compelling, using rigorous state-of-the-art methods to demonstrate functional redundancy of these genes in regulating the Lhx2/Lhx5 axis. The major strengths of the study are the dramatic morphogenic phenotypes, and the resultant altered gene networks. These findings have theoretical or practical implications beyond a single field, and will be of interest to geneticists, developmental neurobiologists and chromatin biologists among others.

eLife assessment:

This study offers new fundamental information on a role for the sodium/potassium pump in sleep regulation. Elegant methods were used to provide compelling evidence supporting the claim. The work will be of interest to sleep researchers in zebrafish as well as in other species for future investigation.

eLife assessment

This important study provides a framework bearing on the role of Eph-Ephrin signaling mechanisms in the clinically condition of amyotropic lateral sclerosis. It provides compelling evidence for the roles of glial cells in this condition. This novel astrocyte-mediated mechanism may help identify future therapeutic targets.

eLife assessment

This is an important study that revealed a new noncoding RNA regulatory circuit involved in T cell function. The authors provide compelling evidence, that is more rigorous than the state-of-the-art, using genetically engineered mice and cell-based experiments. The interpretation of the results should be tempered due to the small effect size observed.

eLife assessment

This important study aims to discover the mechanisms governing the switch between conventional DNA replication and the specialized mechanism of telomere end replication. Solid genetic and biochemical assays suggest an interplay between sumoylated PCNA and chromosome terminal capping proteins. The questions addressed have implications for several fields, such as genome stability.

eLife assessment

This valuable Tools and Resources paper presents new tools for investigating GLP-1 signaling: a genetically-encoded sensor constructed from a mutated GLP1R receptor as well as a caged agonist peptide. The evidence for these tools working as advertised is largely convincing and they may be helpful for screening compounds that bind to GLP1R. On the other hand, their overall utility is limited by their very weak apparent affinity relative to the likely biological concentration and response. Incomplete characterization of the properties of the tools makes it difficult to anticipate which applications are most likely to succeed.

eLife assessment

This valuable Tools and Resources paper presents new tools for investigating GLP-1 signaling: a genetically-encoded sensor constructed from a mutated GLP1R receptor as well as a caged agonist peptide. The evidence for these tools working as advertised is solid and they may be helpful for screening compounds that bind to GLP1R.

eLife assessment

This study examines the role of the locus coeruleus in the extinction of instrumental behaviors. The work is valuable to highlight the function of this part of the brain. Evidence is incomplete as spontaneous recovery is not demonstrated in control subjects. Further analyses on the effect of the manipulations on baseline lever pressing, magazine entries, and the coupling of lever-presses and magazine entries help capture the function of the locus coeruleus.

eLife assessment

This study aggregates across five fMRI datasets and reports that a network of brain areas previously associated with response inhibition processes, including several in the basal ganglia, are more active on failed stop than successful stop trials. This study is valuable as a well-powered investigation of fMRI measures of stopping. However, evidence for the authors' conclusions regarding the role of subcortical nodes in stopping is incomplete, due to the limitations of fMRI and a lack of theoretical synthesis.

eLife assessment

Based on a technological advance which couples onboard calcium imaging with in vivo electrophysiology in freely behaving mice, this work presents important insights about the brain circuits through which the cerebellum could participate to social interactions. In particular, correlative measurements provide interesting but incomplete evidence that connections between cerebellum and cingulate cortex connections specifically contribute to the complex sensory-motor computations underlying social contacts. This study is of interest for a broad range of neurophysiologists.

eLife assessment

This important study reveals the use of an allocentric spatial reference frame in how the perception of the location of a dimly lit target is updated during locomotion. The evidence supporting this claim is convincing, based on a series of cleverly and carefully designed behavioral experiments. The results will be of interest not only to scientists who study perception, action and cognition, but also to engineers who work on developing visually guided robots and self-driving vehicles.

eLife assessment

This important work advances our understanding of the differences in locomotion-induced modulation in primate and rodent visual cortexes. The evidence in support of these differences across species is convincing, although greater use of the primate dataset with some additional analyses would have strengthened the claims. This work will be of broad interest to neuroscientists.

eLife assessment

The study provides valuable insights into allosteric regulation of BTK, a non-receptor protein kinase, challenging previous models. Using a variety of biophysical and functional techniques, the paper presents evidence that the N-terminal PH-TH domain of BTK exists in a conformational ensemble surrounding a compact SH3-SH2-kinase core, that the BTK kinase domain can form partially active dimers, and that the PH domain can form a novel inhibitory interface after SH2/SH3 disengagement. Overall the presented evidence is solid, but the EM results may be over-interpreted and the work would benefit from additional functional validation.

eLife assessment

The manuscript describes a valuable theoretical calculation focusing on the structural changes in the photosynthetic reaction center postulated by others based on time-resolved crystallography using X-ray free-electron laser (XFEL) (Dods et al., Nature, 2021). The authors argue that calculated changes in redox potential Em and deformations using the XEFL structures may reflect experimental errors rather than real structural changes. The study is still incomplete in the sense that it focuses on explaining why the proposed structural changes do not match the theoretical calculations, but it does not yet provide an alternative model.

eLife assessment

This is a valuable study of the molecular basis of summer-to-winter transition in Cacopsylla chinensis. Despite the convincing molecular and organism-level experiments, evidence of cold sensitivity in the protein of interest is incomplete, with a lack of methodological detail. The results of this study will be of interest to entomologists.

eLife assessment

This study and associated data is compelling, novel, important, and well-carried out. The study demonstrates a novel finding that different chemotherapeutic agents can induce nucleolar stress, which manifests with varying cellular and molecular characteristics. The study also proposes a mechanism for how a novel type of nucleolar stress driven by CDK inhibitors may be regulated. The study sheds light on the importance of nucleolar stress in defining the on-target and off-target effects of chemotherapy in normal and cancer cells.

eLife assessment

This interesting study describes the development of a three-dimensional cell culture system to investigate muscle tissue development and homeostasis. It is a solid study that could be valuable in the study of human as opposed to animal cells in studying muscular disorders.

eLife assessment

This study presents useful findings regarding the impact of forest cover and fragmentation on the prevalence of malaria in non-human primates. The evidence supporting the claims of the authors is, however, incomplete, as the sampling design cannot adequately address the geospatial issues that this study focuses on.

eLife assessment

This study by Verdikt et al. provided solid evidence demonstrating the potential impacts of Δ9-tetrahydrocannabinol (Δ9-THC) on early embryonic development using mouse embryonic stem cells (mESCs) and in vitro differentiation. Their results revealed that Δ9-THC enhanced mESCs proliferation and metabolic adaptation, possibly persisting through differentiation to Primordial Germ Cell-Like Cells (PGCLCs), though the evidence supporting this persistence was incomplete. Although the study is important, it was limited by being conducted solely in vitro and lacking parallel human model experiments.

eLife assessment

This manuscript describes useful information on in vitro binding and hydrogen exchange (HDX) mass spectrometry experiments using various bacterial-expressed BRAF N-terminal fragments, to tease out domain-specific interactions with RAS proteins or wildtype and oncogenic mutant BRAF kinase fragments. The characterization of the auto-inhibitory mechanism of the regulation of BRAF is solid but several concerns remain. The data will be of interest for researchers in the RAS/RAF and general kinase regulation fields.

eLife assessment

The study by Gu et al. presents direct evidence on the role of microglia morphological dynamics during sleep/wake cycles and the modulatory effect of sleep deprivation, making it a valuable contribution to the ongoing investigation of microglial function. The use of a novel miniature two-photon microscope technique adds strength to the evidence supporting the conclusions. However, concerns remain about certain methodological and experimental aspects of the study, indicating that further validation is necessary and that the evidence presented is currently incomplete.

eLife assessment

The discovery of Homo naledi-associated evidence for intentional burial and engravings would undoubtedly have important implications for our understanding of the evolution of complex cognition and behavior. Based on claims made in two related preprints by Berger et al., this study discusses the potential implications of the purported mortuary practice and symbolic behaviors claimed to be associated with the small-brained H. naledi remains. Unfortunately, the evidence presented in the two related submissions that the current paper entirely relies on is incomplete at this stage.

eLife assessment

This paper presents important information about potentially Homo naledi-associated markings discovered on the walls of the Hill Antechamber of the Rising Star Cave system, South Africa. If confirmed, the antiquity, intentionality, and authorship of the reported markings will have profound archaeological implications, as such behaviors are otherwise widely considered to be unique to our species, Homo sapiens. As it stands, the study is incomplete, and the evidence presented does not support the claims about the anthropogenic nature, age, and author of the engravings. While it is appreciated that this report concerns preliminary findings, all reviewers agree that: a) the initial nature of the reported results must be more clearly indicated, b) the anthropogenic nature of the engravings must be adequately demonstrated, c) ideally the chronology of the claimed engravings has to be established for any age estimate to be reliable, and d) the claim about H. naledi being the author of the reported engravings requires robust association.

eLife assessment

The authors study the context of the skeletal remains of three individuals and associated sediment samples to conclude that the hominin species Homo naledi intentionally buried their dead. Demonstration of the earliest known instance of intentional funerary practice – with a relatively small-brained hominin engaging in a highly complex behavior that has otherwise been observed from Homo sapiens and Homo neanderthalensis – would be a landmark finding. However, the evidence for these claims is considered inadequate in the current version of the study. The four reviewers were in strong consensus that the methods, data, and analyses do not support the primary conclusions. Without full excavations, the study is missing crucial geoarchaeology (especially micromorphology) and taphonomic components, among other limitations, that make premature the conclusion that H. naledi intentionally buried their dead. The null hypothesis must be that these skeletons accumulated naturally and the research must then reject the null hypothesis and robustly exclude equifinality in order to justifiably draw the remarkable conclusions made in the present version of the paper.

eLife assessment

Brain inflammation is a hallmark of multiple sclerosis. Using novel spatial transcriptomics methods, the authors provide convincing evidence for a gradient of immune genes and inflammatory markers from the meninges toward the adjacent brain parenchyma in a mouse model. This important study advances our understanding of the mechanisms of brain damage in this autoimmune disease.

eLife assessment

This research advance article describes a valuable image analysis method to identify individual cells (neurons) within a ‎population of fluorescently labeled cells in the nematode C. elegans. The findings are solid and the method succeeds to identify cells with high precision. The method will be valuable to the C. elegans research community.

eLife assessment

This important study characterises the involvement of condensin complexes in the segregation of telomeres in fission yeast. The authors present solid evidence in support of their claims, employing a diverse range of complementary techniques. This research will be of interest for cell biologists working on chromosome biology and cell division.

eLife assessment

This valuable study describes engineered dengue virus variants that can be used to dissect epitope specificities in polyclonal sera, and to design candidate vaccine antigens that dampen antibody responses against undesirable epitopes. The evidence supporting the major claims is solid, although experiments to distinguish the impact on antibody binding versus neutralizing activities would have strengthened the study. This work will be of interest to virologists and structural biologists working on antibody responses to flaviviruses.

eLife assessment

This important article provides insights into the neural centres in the Japanese quail brain that are associated with photoperiod-induced life-history states. The physiological and transcriptomic analyses of the mediobasal hypothalamus and pituitary gland offer evidence for a coincidence timing mechanism for measuring day length, which is relevant for the field of circannual biology. Despite some shortcomings in data analysis, the study's convincing experiments and findings have the potential to captivate the attention of molecular and organismal endocrinologists.

eLife assessment:

This important study describes spatial RNA processing events by combining methods for single-cell transcriptomics data with spatial transcriptomics data. The evidence supporting the claims of the authors is solid, although the analysis could be further strengthened by including a broader range of samples as well as orthogonal validation either by experimental methods or simulated data. The work will be of general interest to researchers in the spatial transcriptomics field as well as researchers investigating alternative pre-mRNA processing across diverse tissues.

eLife assessment:

Trypanosoma brucei evades mammalian humoral immunity through the expression of different variant surface glycoprotein genes. In this fundamental paper, the authors extend previous observations that TbRAP1 both interacts with PIP5Pase and binds PI(3,4,5)P3, indicating a role for PI(3,4,5)P3 binding and suggesting that antigen switching is signal dependent. While much of the evidence is compelling, one reviewer suggested that the work would benefit from further controls.

eLife assessment

This paper describes an important, well-organized study into an under-exploited area of spatial transcriptomics. The limitations of the approach are generally made clear, but there is insufficient orthogonal validation to demonstrate the biological significance of the results, which leads to the evidence for the claims being currently incomplete. Nevertheless, the tools presented will provide a resource to researchers wishing to characterise spatial patterning of mRNAs, and the paper will be of interest to researchers studying cell biology, RNA biology, and method development for spatial transcriptomics/proteomics.

eLife assessment

This important paper reports a novel, compelling method, based on barcoding viral genes and next-generation sequencing, to quantify both viral transcription levels and progeny virus production in influenza virus-infected cells at the single-cell level. The authors show that viral transcription and progeny virus production are unexpectedly poorly correlated, and that cells in which viral RNAs are transcribed at high levels are not necessarily those producing the most progeny virions. Because of its novelty, the study will be of interest to the broader virology community.

eLife assessment

This is an important study that reports the discovery of a new pathway of miRNA sorting to exosomes, involving a mitochondrially-localized protein. The evidence provided by some of the biochemical data is convincing. However, the major body of evidence is still incomplete.

eLife assessment

Overall, this is an interesting topic of study, and the conclusions could be of relevance more broadly. However, mechanistic support, limited TTF frequencies/timing, and visual support of the quantitative data would be critical in order to provide convincing and rigorous support for this interesting concept.

eLife assessment

This study explores the regulatory function of O-GlcNAcylation on DNA methyltransferase 1 and identifies serine 878 as the main target. This study is of interest to those in epigenetics and metabolism. The significance is important and the strength of the evidence is convincing.

eLife assessment

This US study presents findings from an online survey and in-person interviews of healthcare providers in areas associated with cervical screening provision during the post-acute phase of the pandemic. The findings are valuable as they provide insights into a range of areas, from healthcare characteristics to screening barriers and HPV self-sampling. The evidence supporting the claims of the authors is solid, although the inclusion of a nationally-representative sample of healthcare providers and a greater gender/ethnicity/racial mix of interviewees would have strengthened the study. The work will be of interest to public health scientists and a cancer prevention and control audience.

eLife assessment

This manuscript suggests a novel mechanism of purifying selection by which programmed cell death contributes to the selective removal of mtDNA deletion mutations in C. elegans. The evidence for this mechanism of removal is strong although questions remain regarding the underlying mechanism and the role of canonical ageing pathways. Because of the likely central role of mtDNA deletions in ageing and age-dependent diseases, this work will be of interest to scientists in the field of mitochondrial biology as well as ageing.

eLife assessment

This work provides a valuable structural and functional characterization of the neurotransmitter's spatial distribution heterogeneity in cortical and subcortical regions. The authors report a systematic description and annotation of a new "layer" of brain organization that has been relatively poorly integrated with the wider neuroimaging literature to date. In sum, this paper has the potential to be of great interest to a wide audience in neurosciences.

eLife assessment

This important paper describes a valuable systematic review and meta-analysis of mental health problems in polycystic ovary syndrome (PCOS) that drive the excess economic burden associated with this common endocrine disorder. Interestingly, the cost of the diagnostic evaluation is only a relatively minor part of the total costs, but mental health disorders were identified as a significant component of the economic burden. These solid findings could not have been anticipated intuitively and are of considerable value for public health prioritization of PCOS.

eLife assessment

This study presents a valuable and elegant kinetic analysis of the GSKbeta activity as a function of phosphorylation and Axin binding - providing insights into critical steps of Wnt pathway signaling. The results will be of big use to the broader signaling community, however, the incomplete dissection of the mechanism by which Axin binding inhibits GSKbeta inhibitory phosphorylation remains a weakness of this study. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This important study used high-resolution brain imaging methods to visualize and index non-invasively auditory and language pathways of young children born with inner ear malformations or cochlear nerve dysfunction resulting in profound hearing loss. Nerve fiber impairments were compellingly demonstrated in subcortical auditory and cortical language pathways relative to typically-hearing controls. The results suggested novel approaches for clinical assessment of central auditory and language pathways that may influence different intervention strategies, pending further evidence linking these structural findings with functional outcomes.

eLife assessment

Rodberg et al. show systemic β adrenergic antagonism reduces engagement in decision-making, particularly in female rats, and reduces task-related encoding in neural activity. This is a valuable finding that addresses a gap in the field, however, the understanding of the direct contribution of β adrenergic receptors to the observed effects is incomplete. Further, the theoretical grounds, data analyses, and results could be improved in several ways.

eLife assessment

This work provides fundamental new insight into fine axonal morphologies based solely on extracellular action potential recordings. They provide compelling evidence of fine resolution in mapping functional connections between neurons. The work may have broad use in neurobiology, bioengineering, stem cell biology, as well as tissue engineering in functional characterization.

eLife assessment

The tool developed and implemented in this study has valuable significance for the combined analysis of large, diverse omics datasets, but some of the methodology is incomplete. Regarding the strength of evidence, there are some more significant concerns regarding potentially inadequate controls for false discovery and multiple testing corrections.

eLife assessment

The manuscript represents a valuable contribution to an ongoing discussion about the substrate binding site and mechanism of the Bile Acid Sodium Symporter (BASS) family of transporters. Structural and biochemical analysis of a bacterial homolog, ASTBnm, in complex with its native substrate (not bile acids, but a vitamin A precursor, pantoate) show a new binding site that is consistent with classical proposals for elevator-type transport mechanisms. Molecular simulations highlight the improved stability for the substrate in the active site when ions are present, suggesting a binding order during the transport cycle. The structural studies, binding assays, and MD simulations are convincing, although support for the transport mechanism is incomplete without a pantoate transport assay.

eLife assessment

This important study advances our knowledge of how parasites evade the host complement immune system. The new cryo-EM structure of the the trypanosome receptor ISG65 bound to complement component C3b is highly compelling and well-supported by biochemical experiments. This work will be of broad interest to parasitologists, immunologist, and structural biologists.

eLife assessment

This important study identifies two new transporters of the apicoplast, a non-photosynthetic organelle of apicomplexan parasites. In its current state, evidence is incomplete, as it only partially reveals how important those transporters are and as it does not address the metabolic function for the parasite. The results should be of interest to parasitologists and eukaryotic cell biologists.

eLife assessment

This study includes important findings on protein evolution, namely that changes in function are largely attributable to pairwise rather than higher-order interactions, and that epistasis potentiates rather than constrains evolutionary paths. Compelling evidence supporting the conclusions is provided by applying a new model to a previously generated experimental dataset on deep mutational scanning of the DNA-binding domain (DBD) of steroid hormone receptor. The implications of this work are of considerable interest to protein biochemistry, evolutionary biology, and numerous other fields.

eLife assessment

This fundamental study identifies the components of the N6-methyladenosine methyltransferase complexes in yeasts, with major differences with the same complexes in mammals and flies. The evidence supporting the conclusions is convincing, with rigorous high-throughput sequencing approaches and detailed functional analysis. This work will be of broad interest to colleagues in the RNA modification and meiosis fields.

eLife assessment

This valuable 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. The data were collected and analyzed using solid and 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

The paper provides a useful and novel application of recursion theory to the long call vocalisations of orangutans to demonstrate repetitive, rhythmic sub-structuring. However the evidence provided to support the major claims of the paper is currently incomplete. Specifically, it is not yet clear how the rhythmic structuring found in these long calls is more similar to human language recursion per se rather than isochrony as a broader, more common phenomenon.

eLife assessment

This important study describes a combination of in vitro and in vivo results implicating Dyrk1a in the regulation of mTOR. Strengths include the combination of cell and whole-animal (Drosophila) based studies. However, the evidence supporting the conclusions is incomplete and additional experimentation (which could include IPs, more confirmation of the T1462 phosphorylation, and more information about Akt) would strengthen the main conclusions.

eLife assessment

This study reports important findings about new locomotory dynamics of crawling Drosophila larva based on imaging the reaction forces during larval crawling. The new high-resolution microscopy method is compelling, as it significantly improves the spatial, temporal, and force resolution compared to previous methods for studying Drosophila larva and could be applied to other crawling organisms. The manuscript would nevertheless benefit from more details explaining the new technology, limitations, and justifications for the choice of technology and certain experimental details. The work will be of interest to the broad neuroscience community interested in the mechanisms of locomotion in a highly tractable model.

eLife assessment

This study reports the important finding that there appears to be a timer that monitors the repair of DNA after damage and regulates whether cells are subsequently able to enter mitosis. The authors identify proteins important for this decision and propose a mechanism supported by solid but not conclusive data. This study will be of interest to researchers in the fields of DNA damage repair and cell cycle control.

eLife assessment

In this important study, the human membrane receptor guanyl cyclase GC-C was expressed in hamster cells, co-purified in complex with endogenous HSP90 and CDC37 proteins, and the structure of the complex was determined by cryo-EM. The study shows that the pseudo-kinase domain of GC-C associates with CDC37 and HSP90, similarly to how the bona fide protein kinases CDK4, CRAF and BRAF have been shown to interact. The methodology used is state of the art and the evidence presented is compelling.

eLife assessment

This study is useful to scientists studying cell polarity, epithelial morphogenesis, cancer, and primary cilia. The authors confirm the need for CRB3A/B in regulating ciliogenesis by using a combination of a mammary epithelial cell-specific conditional Crb3 knockout mouse model, and cellular, molecular and biochemical approaches. The results are solid, supporting and extending previous findings; the results also indicate that CRB3 affects ciliogenesis by a still incompletely understood mechanism involving Rab11 and gamma-TuRC.

eLife assessment

This study represents an important contribution to the field by supporting the utility of functional ultrasound imaging for evaluating cerebral hemodynamics in rat models of brain injury. Solid evidence is presented supporting the possibility of imaging the effect of thrombolysis during stroke in awake rats. This work will be of interest to researchers working in functional neuroimaging and more precisely with preclinical models of stroke in rodents.

eLife assessment

This important paper reports technical advances for in vivo intramuscular electrical recording from multiple motor units in behaving animals. This new muscle recording method has the potential to provide new insight into a range of questions in motor neuroscience. The paper includes compelling demonstrations of the efficacy of this new technique in multiple animal species, although further evidence is needed to support the claim that electromyogram "spike sorting" can reliably disambiguate individual motor units.

eLife assessment

This study documents valuable findings on three variants in SNAP25 that are associated with developmental and epileptic encephalopathy. The thorough characterization of synaptic release and in vitro vesicle fusion phenotypes provides interesting information about the nature of the SNAP25 variants. The evidence supporting the claims is compelling, and this work will be of interest to neuroscientists working on SNAP25, SNAP25-associated encephalopathy, and synaptic vesicle exocytosis.

eLife assessment

This important work examines the potential utility of socio-emotional and socio-cognitive mental training on hippocampal subfield structure and function, and cortisol levels. The evidence provided here is solid, but additional methodological considerations are needed to strengthen the evidence in support of their claims. The work will be of broad interest to neuroscience researchers including those in cognitive, social, and clinical neuroscience.

eLife assessment

This study examines how self-citations in the neuroscience literature differ according to geography, gender, seniority, and subfield within neuroscience. The evidence supporting the claims is mostly solid, but aspects of the analysis - notably concerning estimates of uncertainty, and the exact interpretation of the results - would benefit from further work. Overall, the article is a valuable addition to the literature on self-citations

Editor’s Assessment

This work has generated metabolic models for the human pathogens Mycobacterium leprae and Mycobacteroides abscessus, alongside a new computational tool that can be used to identify potential drug targets. The standardised genomic scale metabolic models have been developed using the systems biology community standards for quality control and evaluation of models. After providing more detail on reproducibility, comparative performance of the models, and reuse, these resources are now published and are available for reuse by the global scientific community via the GigaDB, Biomodels, and PatMeDB repositories.

This assessment refers to version 1 of this preprint.

eLife assessment

This study demonstrates that vitamin D-bound VDR increased the expression of SIRT1 and that vitamin D-bound VDR interacts with SIRT1 to cause auto-deacetylation on Lys610 and activation of SIRT1 catalytic activity. This is an important finding that is relevant to the actions of VDR on colorectal cancer. The data presented to support the presented conclusion are convincing.

eLife assessment

This valuable study provides solid evidence that acute experimental pain induces changes in cortical excitability and GABAergic neurotransmission. The findings will be of interest to researchers interested in the brain mechanisms of pain and may lay the ground for future studies on acute pain-related excitability changes as probed by TMS and EEG.

eLife assessment

This manuscript addresses an important question, that in countries endemic for P. vivax the need to administer a primaquine (PQ) course adequate to prevent relapse in G6PD deficient persons poses a real dilemma. On one hand PQ will cause haemolysis; on the other hand, without PQ the chance of relapse is very high. As a result, out of fear of severe haemolysis, PQ has been under-used. This manuscript is convincing that regimen (1) can be used successfully to deliver within 3 weeks, under hospital conditions, the dose of PQ required to prevent P. vivax relapse.

eLife assessment

This important study tested the hypothesis that liver-derived but not serum-derived antibodies that are cross-reactive to E.coli and to host proteins can play a role in the hepatic damage found in severe alcoholic hepatitis (SAH). Using a solid methodology that includes state-of-the-art microscopy, proteome arrays, and gene ontology assays, it provides strong evidence that liver-derived IgG and IgA with cytotoxic properties and reactivity to both gut-derived E.coli and autoantigens accumulated in hepatocytes of SAH patients but not of healthy controls. The study would benefit from a broader analysis of gut microbiota proteome and further characterization of B cells infiltrating the liver tissue including their numbers/field and their origin (infiltrating versus resident cells). The work opens new avenues of understanding for the pathogenesis of severe alcoholic hepatitis and is of great interest to researchers and clinicians in the field.

eLife assessment

This paper presents a useful study regarding the meiotic functions of ARID1A, the DNA-binding component of the SWI/SNF chromatin remodeler BAF. Whereas this work suggests that ARID1A regulates chromatin composition of the sex body relative to the autosomes, the reviewers raised substantial issues with the data and interpretation. The efficiency of the conditional deletion allele seems low and the CUT&RUN experiments are inadequate.

eLife assessment

The OpenApePose dataset presented in this manuscript represents an important contribution to the field of primate behaviour and computer-vision science with methodological applications that are sure to be applicable for a wide variety of taxa. The analysis supporting the utility of this database is solid and compelling but would benefit from some additional clarity, particularly with regards to the landmark annotations, model parameters and division of the dataset for training, validation and testing.

eLife assessment

This study presents a valuable finding on the role of fragile X messenger ribonucleoprotein (FMRP) and its target the microtubule associated protein 18 (MAP1B) in postnatal tangential migration of neuroblasts. The study combined molecular genetics (FMRP knock-out mice) with acute inactivation of FRMP and MAP1B to conclusively support the notion that FMRP-dependent regulation of MAP1B is necessary for proper neuronal migration toward the olfactory bulb using the rostral migratory stream. The evidence supporting the claims of the authors is solid, although inclusion of additional controls for experiments and/or more rigorous description of the finding and conclusions would have strengthened the study. The work improves our knowledge of the molecular mechanisms that control how neurons migrate in the brain to reach their final destinations and confirms that cytoskeleton regulators are key players in this process. will be of interest to developmental neurobiologists.

eLife assessment

This important study unravels the interaction between effort cost, pupil-indexed brain state, and movement (saccadic) vigor during foraging decisions in marmoset monkeys. Based on a computational model, the authors derive the prediction that anticipated effort should affect both decisions and movement vigor during foraging; and then provide solid behavioural and pupillometric evidence for this prediction in a foraging task. This paper will be of interest to decision and motor neuroscience as well as to all researchers studying animal behavior.

eLife assessment

This is an important paper that links distinctive stinging behavior of two related anemones occupying different ecological niches to varying inactivation properties of voltage-gated calcium channels conferred by auxiliary Cavβ subunits. Further convincing evidence is provided that these differences are mediated by alternative splicing of Cavβ subunit of the calcium channel. The study will be of interest to scientists studying Ca2+ signaling, ion channel biophysicists, and marine biologists.

eLife assessment

Gap junctions, formed from connexins, are important in cell communication, allowing ions and small molecules to move directly between cells. By determining the Cryo EM structure of the structure of connexin 43 in a putative closed state involving lipids, the study makes an important contribution to the development of a mechanistic model for connexin activation. The connexin 43 structure is solid and its presentation will appeal to the channel and membrane protein communities.

eLife assessment

This important paper uses a genome-wide, massively parallel reporter assay to determine how CpG methylation affects regulatory sequences that control the expression of human genes. The authors provide compelling evidence that methylation not only influences baseline activity of regulatory sequences but also the magnitude of acute responses to environmental stimuli. The findings are of broad interest, and the extensive data set will likely become a key resource for the community.

eLife assessment

This study describes important findings on how a core component of the circadian clock impacts the effect of dietary restriction (DR) on longevity and fecundity in Drosophila, which lead the authors to postulate rhythmic control of proteostasis in the fat body as a critical aspect of DR effects. The evidence presented is still incomplete, not fully supporting the conclusions of the study, as alternative hypotheses/explanations have not yet been systematically explored. The work will nevertheless be of substantial interest to researchers working in circadian and cell biology, metabolism, and aging, with an interesting hypothesis to be explored further.

eLife assessment

This valuable study provides insights into mechanisms of placental aging and its relationship to labor initiation. The authors provide solid evidence and have thoroughly investigated the molecular characteristics of normal placental aging using in vivo and in vitro model systems and human placental tissue analysis to corroborate their findings. This work contributes to existing work in placental aging and preterm birth and will be of interest to reproductive scientists.

Editor’s Assessment

Like other mollusc species, the freshwater pearl mussel (Margaritifera margaritifera) has a challenging genome to assemble owing to the large size of their genomes, heterozygosity, and repetitive sequence. The first published M. margaritifera genome was highly fragmented, but here an improved reference genome assembly was generated using PacBio CLR long reads to reduce fragmentation levels, missing and truncated genes, and chimerically assembled regions. The number of gene models predicted is a bit higher compared than other molluscan genomes, but after clarification and double checking these seem in line with some Mollusca and Bivalvia with similar and higher numbers of gene predictions. This new genome represents a new resource to start exploring the many biological, ecological, and evolutionary features of this threatened and commercially important group of organisms.

This assessment refers to version 1 of this preprint.

Editor’s Assessment

Hybrid genomes are tricky to assemble, and few genomic resources are available for hybrid grapevines such as ‘Chambourcin’, a French-American interspecific hybrid grape grown in the eastern and midwestern United States. Here is an attempt to assemble Chambourcin’ using a combination of PacBio HiFi long-reads, Bionano optical maps, and Illumina short-read sequencing technologies. Producing an assembly with 26 scaffolds, an N50 length 23.3 Mb and an estimated BUSCO completeness of 97.9% that can be used for genome comparisons, functional genomic analyses, and genome-assisted breeding research. Error correction and pilon polishing was a challenge with this hybrid assembly, but after trying a few different approaches in the review process have improved it, and as they have documented what they did and are clear about the final metrics, users can assess the quality themselves.

This assessment refers to version 2 of this preprint.

eLife assessment

In this valuable study, advanced simulation methodologies are used to extract the mechanisms of inactivation for the potassium ion channel KcsA. The string method approach provides solid evidence that reveal features associated with the interplay between gate size and collapse of the selectivity filter, as well as remarkable differences between different force fields. While this manuscript does not address recent discoveries in K channel inactivation involving dilated selectivity filter structures obtained by Xray and cryo-EM, it does help us understand the KcsA constriction process. With added descriptions and analysis of collective variables, improved reproducibility of results, consistency between string method free energies and unbiased simulations, and improved transition rate calculation, this manuscript will be of interest to the ion channel field.

eLife assessment

The primary goal of this paper is to examine microtubule detyrosination as a potential therapeutic target for axon regeneration. The valuable findings of this study provide convincing evidence for mechanistic links between microtubule detyrosination and neurite outgrowth in vitro and some evidence for axon regeneration in vivo.

eLife assessment

This fundamental study provides a framework for leveraging systems genetics data to dissect mechanisms of gut physiology. The authors provide compelling analyses to highlight diverse modes of interrogating intestinal inflammation, dietary response, and consequent impacts on inflammatory bowel disease. As a resource, it will have great utility for linking genetic variation and diet to gut-related pathophysiologies.

eLife assessment

This study presents an important description on the dynamics of histone variant exchange controlling the organization of the chromatin state of the Arabidopsis genome, combining the analysis of histone variants, histone modification, and chromatin states. The evidence supporting the claims of the authors is compelling. This work will be of great interest to those in the field of epigenetics and chromatin biology.

eLife assessment

This important study uses machine learning-based network analysis on transcriptomic data from different tissue cell types to identify a small set of conserved (pan-tissue) genes associated with changes in cell mechanics. The new method is compelling and, together with rigorous in silico and experimental validation, provides convincing evidence for the claims. The study would be strengthened with an expanded set of validation (e.g. testing genes with hitherto unknown roles and different perturbation techniques), but will nonetheless be of broad interest to cell biologists, biophysicists, and bioengineers.

eLife assessment

This important study combines virology experiments and mathematical modeling to determine the nuclear export rate of each of the eight RNA segments of the influenza A virus, leading to the proposal that a specific retention of mRNA within the nucleus delays the expression of antigenic viral proteins. The proposed model for explaining the differential rate of export is compelling, going beyond the state of the art, but the experimental setup is incomplete and would benefit from additional approaches. The insight so far is interesting, but because in the end it is left as an observation, the overall advance remains limited.

eLife assessment

This study presents the valuable finding that sustained calcium signaling in induced-Treg (iTreg) cells can lead to the loss of Foxp3 expression and iTreg identity by altering the chromatin landscape. The evidence supporting the claims of the authors is solid, but alternative interpretations of the data should be considered and tested. The work will be of interest to immunologists working on Treg cell therapy.

eLife assessment

This study provides useful findings regarding the capacity for mental state attribution on the Frith-Happé task in a highly social non-human primate species, the marmoset. The methods are solid, integrating validated brain imaging and eye-tracking techniques, however, the theoretical analysis is incomplete due to the omission of a "goal-directed condition." The inclusion of the goal-directed condition would enable a stronger interpretation of the findings and would be of broad interest to neuroscientists working in social and affective sciences.

eLife assessment

This study provides important new insights into how learning affects behavior in the Drosophila model. Using a combination of connectomics, neurophysiology, and behavioral analysis, a small group of neurons in the Drosophila brain that integrates learned odor valences and promotes odor tracking by driving upwind orientation and movement is described. The study's conclusion is supported by convincing evidence and rigorous quantitative analysis. Insights from the neural circuit mechanism that translates learning-induced plasticity into appropriate behavioral actions will be of broad interest to neuroscientists.

eLife assessment

This simulation work with open source code will be of interest to those developing visual prostheses and demonstrates useful improvements over past visual prosthesis simulations. While the authors provide compelling evidence to support the generation of individual phosphenes and integration into deep-learning algorithms, the assumptions beyond individual phosphenes and the overall validation process are inadequate to support the claim of fitting the needs of cortical neuroprosthetic vision development.

eLife assessment

This study provides useful information on the impact of the pandemic on the quantity of healthcare delivered to patients with pancreatic cancer in England. The authors showed that there was no difference in the number of diagnoses of pancreatic cancer during the pandemic compared to the preceding 5-year period, but a reduction in surgical resections by nearly 25%. They reported no difference in deaths between the two periods. They show no differences in rates of diagnosis, but the clinical relevance is incomplete as they have not compared survival from cancer between those time periods.

eLife assessment

This is an important study reanalysing previously published datasets to understand methylation changes during aging. The evidence supporting the conclusions is solid and sheds new light on features of aging in cells, highlighting the concept of cell-specific methylation changes and their relationship to other physiological changes such as inflammation that may impact methylation patterns. This work will be of broad interest to cell and molecular biologists.

eLife assessment

This important study reveals the genetic regulation of changes in cuticular hydrocarbon profiles in a Hymenopteran insect and links these changes with courtship behaviour and sexual attractiveness. It provides convincing empirical evidence, spanning genetic, chemical, and behavioural data. It adds valuable new perspectives on the mechanisms that underlie chemical recognition and communication systems in nature.

eLife assessment

The significance of this manuscript is that is provides useful information for the field of hepatology and endocrinology on the regulatory mechanisms of cholesterol homeostasis by melanocortin. The authors provide solid evidence utilizing both in vivo and in vitro molecular, cellular, and biochemical approaches to support their claims.

eLife assessment

This important work advances our understanding of the import of clonal heterogeneity in cancers in immune response to individual antigens. The evidence supporting the conclusions is convincing, and uses interesting tools, although the mechanistic basis of the observations is unclear. The work will be of broad interest to immunologists including cancer immunologists.

eLife assessment

This is an important study describing the mechanism of Spermidine modulation of Src kinase, identifying the interacting amino acids and the effect on indoleamine 2,3-dioxygenase 1 (IDO1) activation based on solid evidence. Considering the important role of IDO1 in the immune response this study could provide important information for the design of allosteric modulators capable of turning SRC on/off.

eLife assessment

This work examines a role for altered splicing in pancreatic tumorigenesis by interrogating effects of a specific mutation in the Sf3b splicing factor in pancreatic organoid and cell line growth primarily, with some in vivo work also performed. There is significant potential in the study but there is a concern about the lack of in vivo validation of claims that are most relevant to metastatic progression and the focus on one specific mechanism at the expense of other possible effects on splicing of factors important for disease progression.

eLife assessment:

This fundamental study provides compelling evidence that long-range resection is important for recombination between distal, but not proximal, homologous sequences. It is thus proposed that a major role of long resection of a double-strand break mediated by Sgs1 and Exo1 is to activate the DNA damage checkpoint to allow the chromosomal mobility needed for the DNA ends to find a distant homologous sequence with which repair via homologous recombination, adding a new biological meaning to the role of long DNA resection in homologous recombination.

eLife assessment

The mechanisms underlying mirror neurons are a topic of wide interest for all who study the workings of the brain. The authors use an elegant decoding approach to test whether mirror neurons encode action categories in the same framework regardless of whether actions are executed in the dark or observed in the light. This new approach identifies only a small subset of mirror neurons with fully matched coding among a larger set showing partial matches. The thought-provoking study opens up new principled avenues to probe the mechanics of matching action and perception.