7,019 Matching Annotations
  1. Apr 2024
    1. eLife assessment

      In this study, the authors provide valuable evidence that the LGE is not a significant source of oligodendrocytes for the cortex. The reviewers did find some technical considerations that call for some modulation of the strength of the authors' conclusions and also pointed out some aspects of the data that were incomplete as presented.

    1. eLife assessment

      This useful work describes a novel microscopy-based method to correlate the degree of pigmentation with the gene expression profile of human-induced pluripotent stem cell-derived Retinal Pigmented Epithelial (iPSC-RPE) cells at the single cell level. The presented evidence is solid in showing that there is heterogeneous gene expression in iPSC-derived RPE cells, and there is no significant correlation with the pigmentation. By analyzing the expression of some genes related to function, lysosomal- and complement-related pathways were partially enriched in darker cells. This methodology can be used by other researchers interested in analyzing gene expression related to microscopic images.

    1. eLife assessment

      This useful study reports that a week or more of hypoxia exposure in mice increases erythropoiesis and decreases the number of iron-recycling macrophages in the spleen, compromising their capacity for red blood cell phagocytosis – reflected by increased mature erythrocyte retention in the spleen. Compared to an earlier version, the study has been strengthened with mouse experiments under hypobaric hypoxia and complemented by extensive ex vivo analyses. Unfortunately, while some of the evidence is solid, the work as it currently stands only incompletely supports the authors' hypotheses. While the study would benefit from additional experiments that more directly buttress the central claims, it should be of interest to the fields of hemopoiesis and bone marrow biology and possibly also blood cancer.

    1. eLife assessment

      This study presents valuable framework and findings to our understanding of the brain as a fractal object by observing the stability of its shape property within 11 primate species and by highlighting an application to the effects of aging on the human brain. The evidence provided is solid but the link between brain shape and the underlying anatomy remains unclear. This study will be of interest to neuroscientists interested in brain morphology, and to physicists and mathematicians interested in modeling the shapes of complex objects.

    1. eLife assessment

      In this valuable study, the authors examine the role of the cytoskeletal regulatory protein Abba in governing the process of cell genesis in the developing cortex. This study provides insights into the mechanisms of microcephaly, a developmental malformation. The evidence supporting the study was felt to be solid, but the reviewers did note some technical weaknesses that limit the strength of some of the interpretations.

    1. eLife assessment

      This is an important study on changes in newborns' neural abilities to distinguish auditory signals at 37 weeks of gestation. The evidence of change in neural discrimination as a function of gestational age is convincing, but further analysis of the acoustic signals and description of the infants' language environment would strengthen the interpretation of the results. The work contributes to the field of neurodevelopment and suggests potential clinical applications in neurodevelopmental disorders.

    1. eLife assessment

      This important study investigates the structural organization of a series of diblock elastin-like polypeptide condensates. The methodology is highly compelling, as it combines multiscale simulations and fluorescence lifetime imaging microscopy experiments. The results increase our understanding of model biomolecular condensates.

    1. eLife assessment

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

    1. eLife assessment

      This valuable study further discloses the function of LRRK2 in BDNF-dependent synaptic processes in identifying postsynaptic actin cytoskeleton as a convergent site of LRRK2 pathophysiological activity. Multiple approaches in different cellular models provide mostly solid (but at times preliminary) evidence to support (many) of the conclusions, overall consistent with bioinformatics analyses covering previously published work. While an exciting start that should be pursued, examples are suggested by reviewers to add in additional experimentation to better support the expansive interpretation. The identification of mechanisms of LRRK2 action at the synapse is considered highly significant, as better knowledge in this regard may provide insight into why dopaminergic cells die with over-active LRRK2.

    1. eLife assessment

      This is a valuable study of the spatial organization of innate granulomas following Chromobacterium violaceum infection and the expression of CC and CXC chemokines in the granuloma at several time points following infection. There is a wealth of information to be gained from this study. However, the analysis of these granulomas is incomplete, with room for orthogonal validation of some of the key findings with additional animals (using ISH or IHC), in addition to a more quantitative analysis of some of the currently more qualitative conclusions.

    1. eLife assessment

      This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. Compared to an earlier version, the quality of the manuscript has been enhanced, for example Figure 5 now illustrates the key features of survival probability estimates over time for patients assigned to with the test or training set.

    1. 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.

    1. eLife assessment

      This useful manuscript explores conditions for epigenetic inheritance by studying the stability of simple network models to permanent and transient perturbations. A novel aspect of the study is that it unifies non-genetic inheritance phenomena across cell divisions of unicellular organisms and in the germline of multicellular organisms. However, the models studied are more a collection of vignettes of numerical studies than a systematic study, therefore the evidence presented remains incomplete. As a first step towards building a more systematic theoretical framework, this work will be of interest to colleagues in the field of epigenetic inheritance.

    1. eLife assessment

      This fundamental study reports compelling findings that intermediate states exist in epithelial-mesenchymal transition (EMT) during natural development and differentiation of mammalian neural crest cells, similar to recent reports in cancer. The authors determined that there were at least two paths to delamination and migration - one that occurs during S-phase of cell cycle and another during G2/M phase, and that the process of delamination is not restricted to cell fate. Finally, the authors showed that expression of Dlc1 may be used to identify cells in an intermediate state of EMT as well as their spatial location in the mouse embryo. The work will be of interest to developmental biologists, neurobiologists and cancer researchers.

    1. eLife assessment

      This valuable study by Bartas and colleagues examined how patterns of monosynaptic input to specific cell types in the ventral tegmental area are altered by drugs of abuse. The authors applied a dimensionality reduction approach (principal component analysis) and showed that various drugs of abuse, and somewhat surprisingly the anesthesia alone (ketamine/xylasin), caused changes in the distribution of inputs labeled by the transsynaptic rabies virus. While there are some issues to be addressed, the evidence supporting the conclusions is overall solid, and provides information that is of value to the field, as well as a cautionary note on the interpretation of rabies virus-based tracing experiments.

    1. eLife assessment

      This study makes a valuable contribution to spatial transcriptomics by rigorously benchmarking cell-type deconvolution methods, assessing their performance across diverse datasets with a focus on biologically relevant, previously unconsidered aspects. The authors demonstrate the strengths of RCTD, cell2location, and SpatialDWLS for their performance, while also revealing the limitations of many methods when compared to simpler baselines. By implementing a full Nextflow pipeline, Docker containers, and a rigorous assessment of the simulator, this work offers robust insights that elevate the standards for future evaluations and provides a resource for those seeking to improve or develop new deconvolution methods. The thorough comparison and analysis of methods, coupled with a strong emphasis on reproducibility, provide solid support for the findings.

    1. eLife assessment

      This study represents a valuable finding on the neuron-glia communication and glial responses to traumatic brain injury (TBI). The data supporting the authors' conclusions on TBI analysis, RNA-seq on FACS sorted astrocytes, genetic analyses on Pvr-JNK/MMP1 are solid. However, cellular aspects of the response to TBI, statistical analysis, and molecular links between Pvr-AP1 are incomplete, which could be further strengthened in the future by more rigorous analyses.

    1. eLife assessment

      Dasgupta and colleagues make a valuable contribution to the understanding how the guidance factor Sema7a promotes connections between mechanosensory hair cells and afferent neurons of the zebrafish lateral line system. The authors provide solid evidence that loss of Sema7a function results in fewer contacts between hair cells and afferents through comprehensive quantitative analysis. Additional work is needed to distinguish the effects of different isoforms of Sema7a to determine whether there are specific roles of secreted and membrane bound forms.

    1. eLife assessment

      This important study discovered DBT as a novel gene implicated in the resistance to MG132-mediated cytotoxicity and potentially also in the pathogenesis of ALS and FTD, two fatal neurodegenerative diseases. The authors provided convincing evidence to support a mechanism by which loss of DBT suppresses MG132-mediated toxicity via promoting autophagy. This work will be of interest to cell biologists and biochemists, especially in the FTD/ALS field.

    1. eLife assessment

      This valuable study investigates the role of mechanosensory feedback during swallowing in adult Drosophila. The authors provide convincing evidence that three mechanotransduction channel genes are required for ingestion rhythms and localize the role of these genes to a specific subpopulation of pharyngeal mechanosensory neurons. However, there is incomplete evidence to support the conclusions that these sensory neurons are necessary for swallowing, respond to stretch during swallowing, and connect to the motor neurons that control swallowing. This work may be of interest to neuroscientists interested in motor control of feeding behavior.

    1. eLife assessment

      This work identifies cnidarian neuropeptides and pairs them to their GPCR, then shows that neuropeptide signaling systems have evolved and diversified independently in cnidarians and bilaterians. Neuropeptide-receptor partners were experimentally identified using established and widely used methodologies including single cell mapping, providing compelling evidence for the conclusions of the paper. This impressive accomplishment provides fundamental new insights into the evolution of neuropeptide signaling systems and will be of broad interest to neurobiologists and evolution of development researchers.

    1. eLife assessment

      Chen and colleagues utilize an in situ explant model of the neural retina and retinal pigment epithelium (RPE), along with small molecule inhibition of key metabolic enzymes and targeted metabolomic analysis, to decipher key differences in metabolic pathways used by rods, cones, Muller glia, and the RPE. They conclude that rods are heavily reliant on oxidative metabolism, cones are heavily reliant on glycolysis, and multiple mechanisms exist to decouple glycolysis from oxidative metabolism in the retina. This study provides valuable metabolomic data and insights into the metabolic flexibility of different retinal cells. However, current evidence is still incomplete as several of the conclusions from the paper stand in contradiction to other published findings and the authors naturally suggests experiments that will be needed in the future to validate the hypothesized pathways and refute existing published data. Such future validation includes animal models with tissue specific knockout of the key enzymes probed in the study; inhibiting the targets of this study with more than 1 small molecule that is structurally different, and at different doses and timings; using retinal explants from matured animals; performing labeled metabolite tracing experiments; and direct assessment of mitochondrial function (via OCR) under various manipulations.

    1. eLife assessment

      The valuable findings in this study show that subpopulations of peripheral sensory neurons display different capacities for regeneration after a similar injury. Nociceptor neurons have greater regeneration over mechanoreceptor, proprioceptors and motor neurons. This differential responsiveness of neuronal subtypes was traced to activation of different transcriptional programs, which were carefully analyzed and quantitated, resulting in solid evidence for the conclusions.

    1. eLife assessment

      The authors identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate, that show distinct developmental properties. The discovery of a new germinal zone giving rise to a new population of CN neurons is an important finding, and it enriches our understanding of cerebellar development. The claims are supported by solid evidence and the authors use a wide range of technical approaches, including transgenic mice, that allow them to disentangle the influence of distinct developmental organizers.

    1. eLife assessment

      This study convincingly demonstrates the ability of reverting a neurodevelopmental defect with a dietary intervention. While the exact mechanisms remain to be elucidated, the authors establish a simple but important system to study the PI3K/Akt/FOXO pathway but also the action of ketone bodies and their potential therapeutic use. This study will be of particular interest to the large community of scientists studying E/I disequilibrium in the nervous system.

    1. eLife assessment

      This valuable study presents new observations on white matter organisation at the micron scale, using a combination of synchrotron imaging and diffusion MRI across two species. Notably, the authors provide solid evidence for the fasciculation of axons within major fibre bundles into laminar structures, though these structures are not consistently observed across modalities or species. The study will be of general interest to neuroanatomists and those interested in white matter imaging.

    1. eLife assessment

      This study describes important findings related to early disruptions in disinhibitory modulation exerted by VIP+ interneurons, in CA1 in a transgenic model of Alzheimer's disease pathology. The authors provide a convincing analysis at the cellular, synaptic, network, and behavioral levels on how these changes correlate and might be related to behavioral impairments during these early stages of AD pathology.

    1. eLife assessment

      This paper expands the genetic toolset that was previously developed by the Rao lab to introduce the conditional downregulation of neurotransmission components in Drosophila. As a proof of principle, the authors tested their new collection and provide evidence of the contribution of CNMamide (a neuropeptide) to the temporal control of locomotor activity patterns. These are overall important findings supported by compelling evidence.

    1. eLife assessment

      This fundamental study provides an unprecedented understanding of the roles of different combinations of NaV channel isoforms in nociceptors' excitability, with relevance for the design of better strategies targeting NaV channels to treat pain. Although the experimental combination of electrophysiological, modeling, imaging, molecular biology, and behavioral data is convincing and supports the major claims of the work, some results remain inconclusive and need to be strengthened by further evidence. The work may be of broad interest to scientists working on pain, drug development, neuronal excitability, and ion channels.

    1. eLife assessment

      The large-conductance Ca2+ activated K+ channel BKCa has been reported to promote breast cancer progression. The present study presents convincing evidence that an intracellular subpopulation of this channel reprograms breast cancer cells towards the Warburg phenotype, one of the metabolic hallmarks of cancer. This important finding advances the field of cancer cell metabolism and has potential therapeutic implications.

    1. eLife assessment

      This is a useful study that identifies circadian changes in the gene expression profile of cultured mouse astrocytes. Mechanistic details linking circadian rhythmicity in HERP, a regulator of calcium signals in the endoplasmic reticulum, to altered phosphorylation of Connexin 43 remain currently incomplete. With improved manuscript clarity and statistical analysis, this work could be of interest to the field of astrocyte and circadian biology.

    1. eLife assessment

      This fundamental work substantially advances our understanding of cell migration, especially in that of cranial neural crest. The additional evidence provided to support the conclusion is exceptional, with rigorous biochemical assays for materials used and with intensive genetic interventions. The work will be of broad interest to developmental biologists and cell biologists.

    1. eLife assessment

      This important study reports a novel approach to studying cerebellar function based on the idea of selective recruitment using fMRI. It provides convincing evidence for task-dependent gating of neocortical input to the cerebellum during a motor task and a working memory task. The study will be of interest to a broad cognitive neuroscience audience.

    1. eLife assessment

      This important study reports the fungal composition and its interaction with bacteria in the Caesarean section scar diverticulum. The data are solid and supportive of the conclusion. This work will be of interest to researchers and clinicians who work on women's health.

    1. eLife assessment

      This study presents fundamental insights into the heterogeneity of chronic myeloid leukemia (CML) stem cells and their response to tyrosine kinase inhibitor therapy, shedding light on potential mechanisms underlying treatment failure. The study's robust methodology, supported by validation with bulk RNA-seq data and surface marker analysis, provides compelling evidence for the identified associations between cellular composition and treatment outcome. These findings contribute to our understanding of CML pathogenesis and may inform the development of more targeted therapeutic strategies.

    1. eLife assessment

      This important manuscript reports interactions between genetic variation, DNA accessibility, and chromatin structure in gene expression at a genome wide scale. The authors found that most of these interactions occur within topologically associating domains (TADs) and 3D genome structure data can be efficiently used to guide the discovery of significant genetic and epigenetic influences on gene expression. Overall, this convincing study highlights the importance of 3D chromatin structure in controlling how gene expression is regulated by genetic and epigenetic processes.

    1. eLife assessment

      This study presents valuable findings that could be utilized for identifying women at risk for preeclampsia before the onset of the disease. The novel aspect of this study lies in the utilization of exosomes of two different sizes. The data are solid: the methods, data, and analysis broadly support the claims. This work will be of interest to medical researchers and clinicians who work on preeclampsia and women's health.

    1. eLife assessment

      This fundamental study significantly advances our understanding of how parasites evade the host complement immune system. The new cryo-EM structure of 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, immunologists, and structural biologists.

    1. eLife assessment

      This study advances our understanding of the allosteric regulation of anaerobic ribonucleotide reductases (RNRs) by nucleotides, providing valuable new structural insight into class III RNRs containing ATP cones. The cryo-EM structural characterization of the system is solid, but some open questions remain about the interpretation of activity/binding assays and the newly incorporated HDX-MS results. The work will be of interest to biochemists and structural biologists working on ribonucleotide reductases and other allosterically regulated enzymes.

    1. eLife assessment

      This useful study tests the hypothesis that Mycobacterium tuberculosis infection increases glycolysis in monocytes, which alters their capacity to migrate to lymph nodes as monocyte-derived dendritic cells. The authors conclude that infected monocytes are metabolically pre-conditioned to differentiate, with reduced expression of Hif1a and a glycolytically exhaustive phenotype, resulting in low migratory and immunologic potential. However, the evidence is incomplete as the use of live and dead mycobacteria still limits the ability to draw firm conclusions. The study will be of interest to microbiologists and infectious disease scientists.

    1. eLife assessment

      This important study shows, based on analyses of single-cell RNA-seq data sets of thymus cells, that transposable elements (TEs) are broadly expressed in thymic stromal cells, especially in medullary thymic epithelial cells and plasamacytoid dendritic cells. The authors also show that at least some TE-derived peptides are presented by MHC-I molecules in the thymus. The study provides solid findings supporting a role of TEs in thymic T-cell selection and immune self-tolerance.

    1. eLife assessment

      This important study provides an example of integrating computational and experimental approaches that lead to new insights into the energy landscape of a model kinase. Compelling use of molecular dynamics simulations and NMR spectroscopy provide a conformational description of active and excited states of the kinase; one of which has not been captured in previously solved crystal structures. Overall, this comprehensive study expands our understanding of the architecture and allosteric features of the conserved bilobal kinase domain structure.

    1. eLife assessment

      The authors describe an important tool, GromovMatcher, that can be used to compare proteomic data from various experimental approaches. The underlying method is innovative, the algorithm is clearly described, and the validation that is presented is convincing.

    1. eLife assessment

      This study explores the physical principles underlying fluid flow and luminal transport within the endoplasmic reticulum; its important contribution is to highlight the strong physical constraints imposed by viscous dissipation in nanoscopic tubular networks. In particular, the work presents convincing evidence that commonly discussed mechanisms such as tubular contraction are unlikely to be at the origin of the observed transport velocities. As this study is solely theoretical and concerned with order of magnitude estimates, its main conclusions await experimental validation. The work will be of relevance to cell biologists and physicists interested in organelle dynamics.

    1. eLife assessment

      This useful manuscript describes a proteomic analysis of plasma from subjects before and after an exercise regime consisting of endurance and resistance exercise. The work identifies a putative new exerkine, CD300LG, and finds associations of this protein with aspects of insulin sensitivity and angiogenesis, but the evidence to support the main claims remains incomplete.

    1. eLife assessment

      This valuable manuscript presents ImmCellTyper, a new toolkit for CyTOF data analysis. The semi-supervised clustering tool, BinaryClust, integrates prior biological knowledge and demonstrates competitive performance in various benchmarks, but there is room for strengthening the evidence base by addressing concerns about incomplete benchmarking results and the limited consideration of CyTOF markers with binary distribution. Overall, the manuscript offers solid potential for enhancing CyTOF data analysis methodologies.

    1. eLife assessment

      This valuable study provides new insight into how non-synaptic interactions affect the activity of adjacent gustatory neurons housed within the same sensillum. The electrophysiological, behavioral, and genetic data supporting the study's conclusions are solid, although the inclusion of additional control experiments would strengthen the study. This work will be of interest to neuroscientists studying chemosensory processing or regulation of neuronal excitability.

    1. eLife assessment

      This useful study aims to quantify associations between regular use of proton-pump inhibitors (PPI) - defined as using PPI most days of the week during the last 4 weeks at one cross-section in time - with several respiratory outcomes (6 different outcomes) up to several years later in time. Weaknesses were identified in the design of the study, such as the measurement of the primary outcome and also the potential of bias which is inherent to the study design, which means the manuscript provides incomplete evidence.

    1. eLife assessment

      This manuscript describes the mapping of natural DNA sequence variants that affect gene expression and its noise, as well as cell cycle timing, using as input single-cell RNA-sequencing of progeny from crosses between wild yeast strains. The method represents an important advance in the study of natural genetic variation. The findings, especially given the follow-up validation of the phenotypic impact of a mapped locus of major effect, provide convincing support for the rigor and utility of the method.

    1. eLife assessment

      In this valuable study, the authors use Staphylococcus aureus to understand how organic acids inhibit bacterial growth. They provide convincing evidence that acetic acid specifically inhibits the activity of the Ddl enzyme and that S. aureus maintains a high intracellular D-ala concentration to circumvent acetate-mediated growth inhibition. This work will be of interest to researchers studying bacteria and antimicrobials.

    1. eLife assessment

      This study examines an important aspect of the development of the auditory system, the role of guanine nucleotide-binding protein subunits, GNAIs, in stereociliary bundle formation and orientation, by examining bundle phenotypes in multiple compound GNAI mutants. The experiments are highly rigorous and thorough and include detailed quantifications of bundle morphologies and changes. The depth and care of the study are impressive, with convincing results regarding the roles of GNAIs in stereociliary bundle development. Further, the reviewers believe this to be the definitive study of the role of GNAIs in bundle orientation and development.

    1. eLife assessment

      The reprocessing and reanalysis of archived samples can yield further insights from past experiments. Here, a useful procedure to perform tissue clearing and immunolabeling on large-scale formalin-fixed paraffin-embedded brain specimens is convincingly evaluated on a set of archival pathology specimens, and its applicability to further such samples is analyzed. This method will be of interest to both neuroscientists and pathologists.

    1. eLife assessment

      In this important paper, the authors propose a computational model for understanding how the dynamics of neural representations may lead to specific patterns of errors as observed in working memory tasks. The paper provides solid evidence showing how a two-area model of sensory-memory interactions can account for the error patterns reported in orientation estimation tasks with delays. By integrating ideas from efficient coding and attractor networks, the resulting theoretical framework is appealing, and nicely captures some basic patterns of behavior data and the distributed nature of memory representation as reported in prior neurophysiological studies. The paper can be strengthened if (i) further analyses are conducted to deepen our understanding of the circuit mechanisms underlying the behavior effects; (ii) the necessity of the two-area network model is better justified; (iii) the nuanced aspects of the behavior that are not captured by the current model are discussed in more detail.

    1. eLife assessment

      This important study reports human single-neuron recordings in subcortical structures while participants performed a tactile detection task around the perceptual threshold. The study and the analyses are well conducted and provide solid evidence that the thalamus and the subthalamic nucleus contain neurons whose activity correlates with the task, with stimulus presentation, and even with whether the stimulation is consciously detected or not. The study will be relevant for researchers interested in the role of subcortical structures in tactile perception and the neural correlates of consciousness.

    1. eLife assessment

      This study presents a useful method for using multi-electrode spike recordings to track the time-varying functional connectivity between neurons. However, the evidence is incomplete: a demonstration of the utility of the method relative to conventional approaches is needed. If such a demonstration is made, this could be a tool for gaining insight into circuit structure.

    1. eLife assessment

      This important work provides a convincing dataset of neuronal heterogeneity in the raphe nucleus, including their physiological properties, morphology, and susceptibility to the neurodegeneration of noradrenaline and dopamine systems in the Parkinsonian state. These findings suggest a significant interplay between catecholaminergic systems in healthy and parkinsonian conditions, as well as neuronal structure and function. Such findings provide a strong foundation for basic scientists as well as pre-clinical researchers interested in the role of dorsal raphe neurons in Parkinson's disease.

    1. eLife assessment

      The authors report that optogenetic inhibition of hippocampal axon terminals in retrosplenial cortex impairs the performance of a delayed non-match to place task. The significance of findings elucidating the role of hippocampal projections to the retrosplenial cortex in memory and decision-making behaviors is important. However, the strength of evidence for the paper's claims is currently incomplete.

    1. eLife assessment

      This manuscript presents valuable findings on the role of a plant peptide in coordinating developmental and immune responses signaling. The evidence supporting the claims, while mainly descriptive and and somewhat limited due to the main conclusions being drawn from overexpression lines, is mostly solid. The findings are interesting, they align with existing models, and they are of relevance to plant pathologists and developmental biologists.

    1. eLife assessment

      This important study explores the interplay between Legionella Dot/Icm effectors that modulate ubiquitination of the host GTPase Rab10, which undergoes phosphoribosyl-ubiquitination by the SidE family of effectors, which in turn are required for Rab10 recruitment to the Legionella containing vacuole (LCV). The evidence supporting the claims of the authors is convincing. The study is not only relevant for the microbiology community, but will also be of interest to colleagues in the broader fields of membrane trafficking and general cell biology.

    1. eLife assessment

      This valuable study applies voltage clamp fluorometry to provide new information about the function of serotonin-gated ion channels 5-HT3AR. The authors convincingly investigate structural changes inside and outside the orthosteric site elicited by agonists, partial agonists, and antagonists, helping to annotate existing cryo-EM structures. This work confirms that the activation of 5-HT3 receptors is similar to other members of this well-studied receptor superfamily. The work will be of interest to scientists working on channel biophysics but also drug development targeting ligand-gated ion channels.

    1. eLife assessment

      This important manuscript investigates the role of a subpopulation of glutamatergic neurons in the suprammamillary nucleus that projects to the pre-optic hypothalamus area in active coping but not locomotor activity. They provide solid evidence from experiments using fibre photometry or photostimulation during threatening tasks that these neurons allow animals to produce flexible behaviours in response to stress. This work will be of interest to behavioural and systems neuroscientists.

    1. eLife assessment

      This important work substantially advances our understanding of how collagen fibrils are built and maintained in a manner regulated by circadian rhythms in intracellular secretory trafficking pathways. The evidence supporting the data are solid, although further data regarding the molecular mechanisms regulating endocytic recycling of collagen would have strengthened the study. The work will be of considerable interest to those who study extracellular matrix assembly or collagen homeostasis.

    1. eLife assessment

      This elegant study presents important findings into how small molecules that were originally developed to inhibit the oncogenic kinase, BRAF, instead trigger activation of this kinase target. Compelling and comprehensive evidence supports a new allosteric model to explain the paradoxical activation. This rigorous work will be of great interest to biochemists, structural biologists, and those working on strategies to inhibit kinases in the context of human disease.

    1. eLife assessment

      This study provides a valuable theoretical exploration of non-enzymatic sustained replication of RNA systems, in the parabolic growth regime of the evolution of putative primordial replicators. It provides convincing evidence that parabolic growth mitigates the error threshold catastrophe, thus demonstrating another way in which this regime contributes to the maintenance of genetic diversity. The findings shed light on relevant evolutionary regimes of primordial replicators, with potential applicability to our understanding of the origin of life.

    1. eLife assessment

      This valuable study advances our understanding of the brain nuclei involved in rapid-eye movement (REM) sleep regulation. Using a combination of imaging, electrophysiology, and optogenetic tools, the study provides convincing evidence that inhibitory neurons in the preoptic area of the hypothalamus influence REM sleep. This work will be of interest to neurobiologists working on the brain circuits of sleep.

    1. eLife assessment

      This important study provides convincing evidence of artifactual calcium micro-waves during calcium imaging of populations of neurons in the hippocampus using methods that are common in the field. The work raises awareness of these artifacts so that any research labs planning to do calcium imaging in the hippocampus can avoid them by using alternative strategies that the authors propose.

    1. eLife assessment

      The authors used electrophysiology in brain slices and computer modeling and suggest that layer 2/3 pyramidal neurons of the mouse cortex express functional HCN channels, despite little evidence in the past that they are present. The study is useful at the present time, but results are incomplete because the methods, data, and analyses do not always support the conclusions.

    1. eLife assessment

      This valuable study provides incomplete evidence that white matter diffusion imaging of the right superior longitudinal fasciculus might help to develop a predictive biomarker of chronic back pain chronicity. The results are based on a discovery-replication approach with different cohorts, but the sample size is limited, and the clinical relevance is overstated. The findings will interest researchers interested in the brain mechanisms of chronic pain and in developing brain-based biomarkers of chronic pain.

    1. eLife assessment

      This study is valuable in that it aims to demonstrate that genomic insertion of a G4-containing sequence can be sufficient to induce chromosome loops and alter gene expression. However, the evidence remains incomplete because it has not been shown yet that the inserted sequence indeed forms G4 structures in cells and that the observed effects are caused by these structures and not by other elements present in the inserted sequence. Testing of different G4 sequences and other loci would be required to generalize the findings.

    1. eLife assessment

      This important study presents a significant methodological advance by leveraging previously discarded, unmapped DNA sequence reads to estimate pest infestation loads across plant accessions, and map variation in these apparent pest loads to defense genes. While the bioinformatics approach is convincing, the study appears incomplete because actual pest infestation was not systematically quantified, and thus loads inferred from sequencing reads are not validated. The results could have broad implications for phenotype-genotype prediction, especially regarding the use of unmapped reads for GWAS.

    1. eLife assessment

      To investigate the evolutionary relationship between the RNAi pathway and innate immunity, this valuable study uses biochemistry and structural biology to investigate the trimeric complex of Dicer-1, DRH-1 (a RIGI homologue), and RDE-4, which exists in C. elegans. The results described include rigorous kinetic analysis of the enzymatic activity of the complex and a moderate resolution cryo-EM structure. The results are convincing and add to the broader understanding of the evolution of antiviral defense.

    1. eLife assessment

      This valuable study demonstrates how proximity labeling with streptavidin can be used to boost fluorescence signals in otherwise hard-to-label regions of cells. The technique can outperform the immunofluorescence of epitope tags in phase-separated regions, but the experimental verification is incomplete and would benefit from additional controls. This study will be of particular interest to those using correlative light and electron microscopy or expansion microscopy when the signal is limiting or inaccessible.

    1. eLife assessment

      This useful study focuses on gene regulatory mechanisms essential for hindbrain development. Through molecular genetics and biochemistry, the authors propose a new mechanism for the control of Hox genes, which encode highly conserved transcription factors essential for hindbrain development. However, the strength of evidence is incomplete, as the main claims are only partially supported by the data. This work will be of interest to developmental biologists.

    1. eLife assessment

      This important work substantially advances our understanding of osteoblast migration to the sites of bone formation and regeneration. The evidence supporting the conclusion is compelling, with rigorous in vitro assays for cellular and biochemical aspects and with appropriate in vivo models. The work will be of broad interest to developmental biologists and bone biologists.

    1. eLife assessment

      This study presents an important computational tool for the quantification of the cellular composition of human tissues profiled with ATAC-seq. The methodology is solid and its application results on breast cancer tumor tissues are convincing. It advances existing methods by utilizing a comprehensive reference profile for major cancer-relevant cell types, compatible with a widely-used cell type deconvolution tool.

    1. eLife assessment

      It is well-established that cellulose synthesis in higher plants requires three different but related catalytic subunits known as CESA proteins. Here the authors provide convincing cryo-electron microscopy structural information on soybean CESA1, CESA3, and CESA6 and find substantial differences between the structure of these CESA homotrimers and the previously-resolved secondary cell wall CESAs. They present an important model in which the multi-subunit cellulose synthase complexes are made of multiple homotrimers but further evidence is needed to strengthen the conclusions.

    1. eLife assessment

      The manuscript addresses an important subject regarding the effects of the consumption of artificially sweetened beverages. The authors used zebrafish embryos treated with high concentrations of monosaccharides and observed hyperangiogenic characteristics similar to those seen in proliferative diabetic retinopathy. Their findings suggest that caloric and noncaloric monosaccharides induce excessive angiogenesis via the foxo1a-Marcksl1a pathway, but the evidence is currently incomplete.

    1. eLife assessment

      This important study sheds light on several apparent discrepancies observed across animal studies examining neuroimaging biomarkers of functional recovery following focal ischemia. Using 2-photon imaging of calcium activity in awake mice, the authors show compelling evidence that deficits in neuronal activity and functional connectivity after photothrombosis occur within a very small distance from the infarct (<750 microns) whereas these measures were relatively unaltered more distally, even those typically implicated with functional remapping of the forelimb representation in anaesthetized animals. These findings reveal a complex spatiotemporal relationship between perilesional neuronal network function and behavioral recovery that is more nuanced than previously reported, and motivates the need for better criteria for what is considered remapping.

    1. eLife assessment

      This is a valuable study that describes the effects of T. pallidum on neural development by applying single-cell RNA sequencing to an iPSC-derived brain organoid model. The evidence supporting the claims of the authors is solid, although further evidence to understand the differences in infection rates would strengthen the conclusions of the study. In particular, the conclusions would be strengthened by validating infection efficiency as this can impact the interpretation of single-cell sequencing results, and how these metrics affect organoid size as well as comparison with additional infectious agents. Furthermore, additional validations of downstream effectors are not adequate and could be improved.

    1. eLife assessment

      This valuable work describes a highly complex automated algorithm for analyzing vascular imaging data from two-photon microscopy. This tool has the potential to fill gaps in knowledge of hemodynamic activity across a regional network. The underlying methods and results are still incomplete; the biological application provided has several problems that make many of the scientific claims in the paper questionable and the generalizability of the pipeline needs to be further addressed. We believe these concerns could be addressed.

    1. eLife assessment

      This important study investigates various variants of the SARS-COV-2 spike protein using established computational methods, complemented by experimental validation efforts. The evidence, bolstered by an evolutionary approach and protein dynamics, is solid. Placing this research in the broader context of the field could further enrich the manuscript. It will interest biophysicists focused on allostery and protein evolution.

    1. eLife assessment

      This important study presents a framework for combining metagenomic and metabolomic data with genome-scale metabolic models to identify trophic interactions in a root microbiome. Its new approach to integrating these sources of data and model-specific trophic exchanges is compelling, but the benchmarking of the model generation process is incomplete and would benefit from a sensitivity and specificity analysis. With a stronger characterization of their method, this paper could be broadly applicable to other microbiomes and used to understand the composition and functioning of a given community, generate hypotheses, and design interventions.

    1. eLife assessment

      This important study addresses the long-term effect of warming and precipitation on microbial growth, as a proxy for understanding the impact of global warming. The evidence that warming and altered precipitation exhibit antagonistic effects on bacterial growth is compelling and advances our understanding of microbial dynamics affected by environmental factors. This study will interest microbial ecologists, microbiologists, and scientists generally concerned with climate change.

  2. Mar 2024
    1. eLife assessment

      This study presents a useful deep learning-based inter-protein contact prediction method named PLMGraph-Inter which combines protein language models and geometric graphs. The evidence supporting the claims of the authors is solid. The authors show that their approach may be used in cases where AlphaFold-Multimer performs poorly. This work will be of interest to researchers working on protein complex structure prediction, particularly when accurate experimental structures are available for one or both of the monomers in isolation.

    1. eLife assessment

      This important paper provides solid evidence for an alternative conceptualization of the functional role of the place and grid cell network in the medial temporal lobe for memory as opposed to spatial processing or navigation. The theory accounts for many experimental results and generates predictions for future studies. The theory's simplicity and potential explanatory power will be of interest to researchers in this field. The impact of the work at present is limited by insufficient evidence for the advantage of this model over prior models, especially as the theory does not appear to fit with some well-established existing data.

    1. eLife assessment

      This is a useful study describing an implementation of awake mouse fMRI with implanted head coils at high fields. The evidence presented is solid but could with some work become stronger. In particular, the authors need to better contextualize their work with the existing literature on awake fMRI, include further details regarding their experimental methods, and further discuss some of their unexpected (but potentially novel and interesting) brain activations.

    1. eLife assessment

      In this study, the authors develop a strategy for fluorophore-tagging endogenous proteins in human induced pluripotent stem cells (iPSCs) using a split mNeonGreen approach, and they conclude that the system will be appropriate for performing live imaging studies of highly dynamic cellular processes such as cytokinesis in iPSCs. Experimentally, the methods are solid, and the data presented support the authors' conclusions. Overall, these methodologies should be useful to a wide audience of cell biologists who want to study protein localization and dynamics at endogenous levels in iPSCs.

    1. eLife assessment

      This useful study introduces a simple mechanical model of C. elegans locomotion that captures aspects of the worm's behavioral repertoire beyond forward crawling. While the kinetic model (ElegansBot) provides a compromise and starting point to help understand the mechanical components of C. elegans behavior, the claim that this work improves on extant mechanical models is incomplete, including modeling a 3-dimensional turning behavior with a 2-dimensional model without sufficient justification. In addition, the results of the application of the model to previously unstudied behaviors are primarily qualitative and do not produce new predictions.

    1. eLife assessment

      This useful study, which systematically addresses off-target effects of a commonly used chemotherapy drug on bone and bone marrow cells and which therefore is of potential interest to a broad readership, presents evidence that reducing systemic inflammation induced by doxorubicin limits bone loss to some extent. The demonstration of the effect of systemic inflammation on bone loss is convincing. Building on prior work, this study sets the scene for additional genetic and pharmacologic experiments as well as future analyses of the bone phenotypes, which should speak to the mechanisms involved in doxorubicin-induced bone loss – which are not addressed in the current study – and which may substantiate the clinical relevance of targeting inflammation in order to limit the negative impact of chemotherapies on bone quality.

    1. eLife assessment

      This fundamental work advances our understanding of the role of Cbfβ in maintaining articular cartilage homeostasis and the underlying mechanisms. The evidence supporting the conclusion is mostly convincing, although including additional experiments and discussions would have strengthened the study. This paper is of potential interest to skeletal biologists and orthopaedic surgeons who study the pathogenesis and the therapeutics of osteoarthritis.

    1. eLife assessment

      This important study combines in vivo and in vitro models to characterise the role of CYRI-B, an interactor of the small GTPase Rac1, in controlling pancreatic cancer progression towards a higher proliferative and metastatic stage. The evidence supporting the claims of the authors is convincing in characterizing a novel Rac1 binding protein, CYRI-B, as a regulator of metastatic potential in vivo, with distinct functions at different stages of tumour progression. CYRI-B reduces the typical hyperactivation of Rac1 in the early stages of tumour progression; subsequently, CYRI-B mediates internalization of lysophosphatidic acid receptor 1 (LPAR1) uptake through macropinocytosis, thus regulating chemotactic migration of cancer cells towards lysophosphatidic acid (LPA). Although the inclusion of human pancreatic cancer cell lines would have strengthened the study, the work will be of broad interest to cell biologists and the signalling research communities.

    1. eLife assessment

      This study presents an interesting set of findings that connects N-cadherin and glypican-4 to Slit signaling during the regulation of contact inhibition of locomotion of Schwann cells in culture. Solid evidence is provided showing that N-cadherin not only regulates cell recognition but also proper trafficking of Slit to the cell surface. An ex-vivo model demonstrates the importance of Slit signaling during cell migration but the molecular details of how N-cadherin traffics Slit to the surface and role of glypican are unclear. The data would have been strengthened with a similar interrogation of N-cadherin in this system. The work will be of interest to cell biologists studying the mechanisms behind peripheral nervous system regeneration.

    1. eLife assessment

      This work presents a potentially important behavioral finding: that perceptual learning may not only improve but also distort the appearance of visual stimuli. The strength of the presented evidence in support of the main claim is however incomplete, and requires further analyses to confirm that perceptual learning does increase overestimation bias, and clarify why a very large baseline overestimation bias is present in the data.

    1. eLife assessment

      This important study provides a new, apparently high-performance algorithm for B cell clonal family inference. The new algorithm is highly innovative and based on a rigorous probabilistic analysis of the relevant biological processes and their imprint on the resulting sequences, however, the strength of evidence regarding the algorithm's performance is incomplete, due to (1) a lack of clarity regarding how different data sets were used for different steps during algorithm development and validation, resulting in concerns of circularity, (2) a lack of detail regarding the settings for competitor programs during benchmarking, and (3) method development, data simulation for method validation, and empirical analyses all based on the B cell repertoire of a single subject. With clarity around these issues and application to a more diverse set of real samples, this paper could be fundamental to immunologists and important to any researcher or clinician utilizing B cell receptor repertoires in their field (e.g., cancer immunology).

    1. eLife assessment

      The authors present a critique of current usage of principal component analysis in geometric morphometrics, making a convincing case with benchmark data that standard techniques perform poorly. The work is an important contribution to the field and will hopefully lead to a reassessment of the methodology most scientists in morphometrics currently use. The authors also present a new Python package that uses machine learning to provide better-supported results than principal component analysis. While the package is in the title of the manuscript, it is not its main focus.

    1. eLife assessment

      Through a theoretical approach, this study makes important contributions to our understanding of the evolutionary causes of the ageing process. Using a simple individual-based model and computational simulations, the authors provide convincing evidence that ageing can be a trait under natural selection, opening the door for further discussion in the context of lifespan extension research.

    1. eLife assessment

      The study presents valuable findings on compensatory mechanisms in response to glycosuria. The evidence supporting the claims is solid, although a causal relationship is somewhat uncertain and the addition of a more clinically relevant model would have strengthened the findings. The work will be of interest to diabetes investigators.

    1. eLife assessment

      This study explores the interplay between fungal colonization and controlled programmed cell death in Arabidopsis thaliana root cells. The authors reveal how this process is affected by corpse clearance in the root cap, highlighting some of the key elements in this process including a root cap-specific transcription factor. With this, the authors have discovered an important relationship between transcriptional regulation of developmentally controlled cell death and the beneficial colonization of plants by fungi. The work thus establishes a solid basis for further studies of plant-microbiome associations along the root axis.

    1. eLife assessment

      This important work addressed the identifcation of antimalarial drug resistance mutations that do not readily transmit to new human hosts, focusing on azithromycin resistance. The technically challenging analyses of azithromycin-resistant parasites as they traverse the mosquito host and human liver are conducted using state-of-the-art tools, including humanized mice. While the claim regarding the lack of transmission by atovaquone-resistant P. berghei is convincing, the evidence for the lack of transmission by atovaquone-resistant P. falciparum is insufficient. This work will appeal to biologists and biomedical scientists in parasitology and drug discovery, offering insights into combating antimalarial drug resistance and understanding the fitness costs associated with drug-resistant parasites.

    1. eLife assessment

      This study provides important biophysical insights into the molecular mechanism underlying the association of alpha-synuclein chains, which is essential for understanding the pathogenesis of Parkinson's disease. The data analysis is solid, and the methodology can help investigate other molecular processes involving intrinsically disordered proteins. The benchmarking of the cgMD simulations should be improved to give the reader greater confidence in the conclusions presented.

    1. eLife assessment

      The authors present evidence that small extracellular vesicles can be secreted from cells inside larger vesicles that they call amphiectosomes, which then tear to release their small vesicle contents. There are questions and concerns relating to the quality of the data and the in vivo significance of the observations. The findings are potentially important but the data are incomplete and the claims are only partially supported.

    1. eLife assessment

      This work addresses an important biological question: what is the cellular basis of wound healing? Using the Drosophila pupal notum as a model, the paper provides an elegant, thorough, descriptive characterisation of syncytia-driven wound closure using state-of-the-art confocal live imaging of the pupal notum. The authors meticulously characterize the cell-cell fusion events during wound healing, but without any mechanisms to inhibit cell fusion, it is incomplete, since it remains unclear whether cell fusion is required or not for speeding wound healing and/ or increasing the level of actin resources at the leading edge.

    1. eLife assessment

      This important study describes the new observation that nuclear volume responds to confinement in a manner that requires transit through mitosis. The authors present solid evidence demonstrating that nuclear volume decreases upon nuclear envelope reformation under confinement in a manner that reestablishes a homeostatic state of nuclear envelope tension. Additional experimental support could provide a more complete case for the proposed underlying mechanisms governing this response. The work will be of broad interest to cell biologists and those interested in cell and organismal scaling.

    1. eLife assessment

      Tatekoshi et al. endeavored to utilize human-induced pluripotent stem cell-derived cardiomyocytes to create an in vitro model of Heart Failure with preserved Ejection Fraction (HFpEF) to investigate the impacts of inflammation, sera from HIV patients, and the application of cardioprotective and antiviral medications on cardiomyocyte relaxation as a proxy for diastolic function. Their investigations revealed that inflammatory cytokines lead to an increased decay in calcium transients, a process that could be alleviated through the use of SGLT2 inhibitors and mitochondrial antioxidants. These results indicate that inflammation might contribute to diastolic dysfunction and suggest that SGLT2 inhibitors and mitochondrial antioxidants could offer cardioprotective benefits by reducing inflammation in cardiomyocytes. These valuable, yet incomplete results, can be complemented by employing biomechanical and molecular analyses, alongside validation of the therapeutic duration and dosages.

    1. eLife assessment

      This useful study reports data supporting the importance of sterol homeostasis in sperm development and consequently male reproduction. While most of the data are supportive of the conclusion, some remain incomplete and need more experimental verification. This work would be of interest to basic researchers and clinicians working on sterol homeostasis and male fertility.

    1. eLife assessment

      The study is solid and reports interesting findings on the sensitivity of different cell types to EDCs in vitro. The data are valuable but the manuscript requires more experimental details. Bioinformatic analyses need to be improved and the interpretation of results and conclusions adjusted to the results.

    1. eLife assessment

      This study provides important findings on the evolution and function of the X-linked miR-506 miRNA cluster. The evidence supporting the conclusions is convincing, including the generation and characterization of an impressive number of the miRNA deletion mutants. This work will be of interest to RNA biologists, evolution biologists and reproductive biologists.

    1. eLife assessment

      This important study dissects the role of octopamine in the interplay between internal energy homeostasis, food intake and food-related memories. The solid experimental evidence will shed additional light on previously published work and should be of interest to the growing community of biologists interested in how internal state shapes behavior, including decision making processes, learning and memory.

    1. 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.

    1. eLife assessment

      In this valuable study, the authors present findings that suggest that people do not faithfully replicate the physics of the real world but rather have a stochastic world model, specifically a stochastic representation of gravity. This contrasts with prior accounts that suggested a potentially noisy Newtonian model where the noise arises from perceptual uncertainty or (inferred) external perturbations. The experimental evidence is generally solid, with all experiments and model simulations being consistent with the proposed account. In the revision, the authors also added a number of control experiments that address some of the most pressing concerns of the original submission.

    1. eLife assessment

      Following synaptic vesicle fusion events at release sites, vesicle remnants will need to be cleared in order to allow new rounds of vesicle docking and fusion. This fundamental study of Mahapatra and Takahashi examines the role of release site clearance in synaptic transmission during repetitive activity in two types of central synapses, the giant calyx of Held and hippocampal CA1 synapses. The study uses pharmacological approaches to interfere with release site clearance by blocking membrane retrieval (endocytosis). They compare the effects on short-term plasticity with those obtained by pharmacologically inhibiting scaffold protein activity. The data presented make a compelling case for fast endocytosis as necessary for rapid site clearance and vesicle recruitment to active zones. The data reveal an unexpected, fast role for local site clearance in counteracting synaptic depression.

    1. eLife assessment

      This study tests the effects of using neurofeedback, in the form of reward delivery when large sharp wave-ripples (SWRs) are detected, on neurophysiological and behavioral measures. The results are important, and the authors provide convincing evidence that the rate of SWRs increased prior to reward delivery and decreased in the period after reward delivery, with no significant effect on memory performance. The ability to manipulate SWR rate in a naturalistic way is an exciting new tool for studies that seek to understand the function of SWRs.

    1. eLife assessment

      This important study contributes to the understanding of how parafoveal words are neurally processed during naturalistic sentence reading. Solid evidence is provided that the MEG response to a word can be modulated by the semantic congruency of a parafoveal target word. The study addresses a classic question in reading using a new Rapid Invisible Frequency Tagging (RIFT) technique, which can separately monitor the neural processing of multiple words during sentence reading.

    1. eLife assessment

      The study by Zhu et al. provides important insights into cell-specific genome-wide histone modifications in the frontal cortex of individuals with schizophrenia, as well as shedding light on the role of age and antipsychotic treatment in these associations. The evidence supporting the conclusions is solid.

    1. eLife assessment

      This manuscript presents important results indicating a plastic enhancement in the vasomotion response of pial cortical arterioles to external stimulation in awake mice using a wide range of external visual stimulation paradigms. The evidence for this interesting effect, with broad potential applications, is solid. These results are relevant for scientists and clinicians interested in the regulation of blood flow in the brain.

    1. eLife assessment

      This study concerns how macaque visual cortical area MT represents stimuli composed of more than one speed of motion. The study is valuable because little is known about how the visual pathway segments and preserves information about multiple stimuli, and the study involves perceptual reports from both humans and one monkey regarding whether there are one or two speeds in the stimulus. The study presents compelling evidence that (on average) MT neurons represent the average of the two speeds, with a bias that accentuates the faster of the two speeds. Ultimately, this study raises intriguing questions about how exactly the response patterns in visual cortical area MT might preserve information about each speed, since such information could potentially be lost in an average response as described here, depending on assumptions about how MT activity is evaluated by other visual areas.

    1. eLife assessment

      This work provides a valuable analysis of the effect of two commonly used hyperparameters, noise amplitude and firing rate regularization, on the representations of relevant and irrelevant stimuli in trained recurrent neural networks (RNNs). The results suggest an interesting interpretation of prefrontal cortex (PFC) dynamics, based on comparisons to previously published data from the same lab, in terms of decreasing metabolic cost during learning. The evidence indicating that the mechanisms identified in the RNNs are the same ones operating in PFC was considered incomplete, but could potentially be bolstered by additional analyses and appropriate revisions.

    1. eLife assessment

      This important study investigates the transcriptional changes in neurons that underlie loss of learning and memory with age in C. elegans, and how cognition is maintained in insulin/IGF-1-like signaling mutants. The presented evidence is convincing, utilizing a cutting-edge method to isolate neurons from worms for genomics that is clearly conveyed with a rigorous experimental approach. Overall, this study supports that older daf-2 worms maintain cognitive function via mechanisms that are unique from younger wild type worms, which will be of interest to neuroscientists and researchers studying ageing.

    1. eLife assessment

      The authors present valuable empirical and modelling evidence that statistical learning in speech perception may contain processes like segmentation and anticipation. While the evidence for statistical learning effects is solid, the link between the pattern of effects (both empirical and simulated) and the theoretical concepts of segmentation and anticipation would need to be much stronger to exclude other accounts of the data. This work will be of broad interest to researchers working on, or with, statistical learning, and to any researcher interested in the challenges of whether data and modeling can effectively adjudicate between competing theoretical constructs.

    1. eLife assessment

      This important paper presents a thoroughly detailed methodology for mesoscale-imaging of extensive areas of the cortex, either from a top or lateral perspective, in behaving mice. The examples of scientific results to be derived with this method offer promising and stimulating insights. Overall, the method and results presented are convincing and will be of interest to neuroscientists focused on cortical processing in rodents and beyond.

    1. eLife assessment

      The authors report valuable findings that temporary pharmacological inhibition targeting the dorsal or intermediate hippocampus in rats disrupted navigation to a goal location in a new virtual place-preference task and that functional inhibition of the intermediate hippocampus is more detrimental than functional inhibition of the dorsal hippocampus. The work has the potential to provide novel insights into function differentiation along the dorsal-ventral axis of the hippocampus. However, the evidence for the paper's claim that the dorsal hippocampus is responsible for accurate spatial navigation and the intermediate hippocampus for place-value associations is currently incomplete.

    1. eLife assessment

      This paper reports a valuable set of new results. The main result is that the projection from adult-born granule cells in the dentate gyrus to the hippocampal subfield CA2 is necessary for the retrieval of a social memory formed during development, and solid evidence is provided to support this conclusion.

    1. eLife assessment

      In their study, Diana et al. introduce a novel method for spike inference from calcium imaging data using a Monte Carlo-based approach, emphasizing the quantification of uncertainties in spike time estimates through a Bayesian framework. This method employs particle Gibbs sampling for estimating model parameter probabilities, offering accuracy comparable to existing methods with the added benefit of directly assessing uncertainties. Although the paper provides a solid methodological explanation, it lacks a thorough comparison with other inference methods. Nevertheless, it presents a valuable advancement for neuroscientists interested in new approaches for parameter estimation from calcium imaging data.

    1. eLife assessment

      This study explores the role of one the most abundant circRNAs, circHIPK3, in bladder cancer cells, providing convincing data that circHIPK3 depletion affects thousands of genes and that those downregulated (including STAT3) share an 11-mer motif with circHIPK3, corresponding to a binding site for IGF2BP2. The experiments demonstrate that circHIPK3 can compete with the downregulated mRNAs targets for IGF2BP2 binding and that IGF2BP2 depletion antagonizes the effect of circHIPK3 depletion by upregulating the genes containing the 11-mer motif. These valuable findings contribute to the growing recognition of the complexity of cancer signaling regulation and highlight the intricate interplay between circRNAs and protein-coding genes in tumorigenesis.

    1. eLife assessment

      This important study represents a follow-up of previous papers by Huff et al. (2023) in which the authors further investigate a specific medullary region named the Postinspiratory Complex (PiCo) involved in the control of swallow behaviour and its coordination with breathing. In the present work, they tested the impact of chronic intermittent hypoxia on the swallow motor pattern evoked by optogenetic stimulation of the same medullary area in transgenic mice. These solid results indicate that in chronic intermittent hypoxia-exposed mice PiCo stimulation triggers atypical swallow motor patterns. The experimental procedures are rigorous and technically remarkable. The work will be of interest in the field of respiratory physiology and pathophysiology since a disruption of swallowing and possibly discoordination with breathing may be involved in diseases characterized by the presence of hypoxic conditions such as obstructive sleep apnea.

    1. eLife assessment

      This valuable study examines the activity and function of dorsomedial striatal neurons in estimating time. The authors examine striatal activity as a function of time and the impact of optogenetic striatal manipulation on the animal's ability to estimate a time interval. However, the task's design and methodology present several confounding factors that mean the evidence in support of the authors' claims is incomplete. With these limitations addressed, the work would be of interest to neuroscientists examining how striatum contributes to behavior.

    1. eLife assessment

      This valuable study describes early postnatal compartmental differences in the functional maturation of striatal projection neurons. It explores how the postnatal activity of these neurons may determine the GABAergic innervation of dopaminergic neurons in the adult substantia nigra pars compacta. While the functional characterization of striatal neuron development is solid, analysis of how early postnatal activity of striatal projection neurons shapes their functional innervation of dopaminergic neurons is incomplete.

    1. eLife assessment

      This study presents a valuable finding on the structural role of glycosylation at position N343 of the SARS-CoV-2 spike protein's receptor-binding domain in maintaining its stability, with implications across different variants of concern. The evidence supporting the claims of the authors is solid, although a more complete discussion of published data would have strengthened the study by providing a foundation for the new findings. The work will be of interest to evolutionary virologists.

    1. eLife assessment

      This study is a useful showcase of a workflow to perform large-scale characterization of drug mechanisms of action using proteomics. The work is backed by solid evidence, however, more statistical analyses and a user-friendly interface to enhance data mining by the readers are recommended. The strengths of this study include the large number of compounds tested within a common workflow and well-described experimental protocols. This will be of broad interest to medicinal chemists, toxicologists, and biochemists.

    1. eLife assessment

      This is a very strong, well-written, and interesting paper analyzing in an original way how tension pattern dynamics can reveal the contribution of active versus passive intercalation during tissue elongation. The authors apply a new concept of isogonal tension decomposition to extract a global map of tissue mechanics that will be extremely valuable in the field of biomechanics. The model is convincing to explain the authors' data but could be strengthened further by analyzing data from mutant backgrounds that could serve as a test.

    1. eLife assessment

      The study by Long et al. presents valuable findings on the role of the SUL1 gene in yeast longevity, proposing that lifespan extension can occur through signaling pathways independent of its sulfate transport function, offering new insights into aging mechanisms with potential implications beyond yeast biology. However, the evidence supporting the uncoupling of SUL1's transport and signaling functions is inadequate, relying on limited lifespan analysis without measurements for nutrients and nutrient signaling status. This research is of particular interest to the aging research community, although additional experiments are needed to fully substantiate the claims.

    1. eLife assessment

      This paper makes a valuable contribution by implicating S-acylation of Cys-130 in recruitment of the inflammasome receptor NLRP3 to the Golgi. Enzymes are identified as candidates for mediating S-acylation and de-acylation of NLRP3, and evidence is presented that S-acylation plays a role in response to the stress induced by nigericin treatment. Although it seems likely that Cys-130 does indeed contribute to membrane association of NLRP3, the mechanistic analyses are incomplete and the interpretations about the effects of nigericin are not fully conclusive.

    1. eLife assessment

      The authors introduce a valuable machine-learning model for predicting binding sites of diverse ligands, including DNA, RNA, peptides, proteins, ATP, HEM, and metal ions, on proteins. The method is freely accessible and user-friendly. The authors have conducted thorough benchmarking and ablation studies, providing convincing evidence of the model's overall performance, despite some imperfections of the comparisons to other methods that arise from intrinsic differences between training methods and data.

    1. eLife assessment

      This study presents a rather valuable finding that vilazodone can restore the normal platelet level through regulating 5-HT1A receptor. The evidence supporting the claims of the authors is solid, although inclusion of more cell lines and more detailed analysis of the results would have strengthened the study. The work will be of interest to scientists working in the field of thrombocytopenia.

    1. eLife assessment

      This important study unveils the significant impact of prenatal alcohol exposure on epigenetic patterns, offering new insights into its adverse health outcomes through solid evidence from both mouse models and human data. The findings, which reveal how a high-methyl diet can mitigate these epigenetic alterations, present a promising prenatal care strategy. Despite its solid data overall, the study's small sample size and unaccounted confounders suggest the need for further research to confirm these findings and explore their practical implications.

    1. eLife assessment

      The study presented in this manuscript makes important contributions to our understanding of cell fate decisions and the role of noise in gene regulatory networks. Through computational and theoretical analysis, the authors provide solid support for distinguishing distinct driving forces behind fate decisions based on noise profiles and reprogramming trajectories. While acknowledging the potential limitations of small gene regulatory networks in capturing the richness of whole-transcriptome sequencing datasets, this study offers a creative approach for formulating hypotheses about gene regulation during stem cell differentiation using single-cell sequencing data.

    1. eLife assessment

      This work presents some valuable information regarding the molecular mechanisms controlling the regeneration of pancreatic beta cells following induced cell ablation. However, the study lacks the critical lineage tracing result to support the conclusion about the origin of the regenerated beta cells. The results of the pharmacological manipulation of CaN signaling are also incomplete. In particular, these manipulation are not cell-specific, making it difficult to interpret and thus a genetic approach is recommended.

    1. eLife assessment

      This potentially useful work characterizes the changes in microbial composition of the nasal and fecal microbiomes of COVID-19 patients according to the severity of disease. However, the description of methods and statistics used for several figures is incomplete.

    1. eLife assessment

      This comprehensive study provides valuable information on the cooperation of Ikaros with Foxp3 to establish and regulate a major portion of the epigenome and transcriptome of T-regulatory cells. While the data are compelling, the evidence that these features are solely intrinsic, independent of the micro-environment, could be strengthened.

    1. eLife assessment

      The development of this mouse model is an important step to establish the role of the FSH Receptor in tissues beyond the reproductive system, and the data provided in this paper are convincing for a role for the FSH receptor in cell systems well beyond the classic reproductive tissues. Such model(s) have long been needed in this field and will provide expanded opportunities to better define FSH biology in vivo in these important target tissues. Ultimately, this model could shed light on FSH biology in women after menopause, when endogenous FSH levels rise dramatically, or in men with hypogonadism when FSH levels are high.

    1. eLife assessment

      This study on scRNA-seq of allergic contact dermatitis (ACD) is important in that it presents new data on fibroblasts in ACD and links to recent studies on other cell types and their signatures. The evidence presented is solid in that the data support claims of unique roles for subtypes of fibroblasts in ACD. Overall, this paper will be used as a resource by many in the skin inflammation field.

    1. eLife assessment

      This valuable work provides a near-complete description of the mechanosensory bristles on the Drosophila melanogaster head and the anatomy and projection patterns of the bristle mechanosensory neurons that innervate them. The data presented are solid. The study has generated numerous resources for the community that will be of interest to neuroscientists in the field of circuits and behaviour, particularly those interested in mechanosensation and behavioural sequence generation.

    1. eLife assessment

      This important study outlines how the agr quorum sensing system in Staphylococcus aureus confers long-lived protection against oxidative stress, thereby linking bacterial metabolism to virulence in this pathogen. While the findings, which are supported by solid data, seem at first glance to contradict earlier findings that show increased fitness of agr mutants under oxidative stress, the core conclusions of the study are well-substantiated. The topic of the paper holds broad relevance to microbiologists, especially those focusing on host-pathogen interactions and bacterial responses to ROS.

    1. eLife assessment

      This fundamental study substantially advances our understanding of sibling chimerism in marmosets by demonstrating that chimerism is limited to hematopoietic cells. The evidence supporting these findings is compelling, demonstrated through comprehensive analyses, including single-cell RNA-seq data from multiple individuals and tissues. The work will be of broad interest to many fields of biology.

    1. eLife assessment

      This important study uses citizen science-generated diversity records and quantitative methodologies to improve species distribution estimates. This combination of fields, technologies, and methodologies is solid and improves species distribution maps formerly based solely on limited data gathered by scientists in traditional ways/surveys. This paper will be of interest to researchers interested in citizen science and new sources of big data in biodiversity, and to biogeographers exploring the distributions of species on the planet.

    1. eLife assessment

      This study provides important findings on the modulation of cortical neuronal responses to sensory stimuli by motor-driven predictive signals. The study is methodologically sound and well-designed. The data, as analysed, provide incomplete support for the conclusion that audiomotor mismatch responses are observed in the auditory cortex and that these are strongly modulated by cross-modal signals.

    1. eLife assessment

      This important study combines fMRI and electrophysiology in sedated and awake rats to show that LFPs strongly explain spatial correlations in resting-state fMRI but only weakly explain temporal variability. They propose that other, electrophysiology-invisible mechanisms contribute to the fMRI signal. The evidence supporting the separation of spatial and temporal correlations is convincing, however, the support of electrophysiological-invisible mechanisms is incomplete, considering alternative potential factors that could account for the differences in spatial and temporal correlation that were observed. This work will be of interest to researchers who study the mechanisms behind resting-state fMRI.

    1. eLife assessment

      The paper reports rare compound heterozygous deletion variants that affect the kinase domains of non-receptor tyrosine kinases TNK and ACK1 in families with human systemic lupus erythematosus (SLE). Using a mouse experimental model and human induced pluripotent stem cell (hiPSC)-derived macrophages, the study provides solid evidence that clarifies cause-effect relationships and that suggests a potential cellular mechanism underlying the resultant nephritis. With the identification of novel SLE-related genes, this manuscript provides an important basis for understanding the molecular and cellular basis of SLE pathogenesis.

    1. eLife assessment

      This study demonstrates mRNA-specific regulation of translation by subunits of the eukaryotic initiation factor complex 3 (eIF3) using convincing methods, data, and analyses. The investigations have generated important information that will be of interest to biologists studying translation regulation. However, the physiological significance of the gene expression changes that were observed is not clear.

    1. eLife assessment:

      In flies defective for axonal transport of mitochondria, the authors report the upregulation of one subunit, the beta subunit, of the heterotrimeric eIF2 complex via mass spectroscopy proteome analysis. Neuronal overexpression of eIF2β phenocopied aspects of neuronal dysfunction observed when axonal transport of mitochondria was compromised. Conversely, lowering eIF2β expression suppressed aspects of neuronal dysfunction. While these are intriguing observations that are potentially useful, several technical weaknesses limit the interpretation and mean the evidence supporting the current claims is incomplete.

    1. eLife assessment

      This important study combines a range of biophysical techniques to carry out a series of compelling experiments to explore whether glutamine binding protein binds glutamine via an induced fit or a conformational selection process. The evidence supporting the major conclusion of the work is convincing, although it may not be generalized to other protein-ligand or protein-protein systems. The work will be of broad interest to biochemists and biophysicists.

    1. eLife assessment

      The demonstration that the PARG dePARylation enzyme is required in S phase to remove polyADP-ribose (PAR) protein adducts that are generated in response to the presence of unligated Okazaki fragments is potentially valuable, but the evidence is incomplete, and identification of relevant PARylated PARG substrates in S-phase is needed to understand the role of PARP1-mediated PARylation and PARG-catalyzed dePARylation in S-phase progression.

    1. eLife assessment

      This paper provides a useful analysis of the variation of the burden of strokes across geographic regions, finding differences in the relationship between strokes and their comorbidities. This dataset and the correlations found within will be a resource for directing the focus of future investigations. The statistical analyses are incomplete.

    1. eLife assessment

      This study provides valuable information on how Arg-II participates in cardiac aging. Although the phenotypic data appear robust, the study is incomplete in elucidating the mechanisms, particularly in explaining how Arg II influences IL-1b and affects cardiac aging. It would be beneficial to investigate the possibility of NO involvement in this mice model. A co-culture system may be required to understand the non-cell-autonomous functions of macrophages. Lastly, the MI mouse model may not be directly linked to cardiac aging.

    1. eLife assessment

      This useful paper looks for correlations between immunophenotypic markers and several measures of HIV reservoir volume in cross-sectional cohorts of people living with HIV on ART using several bioinformatic and machine-learning tools. The level of evidence linking these variables is incomplete given possible confounding variables, lack of directionality & effect size, and mechanistic basis.

    1. eLife assessment

      This paper reports a valuable platform for cardiac tissue cultivation. The throughput, consistency of the tissue, and the potential integration of high-throughput automation are an advantage over other approaches. The tissues and the platform are validated using appropriate methodology to provide convincing evidence of the tissue cultivation capability.

    1. eLife assessment

      This fundamental study provides evidence that de novo beige adipogenesis from Pdgfra+ adipocyte progenitor cells is blocked during early aging in subcutaneous fat. The depth of the data at early ages is compelling, with rigorous cell tracing methodology employed. The study will aid in identifying new approaches to switch dormant adipocytes into an active thermogenic phenotype, and should be of interest to cell biologists at large.

    1. eLife assessment

      This study includes fundamental 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.

    1. 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.

    1. eLife assessment

      This important study advances our understanding of the biological significance of the DNA sequence adjacent to telomeres. The data presented convincingly demonstrate that subtelomeric repeats are non-essential and have a minimal, if any, role in maintaining telomere integrity of budding yeast. The work will be of interest to the telomere community specifically and the genome integrity community more broadly.

    1. eLife assessment

      In this study, the authors offer a theoretical explanation for the emergence of nematic bundles in the actin cortex, carrying implications for the assembly of actomyosin stress fibers. As such, the study is a valuable contribution to the field actomyosin organization in the actin cortex. While the theoretical work is solid, experimental evidence in support of the model assumptions remains incomplete. The presentation could be improved to enhance accessibility for readers without a strong background in hydrodynamic and nematic theories.

    1. eLife assessment

      This valuable study describes mRNA shortening during cellular stress and interestingly observes that this shortening is dependent on localization in stress granules. Surprisingly, this mRNA shortening does not appear to require the shortening of polyA tails. These are in principle novel findings, but the evidence for them is currently incomplete. Additional experiments would help bolster confidence in how the authors interpret their data.

    1. eLife assessment

      This is an important study on the regulation of chlorophyll biosynthesis in rice embryos. It provides insights into the genetic and molecular interactions that underlie chlorophyll accumulation, highlighting the inhibition of OsGLK1 by OsNF-YB7 and the broader implications for understanding chloroplast development and seed maturation in angiosperms. The results presented, including mutation analysis, gene expression profiles, and protein interaction studies, provide convincing evidence for the function of OsNF-YB7 as a repressor in the chlorophyll biosynthesis pathway.

    1. eLife assessment

      The authors report useful findings on novel function of apical ICAM1 in regulating bile duct homeostasis in the liver. The strength of evidence is solid using appropriate methodolgy with only minor weakness. The findings will be of interest to researchers in hepatology and membrane traffic biology.

    1. eLife assessment

      This important study identifies the mitotic localization mechanism for Aurora B and INCENP (parts of the chromosomal passenger complex, CPC) in Trypanosoma brucei. The mechanism differs from that in the more commonly studied opisthokonts and is supported by compelling RNAi and imaging experiments, targeted mutations, immunoprecipitations with crosslinking/mass spec, and AlphaFold interaction predictions. The findings will be of interest to cell biologists working on cell division, parasitologists, and those interested in the evolution of mitotic mechanisms.

    1. eLife assessment

      This valuable paper presents a new approach for association testing, using the output of neural networks that have been trained to predict functional changes from DNA sequences. As such, the approach is an interesting addition to statistical genetics, and the evidence for the presented method being able to identify trait-associations in regions where GWASs are typically underpowered is solid. A limitation is, however, that it is unclear how the quality of these associations compares to those detected using conventional methods. Additional work assessing this method's power and characterizing false positives / false negative regions would be critical to ensure that the method is broadly adopted by the field.

    1. eLife assessment

      This research advance article describes a valuable image analysis method to identify individual 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.

    1. eLife assessment

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

    1. eLife assessment

      This manuscript supports the intriguing idea that some aspects of novel learning can occur during sleep and outside of awareness. The authors provide solid evidence that presenting participants with novel words and their translations during sleep, especially during slow oscillation troughs, leads to the ability to categorize the semantic meaning of those words during awake testing 36 hours later. These findings represent a valuable contribution to the literature on unconscious processing and learning during sleep, although the claim that the results reflect episodic memory formation, in particular, deviates from the typical use of this term in the literature.

    1. eLife assessment

      This important work illuminates the dynamics of BRAF in both its monomeric and dimeric forms, with or without inhibitors, combining traditional techniques and sophisticated computational analyses. The evidence presented is convincing, though a more detailed description of the analyses could enhance reproducibility and the quality of the results. This study will interest structural biologists, medicinal chemists, and pharmacologists.

    1. eLife assessment

      This 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 solid and multi-faceted, encompassing anatomy, connectivity and gene expression. This paper will be of interest to a broad readership within the neuroscience community, especially for those interested in cross-species correspondences in brain organisation.

    1. eLife assessment

      This study by Ghafari et al. tackles a question relevant for the field of attention as it connects structural differences in subcortical regions with oscillatory modulations during attention allocation. Using a combination of Magnetoencephalography (MEG) and magnetic resonance imaging (MRI) data in human subjects, the valuable results show that inter-individual differences in the lateralisation of alpha oscillations are explained by asymmetry of subcortical brain regions. The strength of evidence is deemed convincing in line with current state-of-the-art.

    1. eLife assessment

      Parkkinen et al. describe distinct biophysical profiles of brain-derived alpha-synuclein vs. in vitro-seeded synuclein fibrils. The findings are important and relevant to the emerging potential role of SAA as a biomarker of PD. The evidence is solid, using appropriate methodology and providing some support for the main claims with some limitations.

    1. eLife assessment

      Songbirds provide a tractable model system to study mechanisms of vocal production and sequencing, and past work showed that the lesions to LMAN, the output of a basal ganglia thalamocortical loop, reduced vocal variability, consistent with a role in motor exploration. In this fundamental work, the authors rigorously examined how lesions to an understudied neighboring region, MMAN, part of a parallel basal ganglia loop, affect singing in Bengalese finches, whose songs exhibit complex sequential transitions. The authors provide compelling evidence that MMAN lesions resulted in increased sequential variability but do not affect syllable acoustic structure, showing that distinct frontal systems can have distinct functions for producing and sequencing song syllables.

    1. eLife assessment

      These ingenious and thoughtful studies present important findings concerning how people can represent and generalise abstract patterns of sensory data. The issue of generalization is a core topic in neuroscience and psychology, relevant across a wide range of areas, and the findings will be of interest to researchers across areas in perception, learning and cognitive science. The findings are convincing in this setting, but future research must establish their generality and interrogate the precise nature of the underlying mechanism.

    1. eLife assessment

      The authors provide convincing experimental evidence of extended motivational signals encoded in the mouse anterior cingulate cortex (ACC) that are implemented by the orbitofrontal cortex (OFC)-to-ACC signaling during learning. The results are valuable to the field of motivation and cognition. The experimental methods used were state-of-the-art. The manuscript would further benefit from theory-driven analyses to inform a mechanistic understanding, particularly for the single-cell calcium imaging results. These results will be of interest to those interested in cortical function, learning, and/or motivation.

    1. eLife assessment

      This study presents important methodologies for repeated brain ultrasound localization microscopy (ULM) in awake mice and a set of results indicating that wakefulness reduces vascularity and blood flow velocity. The efficiency of the technique is however incompletely demonstrated, in particular regarding the reliability of longitudinal imaging. This study is relevant for scientists investigating vascular physiology in the brain.

    1. eLife assessment

      This valuable manuscript shows that the optogenetic stimulation of direct and indirect pathway spiny projection neurons (SPNs) in the dorsomedial versus the dorsolateral striatum has different consequences for locomotor activity, real-time place preference, and action selection, in a contextually mediated manner. The evidence in support of this conclusion is solid but would be further strengthened through deeper analysis of the effect and specificity of optogenetic manipulations on SPN activity. These findings will be of interest to neuroscientists, particularly behavioral neuroscientists.

    1. eLife assessment

      The authors of this study implemented an important toolset for 3D reconstruction and segmentation of dissection photographs, which could serve as an alternative for cadaveric and ex vivo MRIs. The tools were tested on synthetic and real data with compelling performance. This toolset could further contribute to the study of neuroimaging-neuropathological correlations.

    1. eLife assessment

      This paper investigates how the EWS::FLI1 fusion protein organizes chromatin topology and regulates gene expression in an aggressive pediatric bone cancer known as Ewing sarcoma. The authors used the most recent genomics methodologies to provide a solid base of evidence for the role of a short alpha helix in the DNA binding domain of FLI1 in modulating binding to GGAA microsatellites and promoting enhancer activity. The study provides valuable insight into the underlying oncogenic mechanisms in Ewing sarcoma, but is limited to a single cell line and would benefit from consolidation of the main conclusions using additional techniques.

    1. eLife assessment

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

    1. eLife assessment

      This study aims to explore the diabetes-bone paradox using the Mendelian Randomization approach. That diabetes itself is not the direct cause, but rather the complications or associated risk factors increase the risk of fracture, constitutes a valuable insight. Mendelian randomization to explain the relationship of two complex conditions is solid and conducted properly; however, the efforts to reconcile the discrepancies between the Mendelian Randomization analysis and observational studies are incomplete.

    1. eLife assessment

      This is an important paper as it is the first to use a reconstituted translation system to study competition among mRNAs for the initiation machinery. Understanding the principles of the biochemistry of mRNA competition for initiation factors cannot be achieved without such a system. The authors provide compelling evidence that Ded1 is required for efficient initiation of highly structured mRNAs. The findings are significant and validate the in vitro reconstituted system by recapitulating the effects of in-vivo perturbations of translation initiation by Ded1 mutants.

    1. eLife assessment

      This fundamental study advances our understanding of the cell specific treatment of cone photoreceptor degeneration by Txnip. The evidence supporting the conclusions is compelling with rigorous genetic manipulation of Txnip mutations. The work will be of broad interest to vision researchers, cell biologists and biochemists.

    1. eLife assessment

      This valuable study on the molecular and cellular mechanisms of ingestion avoidance of high salt in insects is focused in scope, but the authors present convincing evidence that a specific subset of gustatory receptors in a pair of pharyngeal taste neurons are necessary and sufficient for avoiding ingestion of high salt during feeding. This work will be of interest to Drosophila neuroscientists interested in taste coding and feeding behavior.

    1. eLife assessment

      This valuable paper provides convincing evidence that loss of the tumor suppressor TMEM127 causes disorganization of plasma membrane lipid domains, alters clathrin assembly, and inhibits endocytosis of a variety of cell surface receptors, leading to increased cell surface levels of signaling proteins including RET and other transmembrane receptor tyrosine kinases. The results are significant for understanding how RET127 loss contributes to pheochromocytoma, although the evidence is indirect owing to the lack of human pheochromocytoma cell lines. The results will be of interest for researchers studying pheochromocytoma and endocytosis mechanisms.

    1. eLife assessment

      This fundamental study advances our understanding of how Notch signaling activates transcription by analyzing dynamics of the Mastermind transcriptional co-activator and its role in the activation complex. The evidence is compelling and based on state of the art methods with precise quantitative measurements.

    1. eLife assessment

      This useful study describes expression profiling by scRNA-seq of thousands of cells of recombinant yeast genotypes from a system that models natural genetic variation. The rigorous new method presented here holds promise for improving the efficiency of genotype-to-phenotype mapping in yeast, providing convincing evidence for its efficacy. This manuscript focuses on overcoming technical challenges with this approach. It currently offers somewhat limited new biological insights to place the work within the broader context of the field. Doing so would broaden the interest of the work for all geneticists and evolutionary biologists.

    1. eLife assessment

      This important study presents a new quantitative imaging pipeline that describes with high temporal precision and throughput the movements of late-stage Drosophila embryos, a critical moment when motion first appears. A new approach is used to explore the role of miRNAs in motion onset and presents solid evidence that shows a role for miR-2b-1 and its target Janus in embryonic motion. The data are well supported but do not provide mechanistic insight into the emergence of movement while the writing inflates the importance of the conclusions. The authors must change the name of Janus which is already used in Drosophila genetics.

    1. eLife assessment

      This study presents valuable findings on two distinct modes of endosomal fusion and the roles of actin dynamics in this process. The evidence supporting the authors' claims is solid, although the underlying molecular mechanisms and whether the proposed fusion modes are applicable in other cell types remain unclear. The work will be of interest to cell biologists and biophysicists working on the cytoskeleton and organelles.

    1. eLife assessment

      This important study addresses the mechanisms by which mutations in the PURA protein, a regulator of gene transcription and mRNA transport and translation, cause the neurodevelopmental PURA syndrome. Based on convincing evidence from structural biology, molecular dynamics simulation, biochemical, and cell biological analyses, the authors show that the PURA structure is very dynamic, rendering it generally sensitive to structure-altering mutations that affect its folding, DNA-unwinding activity, RNA binding, dimerization, and partitioning into processing bodies. These findings are of substantial importance to cell biology, neurogenetics, and neurology alike, because they provide first insights into how very diverse PURA mutations can cause similar and penetrant molecular, cellular, and clinical defects.

    1. 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 compelling and provides information for designing drugs that selectively target different subtypes of P2X receptor channels. The work will be of interest to biochemists, structural biologists, and pharmacologists.

    1. eLife assessment

      This important study used Voltage Sensitive Dye Imaging (VSDI) to measure neural activity in the primary visual cortex of monkeys trained to detect an oriented grating target that was presented either alone or against an oriented mask. The authors show convincingly that the initial effect of the mask ran counter to the behavioral effects of the mask, a pattern that reversed in the latter phase of the response. They interpret these results in terms of influences from the receptive field center, and although an alternative view that emphasizes the role of the receptive field surround also seems reasonable, this study stands as an interesting contribution to our understanding of mechanisms of visual perception.

    1. eLife assessment

      In this manuscript, the authors investigate the properties of prokaryotic NADPH oxidases (NOX) and discuss the implications for NOX regulation and function. The structure of the S. pneumoniae Nox protein is an important step forward in our understanding of procaryotic NOX enzymes and the characterization and interpretation are convincing. The results will be of interest to structural biologists as well as biochemists focusing on enzymatic functions.

    1. eLife assessment

      This important study identifies the gene mamo as a new regulator of pigmentation in the silkworm Bombyx mori, a function that was previously unsuspected based on extensive work on Drosophila where the mamo gene is involved in gamete production. The evidence supporting the role of Bm-nano in pigmentation is convincing, including high-resolution linkage mapping of two mutant strains, expression profiling, and reproduction of the mutant phenotypes with state-of-the-art RNAi and CRISPR knock-out assays. The work will be of interest to evolutionary biologists and geneticists studying color patterns and evolution of gene networks.

    1. Editors Assessment:

      MPDSCOVID-19 has been developed as a one-stop solution for drug discovery research for COVID-19, running on the Molecular Property Diagnostic Suite (MPDS) platform. This is built upon the open-source Galaxy workflow system, integrating many modules and data specific to COVID-19. Data integrated includes SARS-CoV-2 targets, genes and their pathway information; information on repurposed drugs against various targets of SARS-CoV-2, mutational variants, polypharmacology for COVID-19, drug-drug interaction information, Protein-Protein Interaction (PPI), host protein information, epidemiology, and inhibitors databases. After improvements to the technical description of the platform, testing helped demonstrate the potential to drive open-source computational drug discovery with the platform.

      This evaluation refers to version 1 of the preprint

    1. Editors Assessment:

      This Data Release paper presents an updated genome assembly of the doubled haploid perennial ryegrass (Lolium perenne L.) genotype Kyuss (Kyuss v2.0). To correct for structural the authors de novo assembled the genome again with ONT long-reads and generated 50-fold coverage high-throughput chromosome conformation capture (Hi-C) data to assist pseudo-chromosome construction. After being asked for some more improvements to gene and repeat annotation the authors now demonstrate the new assembly is more contiguous, more complete, and more accurate than Kyuss v1.0 and shows the correct pseudo-chromosome structure. This more accurate data have great potential for downstream genomic applications, such as read mapping, variant calling, genome-wide association studies, comparative genomics, and evolutionary biology. These future analyses being able to benefit forage and turf grass research and breeding.

      This evaluation refers to version 1 of the preprint

    1. eLife assessment

      This valuable study addresses the role of Rho-associated coiled-coil kinase (ROCK) and the cytoskeleton in the initiation and growth of the calcified endoskeleton of sea urchin embryos. Perturbation by two independent approaches (a morpholino and a selective inhibitor) provides convincing evidence that ROCK participates both in actomyosin regulation and in the gene regulatory network that controls skeletogenesis. Exciting areas of future work will be to elucidate the mechanisms by which ROCK influences gene expression and to further dissect the role of the cytoskeleton in mineralization.

    1. eLife assessment

      This useful work provides insight into agonist binding to nicotinic acetylcholine receptors, which is the stimulus for channel activation that regulates muscle contraction at the neuromuscular junction. The authors use in silico methods to explore the transient conformational change from a low to high affinity agonist-bound conformation as occurs during channel opening, but for which structural information is lacking owing to its transient nature. The evidence supporting the main conclusion that ligands flip ~180 degrees in the binding site as it transitions from a low to high affinity bound conformation is incomplete because little support is available for the starting low affinity docked conformations, and the rather approximate methods for computing binding free energies differ significantly from experimental measures for two of the four tested ligands. Nonetheless, this work presents an intriguing possibility for the nature of a transient conformational change at the agonist binding site correlated with channel opening. If the ligand flip observed in these simulations can be reproduced or verified by other studies, then this work would stand as a significant advance in our knowledge of nicotinic receptor gating.

    1. eLife assessment

      The manuscript reports on an important comparison of a range of approved clinical inhibitors for BTK used for the treatment of chronic lymphocytic leukemia (CLL). The authors provide solid evidence for their claims, using a combination of HDX-MS and NMR spectroscopy. The novelty is that this study also seeks to evaluate resistance mutation bias. The scope of the study is highly exciting but would benefit from a clear link of the biophysical studies to the functional assays - specifically nucleotide binding.