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  1. Last 7 days
    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 perform voltage imaging of CA1 pyramidal cells in head-fixed mice running on a track while local field potentials (LFPs) are recorded. They suggest that synchronous ensembles of neurons are differentially associated with different types of LFP patterns, namely theta and ripples. However, evidence for the potentially useful findings is currently incomplete due to major weaknesses in the experimental and analytical approach.

    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.

  2. Mar 2024
    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 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 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 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. Important 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 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 study addresses an important, understudied question using approaches that link molecular, circuit, and behavioral changes. The novel findings that Netrin-1 and UNC5c can guide dopaminergic innervation from the nucleus accumbens to the cortex during adolescence are solid. The data showing that the onset of Unc5 expression is sexually dimorphic in mice, and that in Siberian hamsters environmental effects on development are also sexually dimorphic are also solid. Reviewers identified some gaps in evidence for specificity of Netrin-1 expression, which, if filled, would strengthen the evidence for some of the claims. Future work would also benefit from Unc5C knockdown to corroborate the results and investigation of the cause-effect relationship. This paper will be of interest to those interested in neural development, sex differences, and/or dopamine function.

    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.

    1. eLife assessment

      In this interesting study, Drożdżyk and colleagues analyze the ability of placental CALHM orthologs to form stable complexes, identifying that CALHM2 and CALHM4 form heterooligomeric channels. The authors then determine cryo-EM structures of heterooligomeric CALHM2 and CALHM4 that reveal a distinct arrangement in which the two orthologs can interact, but preferentially segregate in the channel. This is an important study; the data provide compelling support for the interpretations and overall, the work is clearly described.

    1. eLife assessment

      In this important study, the authors report a novel measurement of the Escherichia coli chemotactic response and demonstrate that these bacteria display an attractant response to potassium, which is connected to intracellular pH level. Whilst the experiments are mostly convincing, there are some confounders regards pH changes and fluorescent proteins that remain to be addressed.

    1. eLife assessment

      This important study describes how PhoP regulates cyclic-AMP production in the human pathogen Mycobacterium tuberculosis. The authors provide convincing evidence that PhoP acts as a repressor of the cyclic-AMP-specific phosphodiesterase, Rv0805, which can degrade cyclic-AMP. The work will be of interest to bacteriologists and whilst the revised manuscript has been substantively improved, there are some outstanding points that could improve clarity and presentation.

    1. eLife assessment

      Morphological characteristics and phenotypes of mutations in key developmental genes suggest that head, trunk, and tail development are regulated by discernible modules. Gdf11 signalling plays a crucial role in orchestrating the transition from trunk to tail tissues in vertebrate embryos. This important study presents convincing evidence that Tgfbr1 acts upstream of Isl1 (a pivotal effector of Gdf11 signalling) and regulates blood vessels, the lateral plate mesoderm, and the endoderm associated with the trunk-to-tail transition. Together with the previous studies, this work identifies a key signal that acts as the pivot of the trunk-to-tail transition.

    1. eLife assessment

      This study presents a valuable finding and developed ME3BP-7 as a novel microencapsulated form of 3BP targeting MCT1 overexpressing PDAC cells, demonstrating its specificity and efficacy in vitro and in PDAC mouse models with significant anti-tumor effects and improved serum stability. The evidence supporting the claims of the authors is solid; however, the study calls for additional comparative in vivo data to enhance its translational significance.

    1. eLife assessment

      This is an important study on the biochemical and biophysical analysis of a transcriptional riboswitch, detailing how Mg2+ and guanidine regulate RNA conformations. The study provides compelling evidence, developing Position-specific labeling of RNA (PLOR) and single-molecule FRET (smFRET) microscopy that are well suited to investigate the conformational dynamics of RNA structure formation. The study would have been strengthened by using a bacterial instead of phage protein to better recapitulate the physiology of the process. The work is of broad interest to those interested in RNA functional architecture and regulation.

    1. eLife assessment

      This is an important study that demonstrates that RNA intermediates arising from improper splicing are exported out of the nucleus via the canonical mRNA export machinery and the nuclear pore basket. The authors provide convincing evidence that the role of the nuclear basket rather than retaining the transcripts is stimulating their export, putting into question the current model of the role of the basket. The conclusions are in line with recent studies in mammalian cells that suggest that the basket's role in mRNA export and quality control has to be revised.

    1. eLife assessment

      The formation of the Z-ring at the time of bacterial cell division interests researchers working towards understanding cell division across all domains of life. The manuscript by Jasnin et al reports the cryoET structure of toroid assembly formation of FtsZ filaments driven by ZapD as the cross linker. The findings are important and have the potential to open a new dimension in the field, but the evidence to support these exciting claims is currently inadequate.

    1. eLife assessment

      The Hippo signaling pathway plays a crucial role in controlling organ size, cell proliferation, and apoptosis, though its role in endocrine pancreas development has remained unclear. In this useful work, the authors study the function of the Tead1 transcription factor, a Hippo effector, specifically in pancreatic beta cells. They provide solid evidence, using multiple different conditional knockout models to reveal Tead1's regulatory functions in insulin secretion and beta cell proliferation. However, deeper exploration of their data and incorporating findings from existing literature on this topic would provide a clearer understanding of Tead1's role in β-cell function, within or beyond the Hippo pathway.

    1. eLife assessment

      The main finding in this paper is that EGFR can be a novel substrate of the membrane ZNRF3/RNF43 E3 ligases. This is significant as the prevailing understanding posits that the Wnt receptors Frizzled and LRP5/6 exclusively served as substrates for these ligases. Given the frequent occurrence of mutations in ZNRF3/RNF43 or compromised expression levels in human cancers, the new evidence that aberrant EGFR expression and signaling may also contribute to the tumorigenic effects of ZNRF3/RNF43 mutations in cancer is important. The conclusions of the manuscript are supported by solid data, but some aspects of the mechanism presented need to be reinforced to fully support the claims made by the authors.

    1. eLife assessment

      This compelling study reports the to-date most comprehensive neurotransmitter atlas of any organism, using fluorescent knock-in reporter lines. It represents an extremely useful tool for a broad audience of scientists interested in neuronal cell type differentiation and function.

    1. eLife assessment

      Dong et al. investigate the role of the small Ras-like GTPase Rab10 in the exocytosis of DCVs in mouse hippocampal neurons, showing that Rab10 depletion hinders DCV exocytosis independently of its effects on neurite outgrowth. Their findings are convincing and provide evidence that Rab10 depletion leads to altered ER morphology, impaired ER-based calcium buffering, and decreased ribosomal protein expression, which collectively contributes to defective DCV secretion. The study comes to the important conclusion that Rab10 is critical for DCV release by ensuring ER calcium homeostasis.

    1. eLife assessment

      Overall, the reviewers found the significance of the work valuable to the field of visual neuroscience, particularly given the large data set and strength of the method used that allowed for spatial analysis of neuronal responses in macaque V1. The evidence was deemed compelling, owing in part to the consistency of responses across animals and the fitness of modeling. The authors have addressed the major comments from reviewers and improved the manuscript through relation to prior literature and addressing specific limitations of the method used.

    1. eLife assessment

      Sisigano et al. report findings about the role of sphingolipids using lipidomics with machine learning in paclitaxel-induced peripheral neuropathy and preliminary translation of the impact of SA1P in cultured neuronal cells. This study presents a valuable finding on the increased activity of two well-studied signal transduction pathways in a subtype of breast cancer. The strength of evidence is incomplete with some support for the main claims with some limitations.

    1. eLife assessment

      This study presents important insights into the dynamical process whereby sensory information is converted from stimulus-driven activity to a working memory representation from which the information can be recalled later. The evidence supporting the claims is convincing, using detailed fits and model-comparison techniques applied to new and existing psychophysical data sets to evaluate a wide variety of potential mechanisms. The overall conclusion, that iconic memory and working memory are not distinct mechanisms but rather two slightly different regimes of the same circuitry, will be of interest to neuroscientists and psychologists studying sensory systems and/or working memory.

    1. eLife assessment

      This valuable study has practical implications for understanding rhythm perception and production in human cognition. The evidence for individual frequency preferences and a deterioration in frequency adaptation with age is solid. These findings may inform existing models of rhythm perception and production, and the reported effects of age may have clinical implications.

    1. eLife assessment

      This manuscript represents a cleanly designed experiment for assessing biological motion processing in children (mean age = 9) with and without ADHD. The group differences concerning accuracy in global and local motion processing abilities are solid, but the analyses suggesting dissociable relationships between global and local processing and social skills, age, and IQ are inconclusive. The results are useful in terms of understanding ADHD and the ontogenesis of different components of the processing of biological motion.

    1. eLife assessment

      This important modeling work demonstrates out-of-distribution generalization using a grid cell coding scheme combined with an attentional mechanism that operates over these representations (Determinantal Point Process Attention). The simulations provide compelling evidence that the model can improve generalization performance for analogies, addition, and multiplication. The paper is significant in demonstrating how neural grid codes can support human-like generalization capabilities in analogy and arithmetic tasks, which has been a challenge for prior models.

    1. eLife assessment

      This study provides solid evidence for differences in habit-learning in obsessive-compulsive disorder versus controls. Contrary to previous studies that employed a single laboratory session to study habit-learning, here a smartphone app delivered motor-sequence tasks daily for a month. These results have important implications for our understanding of goal-directed versus habit learning in obsessive-compulsive disorder.

    1. eLife assessment

      In this work, Huerlimann and colleagues suggest an intertalk between the thyroid and corticosteroid axis in regulating grouper metamorphosis. The work provides valuable genomic resources to address the endocrine control of a life cycle transition in the Malabar grouper fish. The evidence is still incomplete and it does not fully support an interaction between the thyroid and corticosteroid axis.

    1. eLife assessment

      This important study details the development of brain functional connectivity in a longitudinal cohort of Gambian children assessed outside a lab setup with functional near-infrared spectroscopy (fNIRS) from age 5 to 24 months, in relation to early physical growth and cognitive flexibility capacities at 4-5 years of age. Although the evidence supporting some conclusions is solid, the relevance of the results would be improved by defining clearer hypotheses regarding the developmental changes expected for the different connections, and by discussing the unexpected findings on early negative connectivity and connectivity decreases. Considering more advanced analytical approaches would allow the authors to deal with longitudinal data and integrate mediation links, even if the study might be underpowered to link adverse conditions such as undernutrition and later cognitive development. This study will be of interest to neuroscientists, psychologists, and neuroimaging researchers working on infant development in relation to environmental factors.

    1. eLife assessment

      This important study combined fMRI, TMS and computational modelling of behaviour to investigate the functional role of the left superior frontal sulcus (SFS) in both perceptual and value-based decisions. Based on sophisticated analyses, the results provide solid evidence that downregulating left SFS activity through TMS selectively alters perceptual decision accuracy but does not influence value-based decisions. The work will be of interest to cognitive neuroscientists investigating the neural correlates of decision-making and may have implications for computational psychiatry.

    1. eLife assessment

      This work provides a valuable characterization of neural activity in the anterior insular cortex during fear. The data were collected using behavior, single unit recording, and optogenetic control of neural activity. The study is a great starting point on the path to testing hypotheses about bidirectional control of behavior via segregated, anatomically defined output populations, since the authors recorded true neural activity, as opposed to bulk calcium flux, which is often used in this kind of experiment. However, the link between spiking, anatomy, and behavior is incomplete, and additional controls are necessary to support the claim for associative learning.

    1. eLife assessment

      This paper describes the structure and connectivity of brain neurons that send descending connections to motor neurons and muscle in the fruit fly nerve cord, using a synapse-resolution connectome. This valuable work provides a wealth of hypotheses and predictions for future experimentation and modelling. Using state-of-the-art methods, the authors provide solid evidence for their conclusions. Some conclusions however could be qualified to acknowledge currently unavoidable ambiguities associated with current methodologies.

    1. eLife assessment

      This important study reports the first results on the effects of subthreshold kilohertz sinusoidal transcranial magnetic stimulation (TMS) on the brain. Stimulation at fields of 2V/m and 3.5kHz enhances cortical motor excitability as measured by motor-evoked potentials elicited by single-pulse TMS. The evidence in support of this claim is compelling. This result is of importance to the field of non-invasive brain stimulation and to cognitive neuroscience as a whole.

    1. eLife assessment

      This study presents a valuable finding on a potential signaling pathway responsible for the direct effects of nicotine on intestinal stem cell growth and tumorigenesis. However, the evidence supporting the authors' claims remains incomplete. Additional analysis on how stem cells uniquely respond to nicotine could provide more definitive evidence and strengthen the study. This research will be of interest to medical biologists specializing in intestinal tumors.

    1. eLife assessment

      This valuable study advances our understanding of how leaf and soil microbes separately affect the performance of an invasive plant, Ageratina adenophora. The conclusions regarding the roles of litter microbes in regulating the A. adenophora population are currently supported only by incomplete evidence owing to limitations in experimental design and statistical analyses, as well as uncertainties associated with the presentation. The work will be of interest to invasion biologists.

    1. eLife assessment:

      This study reports compelling data supporting the role of beta-catenin on intercellular communication occurring via extracellular vesicles, with implications for immune evasion in hepatocellular carcinoma (HCC). This fundamental insight sheds light on the underlying biology of HCC at a time when an increasing number of treatment options, including targeted small molecular inhibitors and immuno-oncologic drugs are being used to treat patients in the absence of validated predictive biomarkers. This work will be of special interest to researchers investigating the basic biology of liver function and HCC, and also to readers investigating novel pathways for therapeutic targeting of HCC.

    1. Evaluation statement (8 March 2024)

      Seljeset et al. investigate the mechanism by which NMDA receptors are activated by co-agonists glutamate and glycine. By mutating residue Asp732 in the glycine-binding site, they generate receptors activated by glutamate, and not glycine, but inhibited by glycine antagonists. Conventional and unnatural amino acid mutagenesis reveals that Asp732 interacts with nearby residues to influence channel gating as well as ligand binding. Furthermore, a homomeric receptor from Trichoplax adhaerens, which has a tyrosine in the homologous position, displays constitutive activity that becomes glycine-dependent when the tyrosine is mutated to aspartate. The study is valuable because it reveals the importance of position 732 for controlling ligand potency and channel activity in glutamate receptors, which should lead to a better understanding of how these receptors are primed for channel opening.

      Biophysics Colab recommends this study to scientists interested in the structure and function of glutamate receptors

      Biophysics Colab has evaluated this study as one that meets the following criteria:

      • Rigorous methodology
      • Transparent reporting
      • Appropriate interpretation

      (This evaluation refers to version 2 of this preprint, which has been revised in response to peer review of version 1.)

    1. eLife assessment

      Using unbiased transcriptional profiling, the study reports a fundamental discovery of a novel hepatic lncRNA, FincoR, which regulates FXR. The convincing findings have therapeutic implications in the treatment of MASH. The authors use state-of-the-art methodology and use unbiased transcriptomic profiling and epigenetic profiling, including validation in mouse models and human samples.

    1. eLife assessment

      This study represents a step towards integrating human and non-human primate research towards a broader understanding of the neural control of motor strategies. It could offer valuable insights into how humans and non-human primates (Rhesus monkeys) manage visuomotor tasks, such as stabilizing an unstable virtual system, potentially leading to discoveries in neural behaviour mechanisms. While the evidence is mostly solid, some results, particularly from the binary classification of control strategies for non instructed behaviour, require further validation before it could be conclusively interpreted.

    1. eLife assessment

      In this important study, the authors set out to investigate the biogenesis of extracellular vesicles in mycobacteria and provide several observations to link VirR with vesiculogenesis, PG metabolism, lipid metabolism, and cell wall permeability. Whilst some of the evidence provided is convincing, data to support the proposed mechanism are somewhat incomplete. The work will be of interest to bacteriologists.

    1. eLife assessment

      This study addresses the long-standing question as to how different functional pools of synaptic vesicles are organized in presynaptic terminals to mediate different modes of neurotransmitter release. Based on imaging of active synapses with recycling synaptic vesicles labeled by FM-styryl dyes, the authors provide data that are compatible with the hypothesis that two separate reserve pools of vesicles – slowly vs. rapidly mobilizing – feed two distinct releasable pools – reluctantly vs. rapidly releasing. Overall, this study represents a valuable contribution to the field of synapse biology, specifically to presynaptic dynamics and plasticity. The authors' methodological approach of using bulk FM-styryl dye destaining as a readout of precise vesicle arrangements and pools in a population of functionally very diverse synapses has limitations. Consequently, the evidence that directly supports the authors' two-pool-interpretation of their data is incomplete, and alternative interpretations of the data remain possible.

    1. eLife assessment

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

    1. eLife assessment

      This work advances our understanding of transcriptional regulation of virulence and metabolic pathways in plant pathogenic bacteria. Solid evidence for the claims is provided by computational analysis of the newly generated data on the genome-wide binding of 170 transcription factors to their target genes, together with experimental validation of the biological functions of some of these transcription factors. The findings and resources from this study will be valuable to researchers in the fields of systems biology, bacteriology, and plant-microbe interactions.

    1. eLife assessment

      The methods presented in this work provide modest yet consistent accuracy improvements for data classification tasks where certain data are missing. The authors also present a way to use quantum computers for this task. The methodology and results for the classical (non-quantum) case are solid, although evidence for the practical quantum advantage via their approach in 'next generation' quantum computers remains incomplete. The results are valuable and should interest data scientists, life scientists and anyone working in quantum computing.

    1. eLife assessment

      This study provides valuable new insights into the trade-offs associated with the evolution of drug resistance. The authors use a solid approach to evolve and phenotype hundreds of independent strains. They identify distinct phenotypic clusters based on growth across defined conditions that suggest that tradeoffs are diverse but at the same time could be limited to a few classes based on the underlying resistance mechanisms. The methodologies used align with the current state-of-the-art, and the data and analysis are solid as they broadly support the claims, with only minor weaknesses. This work will interest molecular biologists working on the evolution of new phenotypes and microbiologists studying multi-drug therapy.

    1. eLife assessment

      The authors provide useful information, confirming previous observations that heterologous sequecnes affect crossing-over frequency. Surprisingly, they conclude that heterozygous introgressed regions, with greater levels of heterology, have greater noncrossover levels than non-introgressed regions with much lower levels of heterology. As the evidence for this conclusion is incomplete and potentially biased, the significance of these findings relative to previous knowledge in the field remains to be determined.

    1. eLife assessment

      In this important study, the authors manually assessed randomly selected images published in eLife between 2012 and 2020 to determine whether they were accessible for readers with deuteranopia, the most common form of color vision deficiency. They then developed an automated tool designed to classify figures and images as either "friendly" or "unfriendly" for people with deuteranopia. While such a tool could be used by publishers, editors or researchers to monitor accessibility in the research literature, the evidence supporting the tools' utility was incomplete. The tool would benefit from training on an expanded dataset that includes different image and figure types from many journals, and using more rigorous approaches when training the tool and assessing performance. The authors also provide code that readers can download and run to test their own images. This may be of most use for testing the tool, as there are already several free, user-friendly recoloring programs that allow users to see how images would look to a person with different forms of color vision deficiency. Automated classifications are of most use for assessing many images, when the user does not have the time or resources to assess each image individually.

    1. eLife assessment

      This useful manuscript presents an intriguing potential refinement of models for adult SVZ neurogenesis, and highlights the role of RNA splicing at specific stages in the lineage. Unfortunately, the evidence does not fully support the claims, leaving it currently incomplete. The proposed role of RNA splicing in neuronal differentiation, though interesting, remains unexplored and would benefit significantly from targeted gene manipulation studies.

    1. eLife assessment

      This manuscript is an important advance in the study of Histone H1s, finding distinct distributions of various H1 variants in the genome. The controls presented by the authors provide convincing evidence to demonstrate a heterogenous distribution of H1 which might reflect functional regulation of chromatin accessibility by linker histones. This work will be of interest to the genome organization field, and could additionally provide a framework for understanding H1 mis-regulation observed in cancer cells.

    1. eLife assessment

      This valuable work extends previous studies showing that the striatum multiplexes various aspects of locomotion, including velocity and movement transitions, by demonstrating that striatal neurons also encode single-limb gait. The authors present solid evidence to show that gait deficits induced by severe unilateral dopamine depletion are associated with an imbalance in the gait modulation of striatal firing. Although the source and function of this gait modulation remain unclear, this manuscript uncovers a role of striatal activity in gait, which may have implications for understanding gait disturbances in Parkinson's Disease.

    1. eLife assessment

      The manuscript by Jingsong Zhou and colleagues tries to uncover the reasons for the resistance of extraocular muscles (EOMs) to degenerative changes induced by amyotrophic lateral sclerosis (ALS). The findings of the study offer valuable information that EOMs are spared in ALS because they produce protective factors for the NMJ and, more specifically, factors secreted by EOM-derived satellite cells. While most of the experimental approaches are convincing, the use of sodium butyrate (NaBu) in this study needs further investigation, as NaBu might have a variety of biological effects. Overall, this work may help develop future therapeutic interventions for patients with ALS.

    1. eLife assessment

      This useful study uses a chemoinformatics pipeline to identify a list of candidate mosquito repellants that may be pleasant to smell and safe for humans. The computational methodology is solid, but insufficiently benchmarked against other leading models. At the high concentrations tested, there may also be off-target effects of the repellents on the mosquitoes that are not considered. This paper may be of interest to specialists interested in the discovery of new mosquito repellents.

    1. eLife assessment

      This study reports a potentially important discovery that testosterone-induced metabolic changes in seminal vesicle epithelial cells lead to the production of oleic acids in seminal plasma to enhance sperm fertility. The evidence to support metabolic changes in seminal vesicles and the identification of oleic acid as a key factor in seminal plasma is solid. However, the evidence for how oleic acids support enhanced sperm fertility in vivo is not well supported, thus currently remains incomplete, and requires further study.

    1. eLife assessment

      This work is potentially useful because it has generated a mineable yield of new candidate immune inhibitory receptors, which can serve both as drug targets and as subjects for further biological investigation. It is noted however that the work is rather incomplete, in that it does little to validate the putative new receptors, and instead makes a study of their putative distribution across cell types. Experimental follow-up to demonstrate the claimed properties for the proteins identified, or mining existing experimental data sources on gene expression across tissues to at least show that the pipeline correctly identified genes likely to be specific to immune cells, would make this work more complete.

    1. eLife assessment

      This study provides valuable new insights as to how two evolutionary conserved motifs in CD4 contribute to the CD4-mediated enhancement of TCR signaling independently of the CD4-LCK interaction. The data at hand are convincing, even if confined to a cell line model and not substantiated in vivo and with little new mechanistic insight provided regarding the domains of CD4 shown to have significant roles in the signaling process. Without the data from primary cells it is difficult to make statements about the quantitative contribution of LCK-dependent and independent functions of CD4 in TCR signaling.

    1. eLife assessment

      This solid study addresses the unresolved question of why many thousands of small-effect loci contribute more to the heritability of a trait than the large-effect lead variants. The authors explore resource competition within the transcriptional machinery as one possible explanation with a simple theoretical model, concluding that the effects of resource competition would be too small to explain the heritability effects. The topic and approximation of the problem are important and offer an intuitive way to think about polygenic variation, but there are concerns on the derivation of the equations with respect to dropping vs. including certain terms that deal inherently with small numbers.

    1. eLife assessment

      This important study examines the ancestral function of Hippo pathway kinases in contractility and cell density in the ameboid organism Capsaspora owczarzaki, a unicellular animal that is a close relative of multicellular animals. There is convincing evidence for Hippo kinases regulating contractility and cell density but not proliferation in C. owczarzaki. The work complements previous work on the Hippo effector Yorkie homolog in this species, although the unavailability of extensive genetic tools in this species precludes informative epistasis experiments. The work would be of interest to evolutionary and developmental biologists.

    1. eLife assessment

      This manuscript presents valuable findings that contribute to our understanding of how sphingolipids and membrane contact sites, formed by the tethering protein family tricalbins, are involved in regulating vacuolar morphology in S. cerevisiae. The evidence supporting the authors' claims is largely solid: while the reported correlation between sphingolipid levels and vacuole homeostasis is intriguing, the data do not completely substantiate the proposed mechanism. This study will be of interest to cell biologists focusing on intracellular organization and lipid metabolism.

    2. eLife assessment

      This manuscript presents valuable findings that contribute to our understanding of how sphingolipids and membrane contact sites, formed by the tethering protein family tricalbins, are involved in regulating vacuolar morphology in S. cerevisiae. The evidence supporting the authors' claims is largely solid. While the reported correlation between sphingolipid levels and vacuole homeostasis is interesting and intriguing, more work is needed to thoroughly substantiate the proposed mechanism. This study will be of interest to cell biologists focusing on intracellular organization and lipid metabolism.

    1. eLife assessment

      This manuscript presents a valuable approach to exploring CD4+ T-cell response in mice across stimuli and tissues through the analysis of their T-cell receptor repertoires. The authors use a transgenic mouse model with reduced diversity of the T-cell receptor repertoire to elicit more consistent T-cell responses across individuals, demonstrating challenge-specific and tissue-specific responses of regulatory T-cells. The evidence for the authors' conclusions is solid, and the work will be of interest to immunologists studying T cell responses.

    1. eLife assessment

      The study presents valuable findings on sexually dimorphic patterns of osteocytic transcriptomes and low calcium diet-induced osteocytic osteolysis in FNDC5-deficient mice. The authors present solid evidence for sex-specific changes in osteocyte morphology and gene expression under a calcium-demanding setting in this particular strain of mice, although the protective role of FNDC5-deficiency in lactation and low-calcium diet in female mice remains unclear due to lack of mechanistic studies. The study also lacks evidence that irisin, a proteolytically cleaved product of FNDC5, is responsible for the observed phenotypes, as irisin was not directly measured.

    1. eLife assessment

      In this potentially useful study, the authors use deep learning models to provide solid evidence that epithelial wounding triggers bursts of cell division at a characteristic distance away from the wound. The usefulness of the methods to the community will depend on documenting their robustness toward variability in temporal resolution and/or mitotic event duration, demonstrating their overall superiority over existing approaches and making the code possible to use by others.

    1. eLife assessment:

      This valuable work substantially advances our understanding of the organization of neural dynamics relative to behavioral outputs within recurrent neural networks, with implications for biological neural networks. Evidence supporting the conclusions is convincing, with rigorous analyses of neural variance and robustness to noise. The work will be of broad interest to neuroscientists studying computation through dynamics.

    1. eLife assessment

      This work presents a valuable data-driven method to extract the "true" synaptic plasticity rule (or learning rule) operating in a neural circuit from empirical measurements of neural activity. The approach aims to train a generative adversarial network (GAN) to match neural activity measurements in terms of statistics, learning them from the data, rather than being pre-determined by the experimenter. The main conclusion is that the extracted learning rules are not unique, but rather degenerate, meaning that multiple plasticity rules can produce the same neural activity. Although the paper presents a thorough investigation using one learning rule as a case study (the Oja rule), the evidence that the results can be inferred beyond the specific numerical experiments presented in the paper is incomplete.

    1. eLife assessment

      This valuable study presents convincing evidence for an association between PARP-1 and H4K20me1 in transcriptional regulation, supported by biochemical and ChIP-seq analyses. The work contributes significantly to our understanding of how Parp1 associates with target genes to regulate their expression.

    1. eLife assessment

      This paper presents useful results that extend our understanding of how the visual cortex encodes temporal structure, providing new information about sequence representations in superficial layers of the visual cortex. The evidence for prediction errors is solid, however, support for other claims regarding sparsification and simplification of activity following training is incomplete.

    1. eLife assessment

      The authors analyze the role of newborn astrocytes in the modulation of glial scar formation in a middle carotid artery occlusion (MCAO) hypoxia lesion model. The findings are valuable because they have implications for understanding the molecular and cellular processes contributing to brain repair in response to ischemia. The results are currently incomplete, in the absence of data showing: (i) cell-target specificity of molecular markers for newborn astrocytes; (ii) consistent phenomena across different rodent species.

    1. eLife assessment

      This valuable paper by Yao, Dai, and colleagues describes a viral gene drive against herpes simplex virus 1 in cell culture. The authors provided solid evidence that an engineered gene drive sequence, expressing either spCas9 or Un1Cas12f1 nuclease, could spread efficiently in the population of wild-type viruses and induce fewer drive-resistant mutations than spCas9. Limitations include a mechanistically inaccurate title, several methodologic flaws, and a paucity of descriptions of possible therapeutic applications.

    1. eLife assessment

      This fundamental work significantly advances our understanding of how FOG1 nuclear localization is regulated during erythropoiesis and megakaryopoiesis, including the role of EPO and MPL/TPO signaling in this process. The authors provide compelling evidence using both K562 and CD34+ cells that heat shock cognate B (HSCB) can promote the proteasomal degradation of TACC3 to regulate the nuclear localization of FOG1, and that this function is independent of its role in iron-sulfur cluster (ISC) biogenesis. The conclusions would be strengthened in the future by the use of in vivo model systems, however, as written, this work will be of broad interest to cell biologists.

    1. eLife assessment

      This study is an important contribution to our insights into the impact of heat stress on sexual reproduction in plants and provides information about how centromere integrity is affected by heat stress during male meiosis in Arabidopsis thaliana. The evidence supporting the claims, specifically the dynamics of tagged proteins in meiocytes by live cell imaging is solid, even though a deeper mechanistic understanding is still lacking.

    1. eLife assessment

      This manuscript provides important insights into the degradation of the host tRNA modification enzyme TRMT1 by the SARS-CoV-2 protease Nsp5 (nonstructural protein 5 or MPro). The data convincingly support the main conclusions of the paper. These results will be of interest to virologists studying the alterations in tRNA modifications, host methyltransferases, and viral infections.

    1. eLife assessment

      This article provides a review and test of image-analysis methods for bacteria growing in the 'mother-machine' microfluidic device, introducing also a new graphical user interface for the computational analysis of mother-machine movies based on the 'Napari' environment. The tool allows users to segment cells based on two previously published methods (classical image transformation and thresholding as well as UNet-based analysis), with solid evidence for their robust performance based on comparison with other methods and use of datasets from other labs. While it was difficult to assess the user-friendliness of the new GUI, it appears to be valuable and promising for the field.

    1. eLife assessment

      This valuable study informs on the regulation of metabolic flux between glycolysis and respiration in yeast, mediated by inorganic phosphate. The authors propose a novel mechanism involving Ubp3/Ubp10 that potentially mitigates the Crabtree effect, based on an array of assays that offer substantial insight into mitochondrial biogenesis under high glucose conditions. However, the evidence supporting the conclusions remains incomplete because of a limited number of replicates, particularly in protein blot analyses with insufficient normalization methods, which undermines the robustness of the findings. This work could influence the subfield significantly if the methodological weaknesses are addressed to provide more support for the proposed model.

    1. eLife assessment

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

    1. eLife assessment

      This study investigated the factors related to understudied genes in biomedical research. It showed that understudied genes are largely abandoned at the writing stage, and it identified a number of biological and experimental factors that influence which genes are selected for investigation. The study is an important contribution to this branch of meta-research, and the evidence in support of the findings is solid.

    1. eLife assessment

      This study presents a valuable contribution towards understanding the protein target and mechanism of action of an herbicide, which could be applied to the development of herbicide-based technologies to improve crop yields. Evidence is gathered using a variety of technical approaches that enrich and support the findings, but the methodology and the presentation of the results are incomplete.

    1. eLife assessment

      This study provides a detailed evaluation of how HIV evades nascent immune pressure from people living with HIV followed nearly immediately after infection. There is convincing evidence that H173 mutations in the V2 loop was a key determinant of selection pressure and escape. These data are congruent with protection in the RV144 clinical trial, the only trial that showed protection from infection. Overall, this study is an important contribution to the field.

    1. eLife assessment

      This study presents two valuable new mouse models that individually tag proteins from the SMAD family to identify distinct roles during early pregnancy. Convincing evidence is provided that SMAD1 and SMAD5 target many of the same genomic regions as each other and the progesterone receptor. Given the broad effect of these signaling pathways in multiple systems, these new tools will most likely interest readers across biological disciplines.

    1. eLife assessment

      In this useful study, Wang and colleagues investigate the potential probiotic effects of Bacillus velezensis to prevent colitis in a mouse model. They provide solid evidence that B. velezensis limits the growth of Salmonella typhimurium in lab culture and in mice, together with beneficial effects on the microbiota. The work will be of interest to infectious disease researchers and those studying the microbiome.

    1. eLife assessment

      This study addresses an important long-standing controversy in the field of reproductive biology. Using cutting-edge techniques the authors provide compelling evidence supporting a pivotal role of prolactin as the mediator of lactational infertility. Some methodological, technical, interpretive, stylistic, and typographical aspects of the paper need to be strengthened.

    1. eLife assessment

      Spermiogenesis is a complex process allowing the emergence of specific sperm organelle, including the acrosome, a sperm giant vesicle of secretion. This important study reports the key role of Cylicin-1 in acrosome biogenesis and identifies the molecular partners necessary for acrosome anchoring. The compelling demonstration is based on infertile patient samples and two animal models. Overall, this provides results that will be invaluable to the male reproduction community, including scientists and andrologists.

    1. eLife assessment

      This manuscript provides useful findings to further explore the heterogeneity of hematopoietic stem cells and myeloid-biased hematopoiesis during aging. The results presented in this study are incomplete and additional data is needed to strengthen the conclusions. Some of the methods and data analyses, including the replicates and statistical robustness, remain inadequate to support the primary claims.

    1. eLife assessment

      This is a useful study that provides solid, yet confirmatory findings about the complex (FtsEX) that controls peptidoglycan remodeling during bacterial cell division. The authors capitalize on the finding that ATP binding stabilizes the FtsEX complex allowing structural characterization for this system. A model is then developed using biochemical approaches to explain ATP regulation. The resulting model would be strengthened were the authors to incorporate their structural findings as well as previously published work.

    1. eLife assessment

      This important study identifies a novel link between the early keratinocyte response to wounds and the subsequent regenerative capacity of local sensory neurons. The evidence supporting the claims of the authors is solid, although the inclusion of additional pharmacological and genetic manipulations might have strengthened the mechanistic aspects. The work will be of interest to cell and developmental biologists interested in tissue regeneration and cell interactions in a broader context.

    1. eLife assessment

      This study presents an important application of high-content image-based morphological profiling to quantitatively and systematically characterize induced pluripotent stem cell-derived mixed neural cultures cell type compositions. Convincing evidence through rigorous experimental and computational validations supports new potential applications of this cheap and simple assay.

    1. eLife assessment

      This work demonstrates an important regulatory role of the N-terminal disordered tail of small ubiquitin-like modifier (SUMO) proteins, which modulates the function of a variety of proteins in eukaryotic cells. The authors present convincing evidence that the N-terminal region of SUMO inhibits its own interaction with downstream effector proteins and SUMOylation targets. This new discovery significantly advances the field by providing a possible explanation of how SUMO paralogues select their effectors and SUMOylation targets.

    1. eLife assessment

      This manuscript reports important data on the stability of nucleosomes. Convincing evidence obtained by single-molecule FRET experiments shows that DNA unwrapping is found to be slower when a single CC base pair mismatch is introduced at three different positions. The work is carefully conducted and described clearly, but the biological significance and implications of the findings on cellular DNA metabolism remain unclear.