- Nov 2023
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study provides extensive high-quality imaging data and new insights into the process of the endothelial-to-hematopoietic transition (EHT), which generates nascent hematopoietic stem cells from the ventral wall of the dorsal aorta. This study provides strong evidence that, based on apicobasal cell polarity, different morphologies exist for emergent hematopoietic stem cells. The study is incomplete at present in that it does not yet support the additional claim that there are functional consequences, as altered cell fate related to these different morphologies has not been definitively shown.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Studies of synaptic development and plasticity in the nematode C. elegans have been limited by the difficulty of rapid, accurate assessments of synaptic structure. In this valuable work, the authors convincingly introduce and validate a computational pipeline, "WormPsyQi," that allows rapid, reproducible quantitation of fluorescent synaptic puncta while minimizing human error and bias. The authors also describe a new set of strains carrying synaptic markers. Together, these tools should provide many groups studying this model system with the ability to quantitatively characterize chemical and electrical synapses, even in densely packed regions in 3D space such as the nerve ring.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Using the continuum theory of elastic solids, the authors suggest that periodic muscle contraction leads to elongation of C. elegans embryos by storing elastic energy that is subsequently released by extending the embryo's long axis. This important finding could apply to other developmental processes and be exploited in soft robotics. While the presented evidence is in principle convincing, features of the the theory are not explained in sufficient detail.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important demonstration of how the false-positive rate of high-resolution 2D template matching to find particles of a given target structure in 2D cryo-EM images (2DTM) relates to overfitting the data towards the template. The authors present new methods to measure the amount of model bias that gets introduced in high-resolution features of such maps, with compelling evidence that high-resolution features that are not present in the template can still be reconstructed in 3D from images obtained by 2DTM.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a useful new approach for efficient computation of statistics on correlations between genetic variants (linkage disequilibrium, or LD), which the authors apply to quantify the extent of LD across chromosomes. The method and its derivation are solid. The authors document that cross-chromosome LD can be substantial, which has implications for geneticists who are interested in population structure and its impact on genetic association studies.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important proof-of-concept study strongly supports the utility of functional ultrasound imaging for evaluating cerebral hemodynamics in rat models of brain injury. Functional ultrasound affords a distinct coverage/spatial/temporal resolution tradeoff when compared to other modalities for studying brain hemodynamics. The solid data presented indicate high fidelity of the recordings, a particular feat given that the rats were awake. On the other hand, single slice imaging and complexity of registration of subsequent imaging sessions limit the usefulness of the approach, particularly for quantitative imaging, and the small sample size will need to be followed up with and verified by future studies. This work will be of interest to researchers working in functional neuroimaging and more precisely with preclinical models of stroke in rodents.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study shows that pharmacologically enhanced catecholamine levels and increased voluntary spatial attention have overlapping as well as dissociable effects on performance on a visuospatial attention task and corresponding EEG markers. The findings provide solid evidence regarding how neuromodulatory arousal and selective spatial attention jointly shape perceptional decision-making.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable findings about synaptic connectivity among subsets of unipolar brush cells (UBCs), a specialized interneuron primarily located in the vestibular lobules of the cerebellar cortex. The evidence supporting the claims are interesting although incomplete in some areas. The work will be of interest to cerebellar neuroscientists as well as those focussed on synaptic properties and mechanisms. Although several compelling pieces of data were presented, substantial work remains to be conducted in order for the hypothesis and predictions of the manuscript to confirm how these factors play out in the actual brain circuit and how it would impact the processing of feedback or feedforward activity that would be required to promote behavior.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript provides valuable insights to the underlying mechanism for Spinocerebellar ataxia 6 (SCA6) due to defective endolysosomal trafficking of BDNF and its receptor TrkB. The findings are compelling and significant in understanding the underlying pathology of SCA6. The authors have acknowledged the experimental weaknesses and recognize there may be multiple mechanisms to explain the findings.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study illuminates molecular movements of acid-sensing ion channels by combining advanced chemical biology and biophysical techniques. The evidence for the main claim, lack of interaction of molecular termini, is compelling and challenges prior models. This work is expected to pique interest in the ion channel signaling field, providing a fresh perspective.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Miyano et al. study the impact of RIM-BP2 deletion at mossy fiber synapses, using direct electrophysiological recordings from mossy terminals and STED super-resolution microscopy. The paper addresses an important question in the field of synaptic transmission and provides compelling evidence demonstrating reduced calcium channel abundance in mossy terminals upon RIM-BP2 removal.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript provides a useful demonstration that distractor effects in multi-attribute decision-making correlate with the form of attribute integration (additive vs. multiplicative). The evidence supporting the conclusions is generally solid, but there are concerns regarding the robustness of the statistical analyses. In addition, the lack of a clear theoretical motivation complicates the interpretation. The manuscript will be interesting to decision-making researchers in neuroscience, psychology, and related fields.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The study by Ghafari et al. addresses a question that is highly 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, inter-individual differences in the lateralization of alpha oscillations are explained by asymmetry of subcortical brain regions. The results are important, and the strength of the evidence is convincing. Yet, clarifying the rationale, reporting the data in full, a more comprehensive analysis, and a more detailed discussion of the implications will strengthen the manuscript further.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Richevaux and colleagues conducted a valuable study that investigated the integration of thalamic and retrosplenial inputs in the dorsal presubiculum, an essential hippocampal region involved in spatial navigation and memory. Through ex vivo optogenetic electrophysiological experiments, they discovered that many presubicular pyramidal cells receive convergent inputs from both the anterior thalamus and the retrosplenial cortex. These solid findings provide a potential cellular mechanism for anchoring the brain's internal compass to external landmarks, shedding light on how the brain integrates spatial information with an animal's sense of its position in space.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors present a software package called osl-dynamics that uses generative models (Hidden Markov Model and Dynamic Network Modes) that can be adapted to the data, and the latent states and transition across states obtained through the model can be used to describe spectro-temporal characteristics of the brain signals, as well as for oscillatory burst detection. This approach is important and adds to the repertoire of techniques that can be used to study high-dimensional data and having access to this software (with tutorials and examples) will help other researchers test the usefulness of their approach. The evidence is convincing, but could further benefit from an objective way by which the output of their model can be compared/judged or through results from synthetic data with known properties.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper by Aitchison and colleagues describes nanobody neutralizing and binding activity against various SARS-CoV-2 variants of concern. The findings are important in that the described nanobodies may have broad therapeutic relevance against current and future variants of concern and may be able to avoid significant resistance. The claims are incomplete: while the study is well-executed and uses a nice balance of biochemical and cellular assays, the efficacy of the proposed nanobody library against VOCs is not completely supported as IC50 values appear to increase against newer variants and are higher than previously used therapeutic bNAbs, animal data showing in vivo efficacy is lacking, and protection against future possible variants is not proven.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a useful differentiation method that produces syndetome-like cells from human induced pluripotent stem cells as determined through single-cell RNA sequencing analysis. Nevertheless, it is essential to note that the authors' assertion that the efficiency of syndetome differentiation can be enhanced by inhibiting BMP and Wnt requires further substantiation, as the evidence provided remains incomplete. The major weaknesses of the manuscript center on issues related to data representation in figures and their subsequent interpretation. The work holds relevance for scholars in the field of musculoskeletal research who are dedicated to advancing translational medicine for the benefit of patients.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable structural data for the bacterial adhesin PrgB, an atypical microbial cell surface-anchored polypeptide that binds DNA. There is convincing support for the claims regarding the overall function and importance of individual domains, which integrate a wide range of new and previously published experimental data. The structure-based model of PrgB molecular activity will be impactful in the field of bacterial adhesins, conjugation, and biofilm formation, especially because it focuses on a clinically relevant Gram-positive pathogen, whereas most work in the field has been focused on Gram-negative model systems.
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arxiv.org arxiv.org
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eLife assessment
This paper describes innovative force measurements of the bending modulus of gliding cyanobacteria, along with measurements of the critical buckling length of the cells, which combined lead to valuable insight into how these cells produce the force necessary to move. The major findings are well supported by the data; however, the evidence that the results favor an adhesion-based mechanism is currently incomplete.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study identifies the homeodomain transcription factor and suspected autism-candidate gene Meis2 as transcriptional regulators of maturation and end-organ innervation of low-threshold mechanoreceptors (LTMRs) in the dorsal root ganglia (DRG) of mice. For a few years, the view on autism spectrum disorders (ASD) has shifted from a disorder that exclusively affects the brain to a condition that also includes the peripheral somatosensory system, even though our knowledge about the genes involved is not complete. The study by Desiderio and colleagues is therefore not only scientifically interesting but may also have clinical relevance. The work is convincing, with appropriate and validated methodology in line with current state-of-the-art and the findings contribute both to understanding and potential application.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper presents a new method called MINT that is simple yet effective at BCI-style decoding tasks in stereotyped settings. While the reviewers raise caveats, overall they believe the work is a valuable study for the field of motor control, and the evidence to support their claims is solid.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
What makes one member of the species behave differently from another is a core problem in behavioral neuroscience. The authors studied the specific case of odor preference behavior in fruit flies, and searched for links to activity in the first and second stages of the olfactory system. This is a valuable study, but the results are overstated and the evidence incomplete. It is difficult to discern robust links between neural structure/function and behavior in the data set as presented here.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In zebrafish, primary motor neurons (PMNs) control escape movements, and a more heterogeneous population of secondary motor neurons (SMNs) regulate the speed of rhythmic swimming. Using single cell RNA sequencing (scRNAseq), the authors have obtained compelling evidence that PMNs, and two types of interneurons innervating them, express a set of three genes encoding voltage-gated ion channels enabling rapid firing. The PMNs also express high transcript levels of proteins involved in exocytosis, which would be expected to support rapid neurotransmitter release. These results will be important for those working on spinal cord function and zebrafish genomics/transcriptomics.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable set of experiments to test whether Bombus terrestris bumblebees can detect lethal-level doses of a series of pesticides in nectar-mimicking sugary solutions. Behavioural essays were coupled with electrophysiological measurements to show that B. terrestris mouthparts cannot detect high levels of the tested pesticides. If confirmed using pesticide formulas, and other bumblebee species, the study will be of general interest in environmental science research. Most experimental data are compelling, and the conclusions are sound, but the write-up would benefit from a broader ecological context.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Müller glial cells of the zebrafish retina can differentiate into all neural cell classes following injury, providing full regenerative capabilities of the zebrafish retina. This valuable study presents a description of transcriptional changes of Müller glia cells in the adult and regenerating retina using single-cell RNA sequencing. The overall evidence supporting the main claims of the authors is solid.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study identifies the gustatory receptors for sugar sensing in the larval and adult forms of the cotton bollworm, which is responsible for the destruction of many food crops world-wide. The authors find that the larval and adult forms utilise different receptors to sense sugars. The data are convincing and will be of interest neuroscientists working in sensory coding of sugars and to the pest management field.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript will provide a valuable method to evaluate the safety of MR in patients with orthopaedic implants, which is required in clinics. A strength of the work is that the in-silicon testbed is solid, based on the widely available human project, and validated. In addition, the toolbox will be open for clinical practice.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important work by Hann et al. advances our understanding of the role of the survival motor neuron (SMN) protein in coordinating pathogenesis of the spinal muscular atrophy (SMA). The authors provide convincing but, nevertheless, incomplete evidence in terms of skeletal analyses not being able to satisfactorily elucidate SMN regulation of bone development. The paper appears to be descriptive and will benefit from additional experiments to justify the hypothesis. With amendments, this work will be of broad interest to biologists especially those working on the SMA.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable data on how HSCs are expanded under PVA cultures. The functional evidence supporting the claims of the authors is solid, although an extended multi-omic data analysis could have strengthened the study. The work will be of interest to individuals within this HSC field.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable new insights into HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, and delineates the kidney cell types that express HIV genes and are injured in these HIV-transgenic mice. A series of compelling experiments demonstrated that PKR inhibition can ameliorate HIVAN with reversal of mitochondrial dysfunction (mainly confined to endothelial cells), a prominent feature shared in other kidney diseases. Although there are concerns regarding the specificity of C16 to PKR inhibition, as well as with the in situ hybridization studies, the data suggests that inhibition of PKR and mitochondrial dysfunction has potential clinical significance for HIVAN.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study examines the effects of NFKB2 mutations on pituitary gland development through hypothalamic-pituitary organoids. The evidence supporting the main conclusions is solid, although analysis of additional clones to exclude inter-clone variability would strengthen the conclusions. Insight into the mechanism of action of NFKB2 during pituitary development is incomplete. This work will be of interest to endocrinologists and biologists working on pituitary gland development and disease.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful article reports the possible roles of the natural product TRPV1 activator Eugenol on muscle performance and remodeling. It provides as yet incomplete evidence for eugenol, through TRPV1, but nevertheless merits future investigation.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This study presents a valuable report on the first warm autopsy case of a metastatic prostate cancer patient and the follow-up genomic and epigenomic analysis. The evidence supporting the claims of the authors is solid, although inclusion of more discussion of the study limitation and elaboration of mechanistic link for TP53, CDK12, and CDKN1B mutations would have strengthened the study. The work will be of interest to medical biologists working on prostate cancer.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This compelling and novel mathematical method assesses drug pro-arrhythmic cardiotoxicity by examining the electrophysiology of untreated cardiac cells. It will be valuable for future drug safety design.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This study presents valuable findings on diabetogenic risk from colorectal cancer (CRC) treatment. The authors claim that postoperative screening for type 2 diabetes should be prioritized in CRC survivors with overweight/obesity, irrespective of the oncological treatment received. The evidence supporting the claims is solid but requires confirmation in different populations. These results have theoretical or practical implications and will be of interest to endocrinologists, oncologists, general practitioners, gastrointestinal surgeons, and policymakers working on CRC and diabetes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Trypanosoma brucei evades mammalian humoral immunity through the expression of different variant surface glycoprotein genes. In this fundamental paper, the authors extend previous observations that TbRAP1 both interacts with PIP5Pase and binds PI(3,4,5)P3, indicating a role for PI(3,4,5)P3 binding. They therefore suggest that antigen switching might have a signal-dependent component. The evidence is mostly compelling, but with some caveats because tagged proteins were used.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study demonstrates widespread introgression between species of cyanobacteria in hot springs in Yellowstone National Park. Using single cell sequencing of hundreds of genomes, the authors provide one of the most convincing demonstrations to date of the importance of selection and hybridization in shaping polymorphism within a natural community. The strong enthusiasm for the paper is only dampened slightly by the methods not being described in the clearest possible manner.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work provides valuable insights into mucosal antibody responses against SARS-CoV-2 following intranasal immunization by characterizing a large number of monoclonal antibodies at both mucosal and non-mucosal sites. The evidence supporting the claims is overall solid, although the flow cytometric assessment of antibody-expressing cells would benefit from more rigorous controls. The demonstrated in vitro antiviral activity of antibodies characterized provides a rationale for developing mucosal vaccines, especially if confirmed in vivo and benchmarked against antibodies generated following intramuscular vaccination.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
While decades of research findings have supported the idea that action attenuates predicted touch, recent work has countered this, proposing that action actually enhances predicted touch and the previously observed attenuation is due to tactile contact. This present study resolves these contradictory claims regarding the role of prediction in perception of self-action. This important work provides compelling evidence that self-generated touch is attenuated compared to the same touch externally-generated, and a clear explanation for recent high-profile results that appeared to support the opposite view.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work presents useful and potentially valuable findings on how food signals may influence reproduction in the nematode C. elegans. In the current manuscript, the evidence in support of the authors' model is incomplete, and additional experimental data is needed to buttress the authors' conclusions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors studied the mechanisms by which dead cells are removed from the wounded skin in a process called efferocytosis. By analyzing different cell populations in the skin, the authors find that proteins involved in mediating the cell death and marking the cells as undergoing this process are elevated during distinct times in the wound healing program. Interestingly, these same proteins are elevated even higher in diabetic wounds. Finally the authors demonstrate that blocking the process of efferocytosis alters the wound healing program, thus illustrating its importance in effective wound repair.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work is fundamental in providing compelling evidence of mitochondria-encoded RNAs playing a role in controlling nuclear gene expression. How mitochondria and the nucleus communicates is an important but yet not well-appreciated area of biology. Using the iMARI (in situ mapping of RNA-Genome Interactions) technology developed by this team, the authors found that mitochondria-encoded RNAs play an unexpected role in regulating nuclear gene expressions in endothelial cells and intriguingly, depletion or overexpression of a specific mt-caRNA altered stress-induced transcription of nuclear genes encoding for innate inflammation and endothelial activation. Overall, these findings are interesting and supported by experimental confirmation, bulk-RNA-seq, and snRNA and scRNA-seq data and will be of interest to the field studying RNA regulation, gene expression and cell biology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Brodsky and colleagues report here an unexpected cis-activation mechanism of caspase-11. The authors use cellular imaging methods and cleavage site mutants to show that the LPS-induced speck formation by caspase-11 depends on the autoprocessing between two subdomains. This new finding opens multiple doors for further investigating how this non-canonical inflammasome is regulated and activated at the molecular level.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a useful mathematical analysis of different signaling networks in an attempt to provide general rules that give rise to biphasic responses, a widely observed behavior in biology in which the outputs of the network depend non-monotonically on the inputs. Determining general conditions that underlie this behavior would be useful in engineering synthetic biological systems and for mechanistically understanding biphasic responses in biological systems. However, whereas the mathematical approach and methods are solid, as they stand, the analyses are inadequate to assess how these findings are applicable in nature and which are general.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper presents valuable findings from whole-brain modeling of persistent activity states (underlying working memory) in the mouse brain. The most novel finding is that a spatial gradient of the density of inhibitory neurons supports a corresponding spatial gradient of propensity to support persistent activity. However, the evidence for this finding appears to be incomplete.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important work reveals that increased flux towards one carbon metabolism improves neuronal regeneration after injury in C. elegans. The presented data are solid and provide compelling support for this conclusion. The manuscript can still be improved in order to strengthen some of the specific conclusions made and to increase the clarity of the presentation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The paper introduces a new, important framework for neural modelling that promises to offer efficient simulation and analysis tools for a wide range of biologically-realistic neural networks. The paper's examples provide solid support for the ease of use and flexibility of the framework, but the comparison to existing solutions (in particular in terms of accuracy and performance) is incomplete. With a more careful evaluation of the tool's strengths and limitations, the work would be of interest to a wide range of computational neuroscientists and researchers working on biologically inspired machine learning applications.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study presents a tool for hyperaligning functional brain topography between individuals, which is based on fMRI connectivity data gathered when participants watched different movies. The tool is validated through strong correlations between functional topographic maps generated from a participant's own localizer data and those derived from other participants' data based on this hyperalignment, even when the training and target participants were drawn from different datasets. The study will potentially be of interest to researchers working with a wide range of fMRI datasets.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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eLife assessment
The authors establish a Drosophila model to assess the severity of disease-linked alleles of Uba5. Using both in vivo and in vitro experiments, this valuable study demonstrates the alleles fall into mild, intermediate, and severe classes, with convincing evidence to support their conclusion. This well-executed study establishes a model for further characterization of Uba5-related phenotypes in a powerful model system.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study reports differential expression of key genes in full-term placenta between Tibetans and Han Chinese at high elevations, which are more pronounced in the placentae of male than in female fetuses. If validated as functionally relevant, these results will help us understand how human populations adapt to high elevation by mitigating the negative effects of low oxygen on fetal growth. At this time, while the differential gene expression analyses are solid, the downstream analyses offer incomplete support for the connection to hypoxia-specific responses and adaptive genetic variation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study presents a new apparatus and experimental paradigm to examine deficits in finger control in stroke patients, with the goal of understanding their potential (biomechanical and neural) underpinnings. The paper presents solid experimental design and quantitative analyses to characterise these deficits and infer their origin, but a few technical aspects related to data analysis and statistics could be improved, and alternative interpretations of the results considered. In addition to the scientific results, this novel methodology can be used as a starting point for further research on hand function impairments in stroke, which is of significance for theoretical studies in neuroscience and applied research in rehabilitation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this important paper, the authors report a link between brumation (or "hibernation") and tissue size in frogs, summarizing convincing evidence that extended brumation is associated with smaller brain size and increased investment in reproduction-related tissues. The research is of broad interest to ecologists, evolutionary biologists, and those interested in global change biology, as the dataset involves significant field work and advanced statistical analyses for insights into how expensive tissues in these ectothermic animals respond to environmental seasonality.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript describes valuable information on how the extraocular muscles (EOM) are preserved in a mouse model of familial Amyotrophic lateral sclerosis (ALS) that carries a G93A mutation in the Sod1 gene. The authors provide convincing evidence of how the integrity of neuromuscular junction is preserved in EOM but not in limb and diaphragm muscles of G93A mice. Overall, this interesting work provides new evidence regarding the etiopathogenesis of ALS and insights for the development of therapeutic targets to slow the loss of neuromuscular function in ALS.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study reports on how Notch activity regulates the termination of neurogenesis in central brain during larval-pupal stages in Drosophila. The evidence supporting the claims is solid. The work will be of interest to developmental neurobiologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents the valuable finding that sustained calcium signaling in induced-Treg (iTreg) cells can lead to the loss of Foxp3 expression and iTreg identity by altering the chromatin landscape. The evidence supporting the claims of the authors is convincing. The work will be of interest to immunologists working on Treg cell therapy.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study is focused on the requirement of the photoreceptor-specific tetraspanins, ROM1 and PRPH2, for the formation of light-sensitive membrane discs. The evidence supporting the claim that deficiency in one of the proteins can be compensated by the other is convincing, with both established and advanced techniques yielding results that will be of interest to those studying photoreceptor development and membrane curvature.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study aims to advance our understanding of the structure of the native form of a viral toxin secreted from infected cells. Some of the findings confirm previous reports, but the new claims in this study are only inadequately supported by the methods and analyses used. More rigorous approaches are needed to justify the main conclusion that the structure of the viral toxin derived from infected cells in this study is distinct from previously reported structures of recombinantly expressed versions of the toxin.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study shows, based on analyses of single cell RNA-seq data sets of thymus cells, that transposable elements (TEs) are broadly expressed in thymic stromal cells, especially in medullary thymic epithelial cells and plasamacytoid dendritic cells. The authors also show that at least some TE-derived peptides are presented by MHC-I molecules in the thymus. The results suggest a possible role of TEs in thymic T-cell selection and immune self-tolerance, but the current analyses are incomplete and not yet fully support the claims.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work presents fundamental new insights into the conductivity of freshwater cable bacteria. The evidence supporting the conclusions, which was collected using appropriate techniques, is compelling. The work will be of interest to environmental microbiologists and the microbial electrochemistry community.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study reports on several variants of the COVID-2 spike protein that are studied using well-established computational approaches, followed by attempts to validate the findings using experimental approaches. The evidence supporting the claims of the authors is solid, although there are known limitations of the computational approaches. The manuscript would benefit from a deeper discussion of the limitations and better contextualization of the work. The study will be of interest to biophysicists working in the general areas of allostery and protein evolution.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful manuscript explores conditions for epigenetic inheritance by studying the stability of simple network models to permanent and transient perturbations. A novel aspect of the study is that it unifies non-genetic inheritance phenomena across cell divisions of unicellular organisms and in the germline of multicellular organisms. However, the models studied are more a collection of vignettes of numerical studies than a systematic study, therefore the evidence presented remains incomplete. This work will be of interest in the field of epigenetic inheritance as a first step towards building a more systematic theoretical framework.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study reports that auxin exposure perturbs feeding behavior, survival rates, lipid metabolism, and gene expression patterns in adult flies. The solid results are based on proper methods and data analyses, which broadly support the conclusions with only minor weaknesses. This work should be interesting to fly geneticists who are interested in using the auxin-inducible gene expression system for inducing target protein degradation acutely.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript presents valuable findings that inform our understanding of the genetic underpinnings of the model plant Arabidopsis' resistance to turnip mosaic virus (TuMV). The strength of the evidence in the manuscript is convincing, with very large sample sizes, careful controls, multiple follow-up experiments, and broadening to the evolutionary context. There is very good support for each of the manuscript's conclusions and the work could pave the way for functional studies.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents important findings that homo- and heterosynaptic plasticity outside of the window at which a weak associative fear memory is formed can transform this memory into a stronger one, and can produce fear memory even when stimuli were not paired. This work therefore expands our views on the role of time- and input-specificity of plasticity in learning processes. The evidence, based on state-of-the-art in vivo manipulations and activity recordings in behaving mice, supporting the conclusions is solid, although further validation of the methods used is required in order to reaffirm the authors' conclusion. Once resolved, the work will be of broad interest to neuroscientists interested in activity-dependent synaptic plasticity and associative memory.
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eLife assessment
This study enhances our understanding of the relationship between cortico-hippocampal interactions and behavioral performance. Using an inter-areal coherence metric to gate trial initiation in real time, the authors provide solid evidence that links high hippocampal-prefrontal theta coherence to correct performance on spatial working memory and cue-guided decision-making tasks. Although reviewers agreed that the results do not demonstrate causality between hippocampal-prefrontal synchrony and behavioral performance, the findings are viewed as important given their potential implications for brain-machine interface applications in humans.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Host cell death is an effective strategy to protect against infection, and is believed to function primarily by the elimination of the intracellular niche for pathogen replication. Abele and colleagues address an important question: does the mode of cell death affect its effectiveness in pathogen clearance? Consistent with prior observations, the authors provide compelling new evidence that the answer can depend on the cell type and/or tissue involved.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study describes CLEVER, an improved method for fast and efficient rescue and mutagenesis of SARS-CoV2. While the principle of this method is not new, this work significantly improves upon existing protocols, providing an important advancement in the field of viral infectious clones. Convincing proof-of-concept experiments were performed that demonstrate the utility and efficiency of the method.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This manuscript provides fundamental findings on the association between sleep regularity and mortality in the UK Biobank, which is a popular topic in recent sleep and circadian research in population-based studies. The study is based on a large accelerometer study with validated follow-up of incident diseases and deaths, and the data quality and large sample size are convincing and strengthen the credibility of the conclusion. This will be of wide interest to researchers in the sleep study field, epidemiologists, practicing clinicians and the general public.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This small-sized clinical trial comparing nebulized dornase-alfa to the best available care in patients hospitalized with COVID-19 pneumonia is valuable, but in its present form the paper is incomplete.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study unravels the interaction between effort cost, pupil-indexed brain state, and movement (saccadic) vigor during foraging decisions in marmoset monkeys. Based on a normative computational model, the authors derive the prediction that anticipated effort should affect both decisions and movement vigor during foraging; and then provide solid behavioural and pupillometric evidence for this prediction in a foraging task. This paper will be of interest to decision and motor neuroscience as well as to all researchers studying animal behavior.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable observations indicating that the electrophysiological excitability of cultured sympathetic motor neurons progressively increase during aging, and are inversely correlated with the magnitude of KCNQ currents. The alterations in membrane excitability are broadly relevant for those interested in understanding how the nervous system changes during aging. While the data as a whole are solid in showing that the excitability of sympathetic neurons increases in neurons cultured from older mice, the mechanism of the underlying changes and in vivo relevance is incomplete.
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- Oct 2023
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In Drosophila melanogaster, the Store-operated Ca2+ entry (SOCE) channel, Orai, is required for the development of flight-promoting dopaminergic neurons. Here, Mitra et al. determine that expression of a loss-of-function Orai1 mutant during the 72-96 hour window of pupal development impairs gene expression in dopaminergic flight neurons in part through the expression of Set2, a histone methyltransferase. The authors identify a large number of genes that are controlled by Set2, and show that Set2 is controlled by the Trl/GAF transcription factor. Although the findings reported here are important, the evidence supporting some of the claims is incomplete.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides useful insights into the mechanisms of electron transport in STEAP proteins, consistent with current models. The work strengthens and supports previously published biochemical and structural data, and the experimental results are of solid technical quality. The manuscript will be of interest to colleagues who work on STEAP proteins and related electron transfer systems.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents useful insights into core genome mutations that could have contributed to the emergence of the Staphylococcus aureus lineage USA300, a frequent cause of community-acquired infections. The solid approach used is innovative in combining genome-wide association studies and RNA-expression analyses, both applied to extensive publicly available datasets. This strategy reduces the rate of false positives attributed to high genome-wide linkage disequilibrium. It is noted that this method cannot be used for most phenotype-genotype studies, especially those requiring essential population structure correction, and it can therefore not be readily replicated in different datasets.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Understanding how genomic regulatory elements interact to control spatiotemporal gene expression is essential to explaining cell type diversification, function, and delineating genetic variation and disease. In this important study, the authors provide solid evidence showing that, in general, enhancers influence gene expression in an additive way. The findings contribute to ongoing discussions about the selectivity and combination of regulatory elements. Improved clarity regarding the statistical analysis, computational methods, and definitions used would strengthen the conclusions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript describes an important NMR investigation of allosteric interactions within Abl kinase. The authors identify helix I as a major element that couples the Abl active site with the myristate-binding pocket. The convincing findings have implications for understanding Abl kinase activation and how to target Abl kinase in diseases.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides a valuable resource that documents the protein-protein interactions (PPI) network for alpha-arrestins in both human and Drosophila based on affinity purification/mass spectrometry and the SAINTexpress method followed by a series of bioinformatic and functional assessments. Through these, the authors confirmed the roles of known and novel interactions, including proteins involved in RNA splicing and helicase, GTPase-activating proteins, and ATP synthase. This study represents a convincing example of how to adopt comparative molecular interactions and how to interpret the functional implications.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this study, the authors (1) build a detailed model of the process whereby visual information is stored in neuronal activity from the moment that a stimulus is presented until some time later when such information needs to be recalled, and (2) test numerous mechanistic assumptions by fitting the model to rich psychophysical experiments performed by human participants. The evidence supporting the claims is convincing, utilizing detailed model comparison to evaluate potential mechanisms. Overall, the results represent a valuable advance in our understanding of how sensory representations are encoded in and then recalled from, working memory.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a fundamental work that significantly advances our understanding of the role of mossy cells in the dentate gyrus in Fragile X Syndrome. Carefully designed experiments provide evidence that changes in their excitability occur due to up-regulation of Kv7 currents. While the evidence supporting the authors' conclusions is solid, some of their claims did not consider other potential factors and explanations. The work will be of interest to neuroscientists working on unveiling the mechanisms of Fragile X pathology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents useful findings from a large sample of participants from the UK Biobank on the relationship between menopause (including status, type, and age of onset), cognition, neuroanatomical measures derived from magnetic resonance imaging, and Alzheimer's disease. The strength of evidence is incomplete, and the study would benefit from clearer methodological descriptions, more careful consideration of potential confounds, and better theoretical integration with prior work in the field. This paper will be of interest to people working in the fields of cognitive neuroscience, endocrinology, and dementia.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript describes valuable findings on the expression pattern of orexin receptors in the midbrain and how manipulating this system influences several behaviors, such as context-induced locomotor activity and exploration. The overall strength of evidence - which includes anatomical, viral manipulation studies, and brain imaging - is solid and broadly supports claims in the paper, however, there are several areas in which the conclusions are only partially supported by the data provided. These results have implications for understanding the neural underpinnings of reward and will be of interest to neuroscientists and cognitive scientists with an interest in the neurobiology of reward.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this important study, the authors integrated genetic and genomic datasets from humans and mice to unveil shared networks and pathways associated with coronary artery disease. Their compelling analysis led to the identification of new regulatory genes and pathways in vascular tissues and in the liver, allowing for a more in-depth understanding of the pathogenesis of coronary artery disease.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study and associated data is compelling, novel, important, and well-carried out. The study demonstrates a novel finding that different chemotherapeutic agents can induce nucleolar stress, which manifests with varying cellular and molecular characteristics. The study also proposes a mechanism for how a novel type of nucleolar stress driven by CDK inhibitors may be regulated. The study sheds light on the importance of nucleolar stress in defining the on-target and off-target effects of chemotherapy in normal and cancer cells.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study reports that neural activity in the auditory cortex (field L) of singing male songbirds can be modulated by social context. These potentially important findings indicate that the presence of a female conspecific alters the response of auditory cortical neurons to the male bird's own song and to perturbations of auditory feedback that the bird has been trained to expect. While they extend recent work showing that the activity of dopaminergic neurons in songbirds is also affected by an audience, the evidence presented is incomplete since it is unclear how much of the apparent modulation of cortical neurons may be due to other factors, such as changes in the recorded neurons or their properties over time, which will require additional analyses to work out.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study discovered DBT as a novel gene implicated in the resistance to MG132-mediated cytotoxicity and potentially also in the pathogenesis of ALS and FTD, two fatal neurodegenerative diseases. The authors provided solid evidence to support a mechanism by which loss of DBT suppresses MG132-mediated toxicity. While activation of autophagy is shown to be associated with DBT knockdown, it remains unclear if this is the underlying mechanism driving improved survival.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study provides an unprecedented understanding of the roles of different combinations of NaV channel isoforms in nociceptors' excitability, with relevance for the design of better strategies targeting NaV channels to treat pain. Although the experimental combination of electrophysiological, modeling, imaging, molecular biology, and behavioral data is convincing and supports the major claims of the work, some conclusions need to be strengthened by further evidence or discussion. The work may be of broad interest to scientists working on pain, drug development, neuronal excitability, and ion channels.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study summarises the effect of optical stimulation of the A13 region on locomotion in healthy mice and experimental Parkinsonism and could potentially be of interest to basic and clinical neuroscientists. Behavioural analyses and evidence for pro-locomotor effects of stimulation are solid. However, anatomical analyses are incomplete and do not yield mechanistic insights due to various issues with specificity, sample size, statistical analysis, and data presentation in the present form of the study.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides valuable insights into how researchers can use perceptual metamers to formally explore the limits of visual representations at different processing stages. While the study is overall convincing in terms of approach and results, issues were identified with respect to novelty, sample size, incomplete psychophysical methodology, and better motivation of the models tested.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a valuable study of Eph-Ephrin signaling mechanisms generating pathological changes in amyotropic lateral sclerosis. There are exciting findings bearing on the role of glial cells in this pathology. The study emerges with solid evidence for a novel astrocyte-mediated mechanism for disease propagation. It may help identify potential therapeutic targets.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper provides a fundamental expansion of vestibular compensation into transient and partial dysfunction, as well as insights into the adaptation of visual reflexes in this process. The conclusions are convincingly supported with paired histological and behavioral measurements, which are additionally modeled for further interpretation. This work would be of interest to neuroscientists working in multisensory integration and recovery mechanisms.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides valuable findings about pre-saccadic foveal prediction and the extent to which it is influenced by the visibility of the saccade target relative to its background. The results and research methodology are technically solid, but there are questions about the interpretation of data which if addressed, would benefit our understanding of this phenomenon. This work should be of broad interest to visual neuroscientists, as well as those interested in understanding perception in the context of eye movements and in modeling visually guided actions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this study, the authors develop a useful strategy for fluorophore-tagging endogenous proteins in human induced pluripotent stem cells (iPSCs) using a split mNeonGreen approach. Experimentally, the methods are solid, and the data presented support the author's 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.
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www.researchsquare.com www.researchsquare.com
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eLife assessment
This study describes a method to track MHC class II binding peptides on dendritic cell (DC) surfaces using a tetracystein tag and a thiol-reactive dye, which can then be investigated in vitro and in vivo. This is a valuable study for the impact on immunology and potentially other areas where the detection of cell-associated peptides is required. The methods are convincing based on the use of MHC class I/II deficient mice that have significantly reduced signal, but the non-zero background is detected, and it is not clear that this is lower than if the peptides were directly labelled with fluorophores.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable finding on the mechanism of glucocorticoid-induced osteonecrosis of the femoral head. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for functional studies of the development of glucocorticoid-induced osteonecrosis. This paper would be of interest to cell biologists and biophysicists working on the potential pharmacological treatments for glucocorticoid-induced osteonecrosis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors have shown a valuable tumor suppressive function of the non-core regions of RAG1/2 recombinases, by using a set of animal models. The work is solid and the conclusions are supported by their data. Some areas of mechanistic work can be improved.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors studied key characteristics of MYC-driven cancers: dysregulated pre-mRNA splicing and altered metabolism. The reviewers agree that this is an interesting study and that the findings are important. Overall the data was considered solid although the paper would benefit from revisions. The manuscript has the potential to be of broad interest to cancer biologists due to its therapeutic implications.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The study provides important insights into the mechanisms underlying ulcerative colitis, a chronic and debilitating gastrointestinal condition. The article provides solid evidence of the role of the vesicular trafficking protein Rab7 in regulating the colonic mucus system and its implications in ulcerative colitis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The findings of this valuable manuscript advance our understanding of the significance of Bestrophin isoform 4 (BEST4) in suppressing colorectal cancer (CRC) progression. The authors used appropriate and validated methodology, such as the knockout of BEST4 using CRISPR/Cas9 in CRC cells, to provide a solid foundation for elucidating the potential link between BEST4 and CRC progression.
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arxiv.org arxiv.org
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eLife assessment
This paper proposes a valuable new method for the assessment of the mean kurtosis for diffusional kurtosis imaging by utilizing a recently introduced sub-diffusion model. The evidence supporting the claims that this technique is robust and accurate in brain imaging is incomplete. The work could be of interest in the research and clinical arena.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study uses a range of technical approaches to investigate the responses of zona incerta neurons to movement and sensory stimuli. The majority of neurons exhibited movement related activity but only a small proportion were modulated by whisker deflections. The major conclusion of the study is that the zona incerta distributes a general motor signal. The evidence supporting this claim is solid, although the study would be improved by greater transparency and discussion of experimental methods and histological verification of recording sites, viral spread, and which territories of the zona incerta were investigated. The work will be of interest to behavioral and physiological neuroscientists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents an important open-source resource for high-throughput behavioral screening. The protocols employ inexpensive, off the shelf hardware, and allow real-time analysis of hundreds of behaving flies. Although these protocols were developed using Drosophila melanogaster, they could easily be applied to other models. The evidence in support of the conclusions is solid and the revisions carried out by the authors go a long way towards providing the user with an integrated system that is also more user-friendly.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper presents an important contribution to the field of hippocampal registration by introducing a novel surface-based approach that utilizes the topological and morphological features of the hippocampus for anatomical registration across individuals, rather than volumetric-based methods commonly used in the literature. The study provides compelling evidence for the efficacy of this approach using histological samples from three different datasets and offers validation of the method through comparison with traditional volumetric registration. This is significant work given the large number of studies that examine hippocampal shape, thickness, and function in large cohorts, providing strong support for the use of hippocampal unfolding methods in future studies.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript aims to identify the pacemaker cells in the lymphatic collecting vessels - the cells that initiate the autonomous action potentials and contractions needed to drive lymphatic pumping. Through the exemplary use of existing approaches (genetic deletions and cytosolic calcium detection in multiple cell types), the authors convincingly determine that lymphatic muscle cells are the origin of the action potential that triggers lymphatic contraction. This fundamental discovery establishes a new standard for the field of lymphatic physiology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable findings on the presence of 6mA in the Drosophila genome and challenges previous findings regarding the role of TET in 6mA modification. The evidence supporting the claims is solid, and the paper has the potential to stimulate re-evaluations of the significance and regulatory mechanisms of 6mA DNA modifications in Drosophila.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study advances our understanding of how Notch signaling activates transcription by analyzing the dynamics of the Mastermind transcriptional co-activator and its role in the activation complex. The evidence is compelling with precise quantitative measurements. The evidence presented by the authors features methods, data, and analyses that are currently state-of-the-art but have not previously been applied to how transcription is regulated in the Notch pathway.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable work on the paleovegetation history of Iceland has implications for the field of paleoecology, and the deglaciation history of Iceland and additional localities in Northern America and Europe via woody shrub colonization. The study uses a sedimentary ancient DNA metabarcoding approach to study this historic process. The strength of evidence is solid, with the methods (analysis of sedimentary DNA) and data analyses broadly supporting the claims.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents initial findings in the generation of 3D cell constructs from endometrial cell mixtures seeded in Matrigel scaffold and treated with hormones as a proof of concept. While the study findings are valuable, functional validation to demonstrate its robustness is lacking, and therefore the strength of evidence is incomplete. The term organoids might not be appropriate to describe this in vitro model.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The current manuscript presents a cryo-EM structure of a tripartite ATP-independent periplasmic (TRAP) transporter that contributes to Haemophilus influenzae virulence. Convincing biophysical and cryo-EM experiments yield a valuable molecular model, but evidence to support some of the mechanistic conclusions is currently incomplete.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable paper examines gene expression differences between male and female individuals over the course of flower development in the dioecious angiosperm Trichosantes pilosa. The authors show that male-biased genes evolve faster than female-biased and unbiased genes. This is frequently observed in animals, but this is the first report of such a pattern in plants. In spite of the limited sample size, the evidence is mostly solid and the methods appropriate for a non-model organism. The resources produced will be used by researchers working in the Cucurbitaceae, and the results obtained advance our understanding of the mechanisms of plant sexual reproduction and its evolutionary implications: as such they will broadly appeal to evolutionary biologists and plant biologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study combines in vitro experiments with simulations to identify the mechanisms governing modulation of microtubule dynamics by GTP hydrolysis. The authors introduce a convincing new approach by using a mixed GDP/GMPCPP lattice and varying GDP concentration to reveal that the nucleotide at the interface of two tubulin dimers determines the strength of the interaction between two dimers. Overall, the findings will be of interest to biophysicists and cell biologists, especially in the field of microtubule biology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study uses CRISPRi to silence multiple effectors in the pathogen, Legionella pneumophila. It provides a technique that will allow researchers to address functional redundancy amongst effectors, a problem that has persisted even after decades of study. The methodology used is convincing, and further improvement (such as using multiple guides per gene) can lead to the identification of novel virulence factors.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
One of the most promising strategies in development of drugs targeting kinases is provided by using allosteric control that allows specific regulation and study of kinase function without directly targeting the active site. This important paper reviews convincingly the current repertoire of tools for regulating the activity of protein kinases with the ultimate goal of developing novel approaches in treating diseases associated with signal dysregulation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study provides convincing evidence that acute experimental pain induces changes of cortical excitability. Although the modality specificity of the findings is not fully clear, the findings will be of interest to researchers interested in the brain mechanisms of pain.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides the fundamental insight that TGN46, a single-pass membrane protein, acts as a cargo receptor for proteins at the Trans-Golgi Network that are destined for secretion. Compelling evidence shows that the luminal domain of TGN46 is crucial for the incorporation of the soluble secretory protein PAUF into CARTS. The clear effect but partial block of secretion after depletion of TGN46 points to the need for further exploration of the process.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study of Iceland's paleovegetation history has implications for the field of paleoecology, as well as shrubification in the Arctic. It presents solid evidence that postglacial colonisation by birch was later than willow in Iceland and nearby areas, based on a new analysis with multiple lines of existing evidence, including one new site with sedimentary ancient DNA. The study would benefit from a clearer description of key methods and results, and more critical reflection on the assessment of colonisation lags and the predictive use of paleo datasets.
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arxiv.org arxiv.org
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eLife assessment
The OpenApePose database presented in this manuscript will be important for many applications within primatology and the behavioural sciences, and a beneficial resource for developing additional tools using computer-vision based methods. The authors have rigorously tested the utility of this database to clearly demonstrate its convincing potential, especially in relation to current alternatives. The transparent and open nature of this work will surely be beneficial to advancing automated methods for pose estimation both in captive and wild settings, and for image and video processing.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript used the sci-Plex system for screening compounds to improve the Ascl1-induced reprogramming from Müller glia to bipolar neurons in vitro, followed by in vivo characterization of two promising compounds in mice. The findings are valuable for future studies to develop cell replacement strategies for treatment of retinal degeneration. The strength of evidence is solid, featuring a scalable drug screening design, albeit with limited mechanistic insights.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study shows that unlike prior reports, cortical spreading depression does not lead to spontaneous activity in the majority of meningeal afferent sensory neurons but that it increases sensitivity to mechanical deformation of the meninges. This has important implications for headache disorders like migraine where cortical spreading depression is thought to contribute to the pathology, but how this occurs is unclear. The current work uses convincing methods in awake and freely moving animals compared to prior studies of this nature that used recordings in anesthetized animals.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The findings of this study are valuable as they provide new insights into the role of acetylcholine in modulating sensory processing in the auditory cortex. This paper reports a systematic measurement of cell activity in the auditory cortex before and after applying ACh during an oddball and cascade sequence of auditory stimuli in anesthetized rats. The results presented are solid given the rigorous experimental design and statistical analysis. The conclusions are provocative and will interest researchers in auditory neuroscience and neuromodulation, as well as clinicians and individuals with auditory processing disorders. However, the findings support multiple interpretations, beyond that offered by the authors.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript reports a useful computational study of the effects of axon de-myelination and re-myelination on models of working memory, with potential applications implications in disorders such as multiple sclerosis. In its present form, the provided evidence is partly incomplete due to certain modeling choices and lack of clarity on model details, but these shortcomings could be addressed.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Building on their own prior work, the authors present valuable findings that add to our understanding of cortical astrocytes, which respond to synaptic activity with calcium release in subcellular domains that can proceed to larger calcium waves. The proposed concept of a spatial "threshold" is based on solid evidence from in vivo and ex vivo imaging data and the use of mutant mice. However, details of the specific threshold should be taken with caution and appear incomplete unless supported by additional experiments with higher resolution in space and time.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Schnell et al report important differences between the strategies used by rodents and humans when discriminating different visual objects. The evidence supporting these findings is convincing, showing that rat performance was influenced far more by low-level cues compared to humans. It is, however, unclear to what extent these differences can be explained by the lower visual acuity of rats. This work will be of general interest to vision and cognition researchers, particularly those studying object vision.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides a valuable contribution to the study of eye-movements in reading, revealing that attention-weights from a deep neural network show a statistically reliable fit to the word-level reading patterns of humans. Its evidence is convincing and strengthens a line of research arguing that attention in reading reflects task optimization. The work would be of interest to psychologists, neuroscientists, and machine learning researchers.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors provide an important series of metabolic measurements characterizing group dynamics in fish, rationalizing that schooling behavior presents several benefits. The strength of evidence supporting this conclusion is solid, but the methodological and analytical approaches taken could be strengthened. Similarly, numerous test-based clarifications and improved statistical analyses could significantly strengthen the study and underlying interpretations.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study reports comprehensive multi-omic data on the changes induced in young and aged male mouse tail fibroblasts after treatment with chemical reprogramming factors. The authors claim that chemical reprogramming factors induce changes consistent with a reduction of cellular 'biological' age (e.g., correlations with established aging markers in whole tissues). However, the study relies on previously identified aging markers (instead of aging in the tail fibroblast system itself), and thus, at this stage, the evidence in support of the observed molecular changes truly reflecting changes in biological age in the study system is still incomplete.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study investigates evolutionary aspects around a single amino acid polymorphism in an immune peptide of Drosophila melanogaster,. This polymorphism is known to be under long-term balancing selection. Using alleles with different substitutions, the investigators found that one allele provides better survival after systemic infections by a bacterial pathogen, but that the alternative allele endows its carriers with a longer lifespan under certain conditions. The authors suggest that these contrasting fitness effects of the two alleles contribute to balancing their long-term evolutionary fate. The strength of the provided evidence is still incomplete and would benefit from more rigorous approaches.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable finding regarding the role of life history differences in determining population size and demography. The evidence for the claims is still partially incomplete, with concerns about generation times and population structure. Nonetheless, the work will be of considerable interest to biologists thinking about the evolutionary consequences of life history changes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a fundamental study addressing a long-standing mystery in splicing regulation. The authors provide compelling evidence that splicing can occur post-transcriptionally. The work will be of broad interest to anyone studying gene regulation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study reports the cryo-electron microscopy structure of a multi-protein complex that recognizes the 5'-end cap of mRNAs and plays a critical role in mRNA export. The structural analyses and biochemical assays in this study provide convincing evidence to support the major claims of the authors, although the inclusion of more functional characterizations in cell-based systems would have strengthened the study. This paper would be of interest to structural biologists and RNA biologists working on mRNA metabolism.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work presents the application of protein language models in combination with current methods for the detection of distant evolutionary relationships. While the results are important, they are supported by incomplete, preliminary evidence. A more comprehensive benchmark and clarification of technical details may turn this exploratory study into an algorithm ready for wide use.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents important findings on a transcription-independent component of the early recovery of proteasome activity from a short pulse of proteasome inhibitor treatment. While the evidence supporting this conclusion is solid, experimental support forthe proposal of an alternative regulatory process operative at the level of proteasome assembly, is incomplete. Lacking is experimental quantification of the effect of proteasome inhibition on the rate at which newly synthesized subunits are assembled into proteasomes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a valuable study that convincingly demonstrates that quantification of EpCAM+/CD24+/Vimentin+ cells in the stroma of human oral cancers followed by machine learning algorithms can be used as a prognostic indicator of metastasis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental work substantially advances our understanding of how cells can tightly modulate small GTPase activity to build and maintain neighboring cytoskeletal structures, in this case microvilli. The evidence supporting these claims is compelling and is supported by both protein-protein interaction assays as well as cell biological studies. The work will be of interest to cell biologist studying the cytoskeleton as well as those interested in G-protein mediated regulation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The study is an important advancement to the consideration of antimalarial drug resistance: the authors make use of both modelling results and supporting empirical evidence to demonstrate the role of malaria strain diversity in explaining biogeographic patterns of drug resistance. The theoretical methods and the corresponding results are convincing, with the novel model presented moving beyond existing models to incorporate malaria strain diversity and antigen-specific immunity. This work is likely to be interesting to malaria researchers and others working with antigenically diverse infectious diseases.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents potentially valuable results on glutamine-rich motifs in relation to protein expression and alternative genetic codes. The author's interpretation of the results is so far only supported by incomplete evidence, due to a lack of acknowledgment of alternative explanations, missing controls and statistical analysis and writing unclear to non experts in the field. These shortcomings could be at least partially overcome by additional experiments, thorough rewriting, or both.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
BTK, a TEC-family tyrosine kinase activated by the B-cell antigen receptor, contains a variety of regulatory domains and it is subject to complex regulation by membrane phospholipids, protein ligands, phosphorylation, and dimerization. This study presents convincing evidence, utilizing various biophysical techniques, to support a model for BTK activation that will be valuable for the field. Overall, the study enhances the understanding of BTK's activation mechanism, autoinhibition, and allosteric control, challenging previous assumptions about BTK.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study is valuable as it sheds light on the pivotal role played by alterations in glycan metabolism within chondrocytes in the onset of cartilage degeneration and early onset of osteoarthritis (OA) through the process of hypertrophic differentiation of chondrocytes, giving insights into the identification of nascent markers for early-stage OA. Although the methods, data, and analyses broadly support the claims, the data shown by the authors are incomplete because the mechanism by which cartilage degeneration induced by changes in glycometabolism occurs has not been fully elucidated. The authors' deductions stand to gain further credence through undertaking additional experiments aimed at analyzing the mechanisms underlying the changes in glycometabolism in cartilage, such as the meticulous identification of the target glycan molecules bearing core fucose and analysis of endochondral ossification in cartilage-specific Fut8 KO mice.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful work provides insight into the formation of associations between the nucleolus and Promyelocytic leukemia nuclear bodies (PML-NBs). The work showed that these associations depend on both the formation of DNA double-strand breaks and the impaired RNA Polymerase I transcription, and also is modulated by the homologous recombination. The evidence supporting the claims is incomplete and the paper needs more experimental support on the dynamics of the association and mechanistic insight into the signaling for its formation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study could potentially represent a step forward towards personalized medicine by combining cell-based data and a prior-knowledge network to derive Boolean-based predictive logic models to uncover altered protein/signaling networks within cancer cells. However, the level of evidence supporting the conclusions is inadequate, and further validation of the reported approach is required. If properly validated, these findings could be of interest to medical biologists working in the field of cancer and would inform drug development and treatment choices in the field of oncology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important study that characterizes a surprising interaction between two different cytokine/hormone receptors using nanoscale resolution (dSTORM) microscopy. The study provides solid evidence that the interaction is ligand-dependent, and is mediated by the receptor-associated intracellular signalling molecule JAK2. While at present limited to growth hormone and prolactin receptors in a limited number of cell lines, there are potentially broad implications for cytokine signalling, as such JAK2-mediated interactions could occur between a range of different cytokines. Moreover, the specific hormone interactions shown in the manuscript may have important implications for understanding how these hormones can have differential effects in breast cancer, under different conditions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a useful study that uses a microfluidic method to evaluate the ability of single human white blood cells to produce combinations of cytokines. The evidence that this takes place is solid. The paper highlights polyfunctionality using similar data to a prior work from the same group.
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eLife assessment
This study presents a valuable finding on the putative molecular patterns underlying characteristic morphological regions observed in colorectal cancer (CRC). The authors provide a morphological framework through which clinicians might improve the performance of molecular signatures and consequently predict the clinical response of patients with better accuracy. The evidence supporting the claims of the authors is solid. The work will be of interest to clinicians and cancer biologists working in the field of CRC.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper presents valuable findings that shed light on the mental organisation of knowledge about real-world objects. It provides diverse if incomplete evidence from behaviour, brain, and large language models that this knowledge is divided categorically between relatively small objects that are at the relevant scale for direct manipulation and larger objects that are outside the typical scope of human affordances for action.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study offers new and convincing support for the idea that about a third of mouse liver DNAse hypersensitivity sites (DHS) showing male-biased chromatin opening are sex-biased because of the male-specific cyclic action of growth hormone pulses to alter chromatin accessibility, as compared to the relative ineffectiveness of the more static pattern of growth hormone secretion in females. Supporting evidence is found in the impact of hypophysectomy and growth hormone treatment on chromatin accessibility, and the binding of specific transcription factors and epigenetic marks at STAT5-sensitive sites. This work uncovers mechanisms that impact sex differences in liver function and will be of broad interest to endocrinologists and hepatologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study addresses epilepsy caused by the loss of a molecule called Pten, resulting in hyperactivity of the mTOR pathway. The findings suggest that inhibiting two molecules called mTORC1 and mTORC2 can reduce epilepsy symptoms but there is much less effect when inhibited separately. The evidence supporting the conclusions is currently incomplete, but could be strengthened after additional experiments.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This study presents important findings linking structural and functional changes in frontotemporal dementia to underlying neurotransmitter systems. The evidence to support the claims is solid, however, relationships are relatively modest and there are limitations regarding the neurotransmitter data. This study will appeal to clinicians and neuroscientists who are interested in the potential effects of certain neurotransmitter systems on clinical features of frontotemporal dementia.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors present a valuable work suggesting that the superficial, retinorecipient layers of the mouse superior colliculus (SC) may participate in figure-ground segregation and object recognition. These data are based largely on optogenetic perturbations of SC but the strength of evidence is currently incomplete: although the effects are statistically significant, there are significant technical limitations that are not adequately addressed via controls.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a valuable report that describes that ACE2 expression is upregulated by SARS-CoV-2 infection via activation of transcription factor Sp1 and inhibition of HNF4α through the PI3K/AKT pathway. Inhibition of Sp1 reduces SARS-CoV-2 infection in vitro and in an animal model. This work is solid and will be of interest to those interested in ACE2 biology and its impact in COVID-19.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The ExA-SPIM methodology developed will be important to the field of light sheet microscopy as the new technology provides an impressive field of view making it possible to image the entire expanded mouse brain at cellular and subcellular resolution. The authors provide solid evidence that mostly supports the conclusions. Certain statements were deemed to be overstating the method's capabilities, in particular, the claim of "near isotropic resolution" is not supported by the data as there is a large discrepancy between the x/y and z-resolution. Improved characterization of the new technology and a more expanded discussion of prior work would also be beneficial to the reader.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study enhances our understanding of the brain circuitry responsible for fear conditioning and provides evidence for an under-appreciated role of dopaminergic output projection from the Locus Coeruleus to the dorsal hippocampus in this fear learning. The evidence supporting the conclusion is convincing, although a direct test of dopamine release in the dorsal hippocampus from Locus Coeruleus projections during fear conditioning would strengthen the study. If done, this would likely raise the strength of the evidence to compelling. This paper is of interest to behavioural and neuroscience researchers studying learning, memory, and neural networks.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study is a useful analysis of the organization of synaptic proteins of a developing synapse in the binocular path visual system and how it is impacted by manipulations in activity. The original images collected by STORM microscopy are state-of-the-art in terms of the high-resolution view of the protein components of a synapse in intact tissue. However, the analysis is incomplete and does not fully support several of the conclusions of the study.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study has the potential to substantially advance our understanding of human locomotion in complex real-world settings. The evidence supporting the conclusions is solid, although the quantitative analysis and presentation of results lack clarity. The work will be of interest to neuroscientists, kinesiologists, computer scientists, and engineers working on human locomotion.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important work shows compelling evidence that Chandelier cells in the visual cortex receive inputs most prominently from local layer 5 pyramidal neurons, only mildly inhibit L2/3 pyramidal neurons, and respond massively to visuomotor mismatch. It also indicates that visual experience in the virtual tunnel activates a plasticity mechanism in Chandelier cells which could be due to the particular visuo-motor coupling experienced in this setting, although a specific control is lacking for this conclusion. This study will be of interest to neuroscientists involved in cortical circuits, visual processing, and predictive coding research.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides useful findings on how phonetic properties of words, i.e., their difficulty and prior knowledge, influence the outcome of targeted memory reactivation (TMR) during sleep. Unfortunately, the small sample size together with a between-subject design, renders the evidence incomplete, thus warranting future work to shed further light on the impact of TMR in language learning.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This potentially important study used single-cell whole-brain imaging of the immediate early gene Fos to identify the brain areas recruited by two anesthetics, ketamine and isoflurane. The utilization of a custom software package to align and analyze brain images for c-Fos positive cells stands out as an impressive component of the approach. The results suggest these anesthetics might induce anesthesia via different brain regions and pathways, and raw fos showed shared and distinct activation patterns after ketamine- v. isoflurane- vs. based anesthesia. However, the support for the primary conclusions is incomplete owing largely to concerns with the data transformation. The results could also be influenced by differences in route of administration between the drugs and depth of anesthesia. With these issues addressed, this paper would be of interest to preclinical and clinical scientists working with anesthetic and dissociative drugs.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study advances our understanding of the machinery that couples DNA synthesis with the deposition of histone proteins onto newly synthesized DNA. A solid array of experiments combines NMR, protein biochemistry, and in vivo analyses of Chromatin Assembly Factor-1 of fission yeast. The work is of interest to researchers in the field of chromosome/chromatin biology as well as epigenetics.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper reports useful findings regarding gut bacteria that metabolize dietary flavonoids, which can enhance, reduce, or otherwise alter the flavonoid bioactivities. With a newly developed bioinformatics tool, the authors predict bacterial species that can metabolize parts of the flavonoid tilianin. Formal proof of concept is missing, but if experimentally confirmed, the study will change the way we think about metabolism of flavonoids and would be of broad interest regarding gut bacterial metabolism. Most of the analyses are compelling, but others require further inquiry.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study uses a multi-pronged empirical and theoretical approach to advance our understanding of how differences in learning relate to differences in the ways that male versus female animals cope with urban environments, and more generally how reversal learning may benefit animals in urban habitats. The work makes an important contribution and parts of the data and analyses are solid, although several of the main claims are only partially supported or overstated and require additional support.
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www.biorxiv.org www.biorxiv.org
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eLife assessment:
This study adds a fundamental new perspective to a long-standing question: What controls the repair of photosystem II (PSII), a key process in maintaining and optimizing photosynthesis? The work supports a role for chemical modification in the recognition and subsequent degradation of a key protein subunit of PSII by a bacterial-type protease, suggesting that tryptophan oxidation of components of the photosynthetic apparatus after high light stress plays a critical role in initiating the PSII repair system. The evidence supporting the authors' conclusions is solid.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study makes use of AlphaFold2 to predict the models of tens of cohesin subcomplexes from different species. The models, which are in most cases consistent with published cohesin variants with compromised in vitro and in vivo cohesin activity, provide convincing evidence that leads to testable hypotheses of cohesin dynamics and regulation. More broadly, this study serves as an example of how to use AlphaFold2 to build models of protein complexes that involve the docking of flexible regions to globular domains.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents useful findings regarding the impact of forest cover and fragmentation on the prevalence of malaria in non-human primates. The evidence supporting the claims of the authors is, however, incomplete, as the sampling design cannot adequately address the geospatial issues that this study focuses on.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a potentially valuable investigation of water coordination in a specific kinase family with a focus on the regulation of osmosensing protein kinases. X-ray crystallographic approaches combined with functional assays are used to address the hypothesis that bound water participates in the osmosensing mechanism as an allosteric kinase inhibitor. Evidence for changes in kinase conformation and space group of the crystal as a function of added low molecular weight polyethylene glycol is solid, but there alternative interpretations for much of the other data cannot be excluded and the work thus remains incomplete. With stronger evidence and/or alternative explanations explored, the work would be of considerable interest to the kinase field as well as colleagues studying allosteric regulation of protein function.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper seeks to understand how the presentation of peptides by medullary thymic epithelial cells may be regulated by the MHCII peptide loading modulator, H2-O, and how this may affect the selection of regulatory T (Treg) cells. Further work is needed to ensure that the findings are robust: currently the analysis of data is inadequate and inconsistencies in the reported findings are not placed in context with results from other groups. The current version does not provide sufficient support for the claims regarding the effects on Treg cell selection.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study reveals ELF3 as a putative candidate driver of luminal progenitor (LP) transformation. Up-regulation of ELF3 during replicative stress conditions and in BRCA1 deficient cells may permit cell proliferation by suppressing genome instability. While the hypothesis is compelling, the experimental support is still incomplete, as it does not adequately demonstrate the role of ELF3 in LP cells per se. The mechanistic underpinnings by which ELF3 promotes cell tolerance to DNA damage were not fully explored either. With improvements, the work has the potential to enhance our understanding of how BRCA1 deficiency fuels LP transformation and thereby breast tumorigenesis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a fundamental study into human spinal neurulation, which substantially advances our understanding of human neural tube closure. Crucial unanswered questions in the field currently rely on model systems, not faithful to human development. The evidence provided is convincing, with a large number of specimens and the use of state-of-the-art methodology providing robustness. The work will be of broad interest to developmental biologists, embryologists, and medical professionals working on neural tube defects, and will act as a precious reference resource for future studies.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
The reviewers believe that this study provides valuable insights into understanding bone fragility in T2D patients through the use of human samples, laying the groundwork for future research. The employed methods were solid, demonstrating the feasibility of studying human samples. However, reviewers identified some minor weaknesses in the form of a limited number of subjects and a relatively small set of genes included in the analysis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study investigated the regulatory role of Mecp2 in quiescence exit during cell cycle progression. The study is significant since it provided fundamental insights into the mechanism controlling the cell cycle process. The evidence is convincing since the authors have presented experimental data from in vitro cell culture and in vivo injury-induced liver regeneration to support their conclusion.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The study's results offer a fundamental insight into how ACC1-mediated fatty-acid synthesis affects the survival and pathogenicity of iNKT cells in allergic asthma. The inclusion of mouse models, involving genetic adjustments and reconstitution experiments, along with the disparities found in iNKT cells between allergic asthma patients and control subjects in human studies, adds compelling evidence that substantiates these findings.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The strength of this important study is that it provides compelling evidence in several biological models, including Xenopus embryos, that Wnt3a increases macropinocytosis and that PMA increases this cellular response. This novel link between Wnt, focal adhesions, lysosomes, and macropinocytosis will be very interesting for cell and tumor biologists. In future work, it will be good to identify the underlying mechanism, i.e., the molecular node whereby this interaction occurs.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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eLife assessment
Drosophila is a powerful model organism for understanding the molecular and neural regulation of sleep. However, methodological limitations exist that would appear to limit the relevance of work done in the fly to our understanding of mammalian sleep. In this important work, the authors provide physiological, behavioral, and molecular evidence for the existence of two potential sleep stages in Drosophila. The experiments are generally well conducted and the authors' interpretations of their results are solid overall. Although technically innovative and conceptually provocative, there are aspects of the approaches used and results obtained that leave the central conclusions open to interpretation.
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eLife assessment
This behavioral modeling study investigates how humans make decisions on the difficulty of perceptual categorization tasks. The study finds that such judgments are best described by an evidence-accumulation model that includes a dynamic comparison of difficulty-related evidence, which terminates when the difference in evidence between two tasks reaches a predetermined bound – a valuable finding for research in perceptual decision-making. The paper provides compelling behavioral evidence for the proposed model through: 1) quantitative model selection/validation procedures, and 2) qualitative analyses of the relation between the optimal model of the task and the human data (and the proposed model).
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides valuable insights into the role of two under-researched sperm-specific proteins (Cylicin 1 and Cylicin 2). The authors provide convincing evidence that they have an essential role in sperm head structure during spermatogenesis, and that their loss leads to subfertility or infertility, with a dose-dependent phenotype. Importantly, the authors identify infertile males with mutations in both Cylicin1 and Cylicin2. Thus, the findings from the mouse models might be applicable to understanding human male infertility with similar structural defects.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work presents H3-OPT, a deep learning method that effectively combines existing techniques for the prediction of antibody structure. This work is important because the method can aid the design of antibodies, which are key tools in many research and industrial applications. The experiments for validation are solid, although several points remain partially unclear, such as (1) which examples constitute proper validation, (2) what the relevance of the molecular dynamics calculations as performed is, (3) the statistics for some of the comparisons, and (4) the lack of comparison with other existing methods.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study provides an example of integrating computational and experimental approaches that lead to new insights into the energy landscape of a model kinase. Compelling use of molecular dynamics simulations and NMR spectroscopy provide a conformational description of active and excited states of the kinase; one of which has not been captured in previously solved crystal structures. Overall, this comprehensive study expands our understanding of the architecture and allosteric features of the conserved bilobal kinase domain structure.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Tissue phenotyping is central to nearly all areas of biology. In this study, the authors use an advanced form of micro-CT (X-ray histotomography) in zebrafish to phenotype blood cells in the intact animal. These approaches build upon prior work from this group and others showing this is a scalable imaging method that could readily be applied to other cell types, and provide an excellent complement to histological analysis of tissues. This is important work, as it demonstrates that the method can provide an approach that is orthogonal to conventional histology. The strength of the presented data is compelling, with description of both the hardware and software needed to implement the protocol, which will make it accessible to other researchers in the field.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper will be of significant interest to the research community working on cytoplasmic transport and microtubule motors, offering important insights into the structural arrangement of autoinhibited Kinesin-1. The paper reports a structural model of full-length kinesin-1 describing its autoinhibitory mechanism using cryo-EM, Alphafold structural predictions, cross-linking, and mass spectrometry. The data are of high quality and together offer a compelling model for how Kinesin-1 is autoinhibited, indicating that auto-inhibition does not rely on the IAK motif alone but on a more extensive intramolecular interface.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a valuable contribution to our understanding of how some bacteria can transport sterols from the cytoplasm to the outer membrane. Though much remains to be tested and explored, the data and analyses presented here provide solid evidence for the genetic and physical interaction of BstA/B/C with bacterially-produced sterols. The manuscript will be of interest to scientists focusing on the characterization of novel bacterial proteins and those studying lipid transport and acquisition in bacterial pathogens.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study informs whether diminishing BDNF expression or alterations in the activity of BDNF-containing neurons in the paraventricular nucleus of the hypothalamus contributes to metabolic alterations in individuals with reduced RAI1 function, including those afflicted with Smith-Magenis syndrome (SMS). The evidence supporting the conclusions is compelling in that RAI1 deficits in BDNF-containing neurons partly contribute, with prominent effects on glycemic control and modest effects on feeding and body weight regulation. This study would be of interest to neuroscientists and medical biologists working on metabolic disorders such as obesity and diabetes, as the findings in this study further links SMS-associated obesity with reduced Bdnf gene expression in the PVH and shed light on the role of the Rai1 gene in the PVH Bdnf neurons and offer a basis for future therapeutic strategies for managing obesity in SMS.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study reports an investigation of ZC3H11A as a cause of high myopia through the analysis of human data and experiments with genetic knockout of Zc3h11a in mice, providing a model of myopia. The evidence supporting the conclusions is currently incomplete. It could be strengthened by a more thorough genetic analysis, fuller presentation of human phenotypic data, and more explanation for the reasons why there was no increased axial length in mice with myopia. The work will be of interest to ophthalmologists and researchers working on myopia.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper addresses a fundamental issue in the field of autophagy: How is a protein responsible for autophagosome-lysosome fusion recruited to mature autophagosomes but not immature ones? The work succeeds in its ambition to provide a new conceptual advance. The evidence supporting the conclusions is convincing, with solid fluorescence microscopy, biochemical assays, and molecular dynamics simulations. This work will be of broad interest not only to cell biologists and biochemists studying autophagy but also those focusing on lipid/membrane biology.
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eLife assessment
This valuable study employs advanced imaging techniques to directly visualize molecular dynamics and presents valuable findings on the regulation of the immune receptor kinase FLS2 organization in specific microenvironments. The evidence supporting the ligand-induced association with remorin and the requirement of a previously reported phosphosite is solid, although it remains unknown whether this phosphorylation is induced by the ligand. The manuscript would be improved with a more adequate description of plant immune signaling, and better presentation of the data in the context of previous work with appropriate references. The work will be of interest to plant biologists working on cell surface receptors.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study uses specific and robust genetic approaches to assess mechanisms of kainic acid-induced neurogenesis. This is a fundamental study that bridges several complementary methods and is a convincing use of existing approaches to explore roles for sonic hedgehog in activity-dependent and aging-associated hippocampal neurogenesis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful manuscript challenges the utility of current paradigms for estimating brain-age with magnetic resonance imaging measures, but presents inadequate evidence to support the suggestion that an alternative approach focused on predicting cognition is more useful. The paper would benefit from a clearer explication of the methods and a more critical evaluation of the conceptual basis of the different models. This work will be of interest to researchers working on brain-age and related models.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors aim to elucidate the mechanism by which pyroptosis contributes to the increased release of procoagulant tissue factor-containing microvesicles. The data are intriguing and attempt to shed light on the mechanism by which GSDMD plays a role in releasing tissue factor-containing microvesicles, albeit incomplete. The manuscript offers valuable information to unveil new therapeutic targets in human diseases such as sepsis, which can be further strengthened by consulting the reviewers' suggestions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable finding on the relationship between a high protein diet and resistance exercise on fat accumulation and glucose homeostasis. The evidence supporting the claims of the authors is solid, although the inclusion of mechanistic insight would have strengthened the study. The work will be of interest to dieticians, diabetologists, and exercise biologists working to understand the link between dietary protein, insulin resistance, and physical activity.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The manuscript analyses the mechanism of action of small compounds that target the WDR5 chromatin protein for tumor therapy. They study a class of compounds termed WIN site inhibitors and show that they affect the expression of ribosome protein genes (RPGs) and cause ribosomal stress, ultimately activating the TP53 tumor suppressor protein. The manuscript provides important insight into the mode of action of these interesting compounds. The evidence is convincing, with a few exceptions detailed in the reviewers' comments.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This study presents an important finding that implicates a rhodopsin gene duplication in the progression of autosomal dominant retinitis pigmentosa in patients. The authors utilize a retinal organoid model to demonstrate a similar disease phenotype and suggest defects can be ameliorated by using photoregulin. However, the data are incomplete and require additional controls and analyses to support their conclusions. If validated the work will be of broad interest to vision researchers.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Bladder dysfunction following spinal cord injury (SCI) represents a severe and disabling complication and we lack effective therapies. Following evidence that AMPA receptors play a key role in bladder function the authors show convincingly that AMPA allosteric activators can ameliorate many of the subacute defects in bladder and sphincter function following SCI, including prolonged voiding intervals and high bladder pressure thresholds for voiding. These valuable results in rodents may help in the development of these agents as therapeutics for humans with SCI-induced bladder dysfunction.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study used a modified PyMT model to investigate whether increased rRNA synthesis provides a therapeutic opportunity to target chemoresistance. The evidence supporting the claims of the authors is solid, although the use of a more rigorous approach to capture all the relevant events during the EMT process would have strengthened the study. The work will be of interest to clinicians or cancer biologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors report the cryo-EM structure of human vesicular monoamine transporter 2 (VMAT2) bound to the noncompetitive inhibitor tetrabenazine (in an occluded state). This important achievement captures the structure of an major facilitator superfamily (MFS) transporter that is critical for human neurotransmission. The evidence for the structure is solid, but there are several concerns regarding the mechanistic insights into the transport mechanism, which make the study more descriptive than explanatory.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
The manuscript by Bull et al provides valuable information on the relationship between metabolic features, in particular different lipoproteins and fatty acids, and colorectal cancer. They use solid methods and combine different data sources to analyze forward and reverse Mendelian Randomizations that support their claims.
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eLife assessment
Erbacher et al. have used new techniques to explore the neuro-cutaneous structures of human epidermis, which is a valuable goal given the lack of in-depth studies in human skin. Human skin is less studied than rodent skin because it presents challenges in obtaining samples and finding excellent immunohistological labels. They have employed expansion microscopy and super-resolution array tomography for histological studies and have developed a human keratinocyte and human iPSC-derived sensory neuron co-culture
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www.biorxiv.org www.biorxiv.org
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eLife assessment:
Interoceptive signals from internal organs activate neurons in the nucleus tractus solitarius (NTS) to help maintain homeostasis. The authors of this paper use gain-of-function and loss-of-function experiments to examine three distinct NTS neuronal populations, individually and in combination, and find that activating (or inhibiting) combinations of these neurons have more robust effects on food intake and body weight than activating (or inhibiting) them individually. The results of this paper are convincing and solid but do not provide mechanistic insights.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Retinal ganglion cells which are intrinsically photosensitive play important and emerging physiological roles. The mechanisms of phototransduction are still not well known and there exists a controversy regarding the ion channels responsible for the photocurrent. The authors of this manuscript present data that can contribute to understanding the actual ionic mechanisms in two of these cell types. This manuscript will be of general interest to biologists and neuroscientists and should help resolve a major issue in retinal physiology.
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eLife assessment
This prospective study advances our understanding of the predictive role of circulating tumor DNA (ctDNA) in the prognosis and of patients with mTNBC as well as other cancers. The evidence supporting the conclusions is convincing with rigorous analysis of the association between ctDNA (ctDNA-positive or not) with the progression-free survival (PFS) of patients. However, there are a few areas in which the article may be improved through further analysis of the clinical outcome and elaboration of the prospective study (i.e., the inclusion and exclusion criteria of the patients). The work will be of broad interest to clinicians, medical researchers and scientists working in cancers.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study demonstrates that the orbitofrontal cortex is causally involved in the detection of local auditory prediction errors. The methods and procedures are convincing, although the precise functional meaning of the reported effects remains to be specified. This work is of interest to neuropsychologists and cognitive neuroscientists working on the prefrontal cortex, predictive processing, auditory perception, and electrophysiology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper is of interest to cell biologists studying the mechanisms of protein posttranslational modifications. The study investigates Cullin-RING ubiquitin E3 ligases (CRLs) that regulate cyclin D1 protein stability in cells by utilizing siRNA screening and ectopic expression approaches. By screening a siRNA library containing different E3 ligases, the authors identified a previously uncharacterized combination of Cullin 1-7 and associated E3 ligases (Keap1-CUL3, DDB2-CUL4A/4B, WSB2-CUL2/5, and RBX1-CUL1-7) that are important for cyclin D1 ubiquitination and proteasome-mediated degradation.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This study presents a valuable finding of a novel combinatory regimen which integrate immunotherapy, radiotherapy and chemotherapy in the current refractory triple negative breast cancer. The evidence supporting the claims of the authors is solid, although inclusion of a larger number of patient samples would have strengthened the study. The work will be of interest to Clinicians working on breast cancer.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study provides solid evidence implicating two transcription factors in the development of the actin cytoskeleton that shapes the mechanosensory hair bundles of the inner ear's hair cells. The work will be of interest to biologists interested in the development and maintenance of the hair bundle, both normal or impaired. Its impact would be improved by providing a mechanistic model for the observed effects.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study examines the expression of HDAC3 within DC compartment. Taking advantage of tamoxifen inducible ERT2-cre mouse model they observe the dependency of pDCs but not cDCs on HDAC3. The requirement of this histone modifier appears to occur during development around the CLP stage. Tamoxifen treated mice lack almost all pDC besides lymphoid progenitors. RNA seq studies identify multiple DC specific target genes within the remaining pDC - using Cut and Tag technology they validate some of the identified targets of HDAC3. Taken together, this study shows the requirement of HDAC3 on pDC but not cDC, congruent with the recent findings of a lymphoid origin of pDC.
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