- Nov 2023
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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.
Tags
Annotators
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable work by Rivera et al. probes to understand how the regulation of oligodendrocyte progenitor cell (OPC) remyelination and function contributes to the treatment of multiple sclerosis. The authors provide incomplete evidence for the platelets to mediate OPC differentiation and remyelination. Both reviewers have raised important questions. This work will be of broad interest to biologists in general.
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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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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 manuscript provides a convincing review of 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 manuscript describes an important web resource for kinases connected to cytokines. The compelling information will be highly useful to researchers across a number of fields including analysts, modelers, and wet lab experimentalists - and clinician-researchers - who are looking to improve our understanding of pathologies and means to correct them through modulating the immune response.
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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.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study offers a compelling molecular model for the organization of rootlets, a critical organelle that links cilia to the basal body, ensuring proper anchoring. While previous research has explored rootlet structure and organization, this study delivers an unprecedented level of resolution, important to the centrosome and cilia field. The model proposed by the authors will serve as a reference 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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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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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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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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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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www.medrxiv.org www.medrxiv.org
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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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www.biorxiv.org www.biorxiv.org
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eLife assessment
These authors present a powerful tool to unbiasedly identify lysosome-associated proteins in C. elegans, and they provide a compelling, in-depth assessment of how this method can be used to understand longevity pathways and identify novel proteins. Understanding lysosomal differences in specific tissues or in response to different longevity conditions are exciting as it provides new insight into how organelles could control specific homeostasis responses. This valuable tool and proteomics datasets also represent a great resource for the C. elegans community and should pry open new studies on the regulation and role of the lysosome at the organismal level.
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www.biorxiv.org www.biorxiv.org
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**Editors Assessment: **
Irises on top of being a popular and beautiful ornamental plant, have wider commercial interest due to the many interesting secondary metabolites present in their rhizomes that have value to the fragrance and pharmaceutical industries. Many of these have large and difficult to assemble genomes, and to fill that gap the Dalmatian Iris (Iris pallida Lam.) is sequenced here. Using PacBio long-read sequencing and bionano optical mapping to produce a giant 10Gbp assembly with a scaffold N50 of 14.34 Mbp. The authors didn’t manage to handle the haplotigs separately or to study the ploidy, but as all of the data is available for reuse others can explore these questions further. This reference genome should also allow researchers to study the biosynthesis of these secondary metabolites in much greater detail, opening new avenues of investigation for drug discovery and fragrance formulations.
This evaluation refers to version 1 of the preprint
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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 work 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 important study provides convincing data in support of the conclusion that weak but not strong fear memories are more easily modified using behavioural and pharmacological approaches potentially as a result of differential connectivity with the amygdala showing greater connectivity through the brain in weak compared to strong memories. The scope of the paper would be strengthened if both sexes were examined and more varied definitions of weak vs. strong memories were used. This paper is of interest to behavioural and neuroscience researchers studying learning, memory, and/or neural networks.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The manuscript offers important findings on the potential influence of maternally derived extracellular vesicles on embryo metabolism. However, while the content is convincing, the title appears to overstate the study's conclusions due to its speculative nature on the DNA transmission and embryo bioenergetics connection. A more measured title would better represent the evidence presented.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Birman et al. present a valuable software interface, Pinpoint, for planning anatomically precise insertions of rigid instruments (e.g., electrodes, injection needles/pipettes, fibre optic implants) into the mouse brain. The authors provide compelling evidence of the potential of this software since, it: (1) incorporates the geometrical constraints of the rig and instruments; (2) interfaces with popular manipulator systems and data acquisition software; (3) runs on any browser; and (4) allows for easy collaboration among users. Despite these exciting features, quantification of the gains in experimental efficiency and accuracy derived from Pinpoint is needed.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important paper examining the relationship between ventral tegmental area dopamine activity and the activity of lateral hypothalamic orexin neurons in the context of reward learning. However, whereas the photometry imaging data are compelling, the functional links to behavior are incomplete since the necessity for dopamine-mediated orexin neuron recruitment in the hypothalamus to the observed behavioral effects is not unambiguously demonstrated. The study expands current notions of dopaminergic function and will be of broad general interest to those interested in reward related behaviors, learning, dopamine, lateral hypothalamus, or orexin function.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable findings on the relationship between prediction error and brain activation in response to unexpected omissions of painful electric shock. The strengths are the research question posed, as it has remained unresolved if prediction errors in the context of biologically aversive outcomes resemble reward-based prediction errors. The evidence is incomplete due to the task design, which induces a disconnect between verbal instructions and experiential learning, and the lack of analyses accounting for learning and updating of expectations, which are crucial to neural prediction error signaling. The work will be of interest to cognitive neuroscientists and psychologists studying appetitive and aversive learning.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study introduces an innovative method for measuring interocular suppression depth, which implicates mechanisms underlying subconscious visual processing. The evidence supporting the effectiveness of this method would be solid after successfully addressing concerns raised by the reviewers. The novel method will be of interest not only to cognitive psychologists and neuroscientists who study sensation and perception but also to philosophers who work on theories of consciousness.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper studies how amacrine cells influence retinal output signals. The approach taken is unusually direct and has the potential to make important contributions to our understanding of amacrine cells, and more generally interneurons, to circuit function. The contributions of the work described, however, are limited by several key concerns. Specifically, the results rely heavily on assumptions made about how signals traverse the retina; as a result, the evidence for adequate separation of signals contributed by the amacrine cells and those from other parallel retinal pathways is incomplete.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study presented a series of results to uncover the role of C-terminal half of the Syx1 SNARE domain. The evidence supporting the conclusions is solid, although more mechanisms in the study would have strengthened the work. The paper will be of interest to biophysicists and neurobiologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study used fMRI in an animal that simulates a type of epilepsy to ask if the responsiveness of the brain was altered during a seizure. The results suggest that the brain responsiveness is reduced during the seizures. The significance of the findings is useful and the strength of the evidence is incomplete but could be strengthened after additional experiments.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This report details convincing evidence that experience with multilingualism in general, and with larger phonological inventories specifically, is related to differences in the structure of the transverse temporal gyri. The project is notable for using a relatively large sample, and confirming the primary finding in a smaller sample. Although results are sometimes slightly counterintuitive (both increases and decreases in cortical thickness are related to experience with multilingualism), the important findings strongly point to experience-dependent plasticity related to language experience as a driver of neuroanatomy of the auditory cortex.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript describes useful data on the mechanisms underlying the activation of the receptor tyrosine kinase FGFR1 and stimulation of intracellular signaling pathways in response to FGF4, FGF8, or FGF9 binding to the extracellular domain of FGFR1. Solid evidence for quantitative differences in the downstream responses induced by the three ligands is presented. This manuscript will be of interest to biochemists and cell biologists working on receptor tyrosine kinases and general cell signalling across membranes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors developed a fundamental tool to improve our understanding of tissue-specific activation of Free Fatty Acid receptor 2 (FFA2). Convincing in vitro and in vivo validation of the tool is presented via the development of new antibody reagents that constitute an important advance in the field. Some of the technical details could be presented more clearly.
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www.biorxiv.org www.biorxiv.org
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eLife assessment:
This study presents valuable findings on the impact of C-natriuretic peptide (CNP) treatment in vivo on the fertility of aged mice. Solid data indicate CNP induces the cAMP-PKA pathway, causing reduced recruitment of Parkin protein to mitochondria in oocytes, resulting in reduced mitophagy, which may be significant for increased mitochondrial bioenergetics and improved cytoplasmic and nuclear maturation. The authors make additional claims regarding the mechanisms by which CNP impacts oocyte quality in vivo for which the evidence is inconclusive. This work will be of interest to reproductive biologists and clinical infertility specialists.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This important study will provide evidence about a novel screen-triage-treat strategy for cervical cancer prevention. The strategy would contribute to improving access to cervical cancer prevention to vulnerable women with low access to health care, and, therefore, at the highest risk of cervical cancer. However, the current protocol description is currently incomplete and missing key information for clarity and reproducibility.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important study that uses chromatin accessibility as a measure to determine the impact of neuronal activity on the state of chromatin regulatory elements in striatal neurons. The authors provide convincing evidence of how Pdyn gene expression is highly dependent on a distal regulatory genomic region both at basal and upon neuronal activation in this particular system, a mechanism conserved as well in human neuronal cells. Although the basic idea of accessibility changes have been studied before, this paper ties previous findings all together in one place and uses the analysis to identify a functionally relevant and conserved enhancer for the prodynorphin gene with potential relevance for neuropsychiatric disorders beyond basic cellular neuroscience. The study will be of interest to neuroscientists studying the striatum, neuronal plasticity, or related neuropsychiatric disorders.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study is useful in identifying several gain-of-function division variants that can suppress the elongated cell division defect phenotype caused by the depletion of Age1 (or AdvA as named in other studies), a known essential cell division protein in Acinetobacter baumannii. However, characterizations of AdvA's localization patterns and its interactions with other divisome proteins are incomplete due to the lack of (1) functional characterizations of fluorescent fusion proteins, (2) considerations for membrane protein topology in the bacterial two hybrid assay, and (3) lack of high-quality fluorescence images for the co-localization studies. The results do not yet support the major claim that Age1 plays a critical role in the assembly of the A. baumannii divisome.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study presents convincing evidence on how the sea slug Aplysia kurodai optimizes its digestion of brown algae, in a classical predator-prey 'arms race' at the molecular level. The experimental protein structures and enzyme assays provide support for the claims of how the A. kurodai avoids inhibition by algal compounds, and also hold promise for biotechnological applications.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study presents convincing evidence on how the sea slug Aplysia kurodai optimizes its digestion of brown algae, in a classical predator-prey 'arms race' at the molecular level. The experimental protein structures and enzyme assays provide support for the claims of how A. kurodai avoids inhibition by algal compounds, and also hold promise for biotechnological applications.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. Although the strength of the evidence supporting these claims is compelling, the authors do not discuss how their results affect our understanding of insect nest construction or animal-built structures more broadly.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study presents an exhaustive structural analysis of a complete tripartite HipBST toxin-antitoxin system of the Enteropathogenic E. coli O127:H6, which represents a fascinating variation on the well-studied HipAB toxin-antitoxin system. The convincing data show that major features of the canonical HipAB system have been rerouted to form the tripartite HipBST, revealing a new mode of inhibition of a toxin kinase.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study demonstrates use of the mammalian Musashi-1 (MSI-1) RNA-binding protein as a tool for regulating gene expression in Escherichia coli. The system could also be used for mechanistic studies of MSI-1. The authors provide solid evidence that MSI-1 functions as an effective repressor that acts post-transcriptionally. The impact of MSI-1 as a synthetic biology tool could be strengthened by expanding the analysis of MSI-1's allosteric regulation by oleic acid. The work will be of interest to synthetic biologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important study that develops a new model of the way muscle responds to perturbations, synthesizing models of how it responds to small and large perturbations, both of which are important to predict how muscles function for stability but also how they can be injured. The evidence presented to support the model is solid, but the work is incomplete as it is particularly lacking a more detailed analysis of the trade-offs associated with using the model to simulate different types of preparations, especially single muscle fibers compared to whole muscles or whole muscles and tendons. With a clearer discussion of the limitations of the model and the situations in which it is best applied, the work will be of interest to those developing realistic models of the stability and control of movement in humans or other animals.
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www.biorxiv.org www.biorxiv.org
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eLife assessment:
This important study combines molecular genetics and target validation to discover genes involved in obesity and determine their role. The reviewers unanimously agree that the work is important in terms of significance: it has conceptual and practical implications beyond metabolism, including embryonic and placental development. They also considered that the strength of evidence is convincing from the use of their forward genetic screen in mice. In some instances, reviewers considered that the work was not more than solid because although the methods, data, and analyses broadly support the claims, minor weaknesses emerge on which they suggest improvements for you to consider and selectively address.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work reports a valuable finding on glucocorticoid signaling in male and female germ cells in mice, pointing out sexual dimorphism in transcriptomic responsiveness. While the evidence supporting the claims is generally solid, additional assessments would be required to fully confirm an inert GR signaling despite the presence of GR in the female germline and GR-mediated alternative splicing in response to dexamethasone treatment in the male germline. The work may interest basic researchers and physician-scientists working on reproduction and stress-related disease conditions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study enhances our understanding of the effects of landscape context on grassland plant diversity and biomass. Notably, the authors use a well-designed field sampling method to separate the effects of habitat loss and fragmentation per se. Most of the data and analyses provide solid support for the findings that habitat loss weakens the positive relationship between grassland plant richness and biomass.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides useful insights into the subcellular localization, interaction with integrins, and function of the cell surface receptor Piezo1 in migrating human T-cells. The data collected is convincing but incomplete. Therefore the idea that Piezo1 is critically sensing mechano-physical cues during T-cell migration is not well supported by direct experimental evidence.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides valuable insight into the role of miR-199a/b-5p in cartilage formation. The evidence supporting the significance of the identified miRNA and its target mRNA transcripts is convincing, however further experiments and a broader contextual analysis are warranted to draw a more robust conclusion. This paper will likely primarily benefit scientists focused on diseases related to this biological process, such as osteoarthritis. Furthermore, researchers interested in miRNAs as a broader subject may find the computational model development methodology useful.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study substantially advances our understanding of mechanisms of TRABID pathogenic patient mutations, studied in vitro and in vivo during neurodevelopment. The evidence supporting the conclusions is compelling with rigorous biochemical and state of the art imaging approaches. The work will be of interest to cell biologists, neuroscientists and clinical neurologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study reports a novel measurement for the chemotactic response to potassium by Escherichia coli. The authors convincingly demonstrate that these bacteria exhibit an attractant response to potassium and connect this to changes in intracellular pH level. However, some experimental results are incomplete, with additional controls/alternate measurements required to support the conclusions. The work will be of interest to those studying bacterial signalling and response to environmental cues.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study addresses the temporal patterning of a specific Drosophila CNS neuroblast lineage, focusing on its larval development. The work is solid: the authors find that a temporal cascade, involving the Imp and Syp genes, changes the fate of one daughter cell/branch from glioblast (GB) to programmed cell death (PCD), as well as gates the decommissioning of the NB at the end of neurogenesis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental work substantially advances our understanding of cell migration, especially in that of cranial neural crest. The evidence supporting the conclusion is compelling, with rigorous biochemical assays for materials used and with intensive genetic interventions. The work will be of broad interest to developmental biologists and cell biologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript examines shared and divergent mechanisms of disruptions of five different mTOR pathway genes on embryonic mouse brain neuronal development. The significance of the manuscript is important, because it bridges several different genetic causes of focal malformations of cortical development. The strength of evidence is compelling, relying on both gain and loss of function, demonstrating differential impact on excitatory synaptic activity, conferring gene-specific mechanisms of hyperexcitability. The results have both theoretical and practical implications for the field of developmental neurobiology and clinical epilepsy.
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arxiv.org arxiv.org
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eLife assessment
The present study offers valuable insights into the emergence of oscillations in neural networks. It underscores the importance of achieving a delicate balance between excitatory and inhibitory links and deals with the topological conditions for oscillations providing incomplete evidence for the observed features. It employs formal mathematical proofs and advanced computational simulations, providing insights for researchers in the field of neural dynamics and network behavior.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors report that an interaction between the sodium-activated potassium channel Slack and Nav1.6 sensitizes Slack to inhibition by quinidine. This is an important finding because it contributes to our understanding of how the antiseizure drug quinidine affects epilepsy syndromes arising from mutations in the Slack-encoding gene KCNT1. The results are largely compelling, although additional data would strengthen the claims of a direct channel-channel interaction in neuronal cell membranes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study demonstrates that disrupting a common protein-folding system restores sensitivity to antibiotics in drug-resistant clinical bacterial pathogens. Although some additional controls would be welcome, the work is overall convincing in showing that targeting protein folding can be used to combat multi-drug resistant pathogens, both by potentiating the efficacy of existing drugs and by therapeutic use of small-molecule inhibitors. This study is significant and timely as it furnishes a new strategy that is relevant to microbiologists and clinicians interested in combating antimicrobial resistance.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study advances our understanding of nitrogen metabolism by identifying a new type of guanidine forming enzyme in eukaryotes. The evidence supporting this pioneering research is convincing, with rigorous biochemical, cellular, and in vivo experiments.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper presents an important discovery of the molecular basis of differential apterous expression during early Drosophila wing disc development. The evidence supporting these conclusions is compelling, ranging from classical genetic approaches to state-of-the-art genetic engineering techniques. By opening new questions, this paper is expected to be of broad interest to developmental biologists and geneticists working on transcriptional regulation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study draws attention to the importance of a previously overlooked structural motif in kinase regulation. While the data presented are intriguing, the analysis is incomplete. Additional experiments are needed to support the authors' hypothesis. The work will be of interest to protein biochemists and enzymologists with an interest in kinases and allostery.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study develops an important method for dissecting out two overlapping cell signaling pathways, phosphoinositide signaling and membrane protein trafficking. The combination of two state-of-the-art techniques provides compelling evidence for a reciprocal influence between an enzyme and a channel. The work will be of interest to the broader cell biology, biophysics and biochemistry communities.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable finding on the key factors of T cell responses associated with durable antibody responses following COVID-19 mRNA vaccinations. The data were collected with solid methods and approaches, but the interpretation of the conclusion may be biased due to the experimental design. If confirmed, it may have a great impact on future COVID-19 vaccine design. However, some of the evidence supporting the claims of the authors is incomplete with a small size of the samples, unproven validity of using the expanded T cells, and over-interpretation on the sequence homology data.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This paper is important because of its integration of movement and contextual information to control a virtual arm for individuals with upper-limb differences. The provided evidence convincingly demonstrates the approach's feasibility for manipulating a single object shape in different orientations within a virtual environment. However, additional improvements are needed for this proof-of-concept neuro-model to fulfil practical requirements.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a new and valuable theoretical account of spatial representational drift in the hippocampus. The evidence supporting the claims is convincing, with a clear and accessible explanation of the phenomenon. Overall, this study will likely attract researchers exploring learning and representation in both biological and artificial neural networks.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable work fills a gap in the mapping of gene expression patterns in the early embryo of C. elegans. The presented data are solid and provides a resource for future analysis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a valuable study of the molecular basis of summer-to-winter transition in the pear psyllid pest, Cacopsylla chinensis (hemiptera). The molecular and organismal experiments using current methodologies to evaluate the cold responsiveness of the target proteins are mostly convincing, but the structural and phylogenetic analyses remain inconclusive. The results of this study will be of interest to entomologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Linker histone variants are prevalent throughout the eukaryotic lineage, but their specific roles in shaping chromatin structure are not well elucidated as antibodies did not exist to study these variant H1s. This useful study provides for a solid advance by addressing where these variants are localized in the human nucleus, finding specific enrichment that might shed light on their function. The work could benefit from a deeper functional dissection and some additional controls to independently validate the localization patterns observed. The findings will be of interest for the chromatin field.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable methodological development, which combines light (confocal) microscopy with high-resolution scanning EM and EM tomography, expands the level of structural detail accessible to large-volume EM studies and thus represents an approach to integrate the analyses of cellular and sub-cellular levels in biological samples. The data provide a convincing proof-of-principle. They will be of particular value to cell biologists interested in the in-depth interpretation of high-resolution ultrastructural information from sparsely distributed targets - at multiple scales and in diverse biological structures.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental work substantially advances our structural understanding of S-layers in Archaea and how they are built to form formidable cell support structures able to stabilise the cytoplasmic membrane under harsh physicochemical conditions. The supporting evidence for the S-layer model is convincing, making excellent use of state-of-the-art 3D cryo-electron tomography reconstructions, although the proposed S-layer model would benefit from some additional validation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript reports important findings in the field of developmental neurobiology, particularly in our understanding of human cortical development. The methods, data, and analyses are solid yet, the lack of clonal resolution or timelapse imaging makes it hard to assess whether the inheritance of centrosomes occurs as the authors claim.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable finding that erythrocyte precursors could re-gain EPO responsiveness after DFP chelation therapy. In addition, the authors investigated iron trafficking in erythroblasts using the MDS mouse model. However, the evidence supporting the claims of the authors is still inadequate. The work will be of interest to medical biologists working on hematology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study transcriptomically profiles the developing zebrafish hindbrain from gastrulation through stages of rhombomere formation. The strength is that the transcriptomic data will be a valuable resource to the field. The paper would profit from a deeper analysis of functional aspects of hindbrain development during its segmentation into rhombomeres.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript posits a novel role for the anterior cingulate cortex (ACC) in coding for sequential action strategies and the prevalence of each strategy. These findings provide important insight into ACC function and will therefore be of broad interest within the field of cognitive neuroscience. The evidence supporting the primary hypothesis is currently incomplete but could be rendered convincing with some further effort to rule out potential confounding factors.
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psyarxiv.com psyarxiv.com
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eLife assessment
This well-written and well-reasoned manuscript describes a behavioral and computational modeling study designed to understand pure exploration, where action selection is driven by pure information seeking and not rewards. Using a novel task, the authors find that a subset of people use information value to drive their selection behavior, consistent with a simple information maximization model of reinforcement learning. The rest of the participants did not exhibit this behavior. This valuable work provides intriguing, yet somewhat incomplete, insights into understanding directed exploration and its computational form.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important study because it provides evidence that specific neuronal firing patterns in deep cerebellar nuclei map onto specific behavioral movement disorder phenotypes. The optogenetic manipulations and resulting neuronal and behavioral outcomes are highly compelling, but the development of the classifier tool was incomplete. This study contributes to the fields of cerebellar physiology and movement disorders because it puts forth a map of relationships between neuronal firing patterns and multiple distinct movement phenomena, providing a comprehensive, potentially fundamental, view that goes beyond most studies which typically examine one phenomenon in isolation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The manuscript from Richter et al. is a very thorough anatomical description of the external sensory organs in Drosophila larvae. It represents an important tool for investigating the relationship between the structure and function of sensory organs. Using improved electron microscopy analysis and digital modeling, the authors provide compelling evidence offering the basis for molecular and functional studies to decipher the sensory strategies of larvae to navigate through their environment.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work presents important findings for the field of Alzheimer's disease, especially for the electrophysiology subfield, by investigating the temporal evolution of different disease stages typically reported using M/EEG markers of resting-state brain activity. The evidence supporting the conclusions is solid and the methodology as well as the descriptions of the processes are of high quality, although a separation of individuals who are biomarker positive versus negative would have strengthened the interpretability of the results and the conclusions of the study.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Lee and colleagues examined how neural representations are transformed between the olfactory tubercle (OT) and the ventral pallidum (VP) using single neuron calcium imaging in head-fixed animals trained in classical conditioning. They show that the dimensionality of neural responses is lower in the VP than in the OT. The study provides important results, and the data are overall solid although the reviewers thought some of the conclusions are not fully supported by the data and overstated, including the main conclusion that the OT neurons primarily encode odor identity but not value.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important study that provides detailed insights into the morphology of the lateral parietal cortex. Through this work new shallow sulci in the parietal cortex were identified and linked to function and behaviour. The evidence presented is convincing, even though some claims about the definition of highly variable sulci should be tampered down, and some important precisions about the labelling process are lacking to secure reproducibility. The present work both advances our understanding of the parietal cortex while also stimulating further debate on precise, detailed manual anatomy vs large scale automated data processing.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this study, the authors present convincing evidence to demonstrate theta cycle skipping by individual neurons of the lateral septum, which they then relate to population coding of future trajectories encapsulated by theta cycles. This valuable finding furthers our understanding of how the septum conveys navigational information downstream.
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