- Jan 2024
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www.medrxiv.org www.medrxiv.org
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eLife assessment
The findings in this study are useful and may have practical implications for predicting DLBCL risk subject to further validating the bioinformatics outcomes. We found the approach and data analysis solid. However, some concerns regarding the drug sensitivity prediction and the links between the selected genes for the risk scores have been raised that need to be addressed by further functional works.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study correlates the size of various prefrontal brain regions in primate species with socioecological variables like foraging distance and population density. The evidence presented is solid but needs to be strengthened with additional analyses that demonstrate the robustness of their results. It is also unclear how this approach would work in other species that show variation in socioecological variables despite lacking clear anatomical markers to define brain areas.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable manuscript reports alterations in autophagy present in dopaminergic neurons differentiated from iPSCs in patients with WDR45 mutations. The authors identified compounds that improved the defects present in mutant cells by generating isogenic iPSC without the mutation and performing an automated drug screening. The methodological approaches are solid, but the claims still need to be completed: showing the effects of the identified compounds on iron-related alterations is crucial. The effects of these drugs in vivo would be a great addition to the study.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Overall, the reviewers found the significance of the work valuable to the field of visual neuroscience, particularly given the large data set and strength of the method used that allowed for spatial analysis of neuronal responses in macaque V1. The evidence was deemed compelling, owing in part to the consistency of responses across animals and the fitness of modeling. Ways to improve the manuscript as outlined include an expanded discussion of similar prior literature and limitations of the method used to read out neuronal responses.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
These are valuable findings that support a link between low-dimensional brain network organisation, patterns of ongoing thought, and trait-level personality factors, making it relevant for researchers in the field of spontaneous cognition, personality, and neuropsychiatry. While this link is not entirely new, the paper brings to bear a rich dataset and a well-conducted study, to approach this question in a novel way. The evidence in support of the findings is convincing.
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eLife assessment
This paper provides a valuable alternative explanation for the influence of environmental volatility on learning, attributing such effects to a mixture of strategies (MoS), rather than changes in the learning rate. The authors demonstrate that the MoS model provides a superior fit to previously published data, and suggest that atypical learning in individuals with anxiety and depression might reflect their use of a suboptimal strategy. While the approach should be of interest to researchers across decision sciences, the evidence is incomplete, limiting its potential impact.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript is a fundamental contribution to the understanding of the role of intrinsically disordered proteins in circadian clocks and the potential involvement of phase separation mechanisms. The authors convincingly report on the structural and biochemical aspects and the molecular interactions of the intrinsically disordered protein FRQ. The paper will be of interest to scientists focusing on circadian clock regulation, liquid-liquid phase separation, and phosphorylation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study highlights several important regulatory pathways that contribute to the control of entry into meiosis by turning down mitotic functions. Central to this regulation is the control of Swi4 level and activity, and convincing overexpression experiments identify downstream effectors of Swi4.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important and comprehensive study describes the development of a heterobifunctional degrader, which is used to provide insights into the mechanism of TEAD proteolysis, with potential implications for signaling pathways in cancer. While the methods are solid, the analyses and descriptions are still incomplete. With further molecular refinements, experimental controls, and a more cohesive and unified story, this article will be of interest to cancer biologists and scientists interested in proteostasis, cellular signaling, and post-translation modification of proteins.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study expands our understanding of the role of two axon guidance factors in a specific axon guidance decision. The strength of the study is the convincing axonal labeling and quantification, which allows the authors to establish precise consequences of the loss of each guidance factor or receptor.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study evaluates the effects of nifuroxazide on radiotherapy for the treatment of hepatocellular carcinoma. Solid evidence is provided to support the conclusion that nifuroxazide facilitates the downregulation of PD-L1 and may improve therapy outcomes when combined with radiotherapy, though the inclusion of additional cell lines and animal models would have strengthened the study. This work will be of interest to cancer biologists and those working in immuno-oncology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper 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 in the design of antibodies, which are key tools in many research and industrial applications. The experiments for validation are convincing, but some further statistical evaluation would be helpful for the readers.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study delves into the complex role of STAT3 signaling and its interplay with TGF-beta and SMAD4 in KRAS mutant pancreatic cancer. The authors demonstrate that both the presence and absence of STAT3, relative to SMAD4, can lead to poor PDAC differentiation and that STAT3 mutations affect p53-null fibroblasts with KRASG12D and induce an EMT-like phenotype. By providing convincing evidence, the authors were able to derive important insights into KRAS mutant cancers.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript presents a detailed characterization of male and female wild-type and CTRP10 knockout mice, revealing that knockout mice develop female-specific obesity that is largely uncoupled from metabolic dysfunction. The data are convincing, and the work is a valuable contribution to understanding how obesity is coupled to metabolic dysfunction, and how this can occur in a sex-specific manner.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents an important method and resource in cell lines and in mice for mass spectrometry-based identification of interactors of the proteasome, a multi-protein complex with a central role in protein turnover in almost all tissues and cell types. The method presented-including the experimental workflow and analysis pipeline, as well as the several lines of validation provided throughout, is convincing. Given the growing interest in protein aggregation and targeted protein degradation modalities, this work will be of interest to a broad spectrum of basic cell biologists and translational researchers.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study investigates the role of the centrosomal protein CEP44 in centriole duplication and mitotic spindle formation. While the analysis of CEP44 mitotic phosphorylation and spindle recruitment is solid, the characterization of CEP44's role at centrioles is incomplete and would benefit from additional controls and analyses. Since the work links CEP44 reduced expression to poor survival in breast cancer patients, it is of interest not only to cell biologists but also to cancer researchers.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important study on the damage-induced checkpoint maintenance and termination in budding yeast that provides convincing evidence for a role of the spindle assembly checkpoint and mitotic exit network in halting the cell cycle after prolonged arrest in response to irreparable DNA double strand breaks (DSBs). The study identifies particular components from both checkpoints that are specifically required for the establishment and/or the maintenance of a cell cycle block triggered by such DSBs. The authors propose an interesting model for how these different checkpoints intersect and crosstalk for timely resumption of cell cycling even without repairing DNA damage with theoretical and practical implications.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study elucidates the function of the cohesin subunit SCC3 in impeding DNA repair between inter-sister chromatids in rice. The observation of sterility in the SCC3 weak mutant prompted an investigation of abnormal chromosome behavior during anaphase I through karyotype analysis. While the evidence presented is largely solid, the strength of support can be substantially improved in some aspects, leaving room for further investigation. This research contributes to our understanding of meiosis in rice and attracts cell biologists, reproductive biologists, and plant geneticists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study focuses on nuclear pore complex dysfunction in a mouse model of Alzheimer's disease related Aβ pathology. The findings are useful in supporting the idea that nuclear cytoplasmic transport defects occur prior to plaque deposition in this disease model and may be caused by Alzheimer's disease pathology. However, the work suffers from overinterpretation of some of the data and remains incomplete in several respects; 1) molecular mechanisms that drive nuclear pore complex dysfunction are not explored, 2) evidence that time-dependent loss of the nuclear pore complex is linked to normal aging is lacking, and 3) a clear description of how the observations reported in this work fit into broader views in the field surrounding amyloid aggregation and accumulation in neurons and pathogenesis in neurons needs to be clarified.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript describes a valuable study aimed at identifying the substrate specificity of two cell wall hydrolases LSS and LytM in S. aureus. The authors show that LytM has a novel function of cleaving D-Ala-Gly instead of only Gly-Gly by using synthetic substrates and convincing NMR-based real-time kinetics measurements. The biological relevance of the reported results will have to be investigated in future in vivo experiments.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a valuable study on K187 acetylation of the nuclear protein, TIP60, required for its phase separation and function. The evidence supporting the primary conclusion is incomplete and warrants more scrutiny.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is a fundamental study describing a novel methylation event on EZH2 that regulates EZH2 protein stability and hematopoiesis. The methodologies are sound and the conclusions are largely supported by solid data. The work will be of interest to biomedical researchers in the field of cancer epigenetics.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study adds to the growing body of evidence that neural responses fluctuate in time to alternatively represent one among multiple concurrent stimuli and that these fluctuations seize when objects fuse into one perceived object. The present study provides solid evidence from multiple brain areas and stimuli types to support this hypothesis. Overall, the study illustrates how the brain can use time dimension and synchrony to either parse or integrate stimuli into a coherent representation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable paper addresses a notable problem, the cell biological control of biomineralization, with the sea urchin embryo as an experimental model. The paper provides evidence that ROCK and the cytoskeleton play a role in biomineralization, but the evidence is deemed currently incomplete, as there are concerns regarding the efficacy and specificity of the reagents used to perturb ROCK function. In addition, the data do not point to a plausible mechanism by which the actin cytoskeleton might regulate the biomineralization process.
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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. The carefully designed and executed extensive series of experiments provide compelling evidence that changes in their excitability occur due to up-regulation of Kv7 currents. The study unveils the underlying mechanisms of the disease, and therefore the work will be of interest to neuroscientists working on various aspects of Fragile X pathology. In addition, it also provides insights into how neuronal activity is balanced in networks through diverse cellular mechanisms.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Drawing on a human population genomic data set, this valuable study seeks to show that potentially advantageous alleles are on average older than neutral alleles, invoking the action of balancing selection as the underlying explanation. Currently it is unfortunately unclear how robust the estimates of allele ages are, and the evidence for the authors' proposal is therefore at this stage incomplete. If confirmed, the conclusions would be of interest to population genomicists, especially those studying humans.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study explored the impact of migraine-related cortical spreading depression (CSD) on the firing of nerves innervating the coverings of the brain that are considered the putative source of migraine-related pain. Using convincing approaches they show that these responses are altered in response to mechanical deformation of the brain coverings. Given that migraine is characterized by worsening head pain in response to movement, the findings offer a potential mechanism that may explain this clinical phenomenon.
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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. Male-biased genes evolve faster than female-biased and unbiased genes, which 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 study identifies two new transporters in the apicoplast, a non-photosynthetic organelle of apicomplexan parasites. While this is important work, it only partially reveals how essential these transporters are, as it does not address the metabolic function of the transporters for the parasite. Although the evidence is still incomplete, the results should be of interest to parasitologists and eukaryotic cell biologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents an important conceptual advance of how vitamin A and its derivatives contribute to atherosclerosis. There is solid evidence for the contributions of specialized populations of T cells in atherosclerosis resolution, including use of multiple in vivo models to validate the functional effects. A limitation is the insufficient analysis of lesions, but the manuscript has been improved from the original preprint version and the overarching conclusions have been refined.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study combines state-of-the art proteomics and genetic manipulation of Chlamydia trachomatis to study the function of a chlamydial effector, Cdu1, with deubiquitination and acetylation activities. Solid evidence is provided to show that Cdu1 is able to protect itself and three other chlamydial effectors, which are involved in the control of chlamydial egress from host cells, from ubiquitin-mediated degradation, and that this depends on the acetylation activity of Cdu1, but not on its deubiquitination activity. This work will be of interest to microbiologists and cell biologists studying host cell-pathogen interactions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study advances our understanding of how different types of communication signals differentially affect mouse behaviors and amygdala cholinergic/dopaminergic neuromodulation. Researchers interested in the complex interaction between prior experience, sex, behavior, hormonal status, and neuromodulation should benefit from this study. Nevertheless, some of the statistical comparisons using baseline normalized data might result in inadequate statistical power at this stage, requiring additional analysis to support the conclusions fully. With a few analytical parts strengthened, this paper will be of interest to neuroscientists and ethologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents important new insights into how best to address common problems encountered in the statistical analysis of neural data, including those related to temporal autocorrelations and unknown variables. The authors show that certain approaches, including those using cross-validation and permutation tests, are better than others at controlling error rates, particularly false negatives. At present, the evidence presented is incomplete, including a lack of more rigorous theoretical justifications for the differences observed between the different approaches tested and a focus on p-values without considering effect sizes, but could be improved with substantial revisions that address these issues.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The aim of this important study is to functionally characterize neuronal circuits underlying the escape behavior in Drosophila larvae. Upon detection of a noxious stimulus, larvae follow a series of stereotyped movements that include bending their body, rolling, and crawling away. This paper combines quantitative behavioral analyses, cell-type specific manipulations, optogenetics, calcium imaging, immunostaining, and connectomic analysis to provide convincing evidence of an inhibitory descending pathway that controls the switch from rolling to fast crawling behaviors of the larval escape response.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable finding on the influence of visual uncertainty and Bayesian cue combination on implicit motor adaptation in young healthy participants. The evidence supporting the claims of the authors is solid, although a better discussion of the link between the model variables and the outcomes of related behavioral experiments would strengthen the conclusions. The work will be of interest to researchers in sensory cue integration and motor learning.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents useful results on glutamine-rich motifs in relation to protein expression and alternative genetic codes. The solid data are based on bioinformatic approaches that are employed to systematically uncover sequence features associated with proteome-wide amino acid distribution and biological processes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors have greatly expanded their important hippocampome.org resource about rodent hippocampal cell types, their physiological properties, and their interactions. With version 2.0, they make a significant advance in providing a user-friendly means to make computer models of hippocampal circuits. The work is convincing, and there are only minor reservations that the figures may be too complex.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This convincing study demonstrates a potentially important role for the factor Numb in skeletal muscle excitation-contraction coupling, since a Numb knockout reduced contractile force. The authors thus demonstrate a novel role for Numb in calcium release in skeletal muscle.
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news.ycombinator.com news.ycombinator.com
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Wirth himself realized the problems of Pascal and his later languages are basically improved versions of Pascal -- Modula, Modula-2, and Oberon. But these languages didn't even really displace Pascal itself let alone C -- but maybe if he had named them in a way that made it clear to outsiders that these were Pascal improvements they would have had more uptake.
Modula and Oberon should have been codenames rather than independent projects.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study reports jAspSnFR3, a biosensor that enables high spatiotemporal resolution of aspartate levels in living cells. To develop this sensor, the authors used a structurally guided amino acid substitution in a glutamate/aspartate periplasmic binding protein to switch its specificity towards aspartate. The in vitro and in cellulo functional characterization of the biosensor is convincing, but evidence of the sensor's effectiveness in detecting small perturbations of aspartate levels and information on its behavior in response to acute aspartate elevations in the cytosol are still lacking.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study presents convincing evidence for the use of orangutan teeth as terrestrial proxies to reconstruct rainfall regimes, while exploring the potentially conflicting impact of breastfeeding signals. The findings will be of broad interest for those using and developing methods and tools to reconstruct environmental conditions in the historical and archaeological past.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents useful work comparing different techniques for monitoring insect species in agricultural settings, including a brand new one using optical sensors. That said, the data were analysed using an inadequately-described -- or potentially inadequate -- framework, and more careful thought must be given to the interpretation of the results before the new methodology can be used as a starting point for insect studies in agricultural fields and beyond.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable manuscript describes a genetic system in yeast used to find mutations in two distinct amino acid transporters that enable the cells to utilize additional amino acids as a nitrogen source. The study provides solid evidence in membrane proteins of a phenomenon that has been previously described in enzymes: that substrate specificity can be altered through the introduction of point mutations to either the ligand binding site or gating helices. This work establishes that amino acid transporters likely evolved specific functionality/specificity from an ancestral transporter that could transport most amino acids.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
By taking advantage of noise in gene expression, this important study introduces a new approach for detecting directed causal interactions between two genes without perturbing either. The main theoretical result is supported by a proof, although clearer statements are needed to ensure that there are no edge cases that can violate the theorem. Preliminary simulations and experiments on small circuits are presented, but the evidence remains incomplete because further investigations are needed to demonstrate the broad applicability and scalability of the method.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents important findings on long-lived proteins in the mouse ovary and oocytes. Convincing evidence using two-generation stable isotope-based metabolic labelling of mice in combination with mass spectrometry analysis describes a resource of enriched long-lived macromolecules in oocytes and somatic cells. Mitochondrial, cytoskeletal, and myosin proteins were identified as long-lived. While this is a unique resource with significant value in the understanding of female reproductive aging, the results would be strengthened if supported by an orthogonal validation and a more in-depth mechanistic explanation of the relationship between mitochondrial and cytoskeletal protein stability and aging.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important paper examined how attention affects temporal binding. Through a combination of careful experimental designs and computational modelling, this study provides solid evidence highlighting the role of attention in shaping temporal binding. Overall, the present findings will be of interest to cognitive scientists studying phenomena related to time perception, temporal binding, and spatial attention.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In an important study that will be of interest to the mechanistic membrane transport community, the authors capture the first cryo-EM structure of the inward facing melbiose transporter MelB, a well-studied model transporter from the major facilitator (MFS) superfamily. Cryo-EM experiments and supporting biophysical experiments provide solid evidence for transporter conformational changes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a useful inventory of immune signatures that are correlated with cancer treatment-related pneumonitis. The data were collected and analysed using solid and validated methodology and can be used as a starting point for further functional studies.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful manuscript focuses on understanding how an Eklf mutation confers anticancer and longevity advantages in vivo. The data demonstrate that Eklf (K74R) imparts such advantages in a background and age independent manner in both female and male mice, and that the benefits are transferable by bone marrow transplantation. Despite added data since a previous version, the paper unfortunately remains incomplete, as it is still unclear whether Eklf affects resistance to malignant progression/metastasis by modulating Pd1 or Pdl1, or by increasing NK cells. The authors provide evidence that supports in principle both mechanisms, and they do not resolve which mechanism is primarily involved.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides useful insights into inter- and intra-site B cell receptor repertoire heterogeneity, noting that B cell clones from the tumour interact more with their draining lymph node than with the blood and that there is less mutation/expansion/activation of B cell clones in tumours. Unfortunately, the main claims are incomplete and only partially supported. This work could be of interest to an audience including medical biologists/immunologists and computational biologists across cancer specialities.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper provides an important assessment of competition dynamics allowing coexistence of the carnivore guild within a large national park. A solid dataset and multiple surveying techniques (camera traps and DNA metabarcoding) provide convincing evidence that spatial segregation represents the main strategy of coexistence, while species have a certain degree of temporal and dietary overlap. Altogether, the manuscript provides important information critical to the conservation and management agenda of the park.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study identifies the gene mamo as a new regulator of pigmentation in the silkworm Bombyx mori, a function that was previously unsuspected based on extensive work on Drosophila where the mamo gene is involved in gamete production. The evidence supporting the role of Bm-nano in pigmentation is convincing, including high-resolution linkage mapping of two mutant strains, expression profiling, and reproduction of the mutant phenotypes with state-of-the-art RNAi and CRISPR knock-out assays. While the discussion about genetic changes being guided or accelerated by the environment is extremely speculative and has little relevance for the findings presented, the work will be of interest to evolutionary biologists and geneticists studying color patterns and evolution of gene networks.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable dissection on how functional HSCs are expanded in PVA cultures. The functional and multi-omic analyses provided are convincing, although the additional data and their analysis provided during revision could have been included in the test to assist readers and to strengthen the published manuscript. Nevertheless, the present work will be of value for stem cell biologists interested in HSC regulation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable findings on the mechanism of glucocorticoid-induced osteonecrosis of the femoral head. The data were collected and analyzed using solid, validated methodology and can be used as a starting point for functional studies of development of glucocorticoid-induced osteonecrosis. This paper would be of interest to cell biologists and biophysicists working on potential pharmacological treatments for glucocorticoid-induced osteonecrosis.
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www.researchsquare.com www.researchsquare.com
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eLife assessment
This valuable paper explores the idea that transient modulations of neural gain promote switches between distinct perceptual interpretations of ambiguous stimuli. Evidence for this idea is provided by pupillometry (an indirect proxy of neuromodulatory activity), fMRI, neural network modeling, and dynamical systems analyses. While this integrative approach is intriguing, the data analysis, as well as computational modeling, are incomplete, especially for supporting the many causal statements in the paper.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important paper uses a genome-wide, massively parallel reporter assay to determine how CpG methylation affects regulatory sequences that control the expression of human genes. The authors provide compelling evidence that methylation not only influences baseline activity of regulatory sequences but also the magnitude of acute responses to environmental stimuli. The findings are of broad interest, and the extensive data set will likely become a key resource for the community.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study investigates the role of the bile acid receptor TGR5 in adult hematopoiesis of the mouse model. The findings are potentially useful because the loss of TGR5 leads to dysregulation of bone marrow adipose tissue (BMAT) that has emerging regulatory functions. However, the study is still incomplete because the mechanism of TGR5 is not clear, the stromal cells expressing TGR5 have not been well defined, and there is not strong evidence for the role of TGR5 in recovery from transplant stress.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents valuable information that demonstrates CCDC146 as a novel cause of male infertility that play key role in microtubule-associated structures. The evidence supporting the claims of the authors is solid using combination of human and mouse genetics, biochemical and imaging approaches. This paper would be of interest to cell and developmental biologists working on genes involved in spermatogenesis and male infertility.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This important study advances our understanding of why diabetes is a risk factor for more severe Covid-19 disease. The authors offer solid evidence that cathepsin L is more active in diabetic individuals, that this higher activity is recapitulated at the cellular level in the presence of high glucose, and that high glucose leads to higher cathepsin L maturation. While not all aspects of the relationship between diabetes and cathepsin L (e.g., effects of metabolic acidosis) have been investigated, the work should be of interest to researchers in diabetes, virology, and immunology.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study uses a mouse model of pancreatic cancer to examine mitochondrial mass and structure in atrophying muscle along with aspects of mitochondrial metabolism in the same tissue. Most relevant are the solid transcriptomics and proteomics approaches to map out related changes in gene expression networks in muscle during cancer cachexia.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study explores the physicochemical properties of SARS-CoV-2 N proteins with mutations that have been found in variants of concern but for which there is limited knowledge of their contribution to the biological activity of such variants. The evidence presented is solid; however, this study could be considerably improved by a more extensive analysis of LLPS in R203K/G204R and in the P31L mutants, as well as a more quantitative analysis of the LLPS droplets.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors present evidence suggesting that MDA5 can substitute as a sensor for triphosphate RNA in a species that naturally lacks RIG-I. The key findings are potentially important for our understanding of the evolution of innate immune responses, but the evidence is incomplete, as additional biochemical and functional experiments are needed to unambiguously assign MDA5 as a bona fide sensor of triphosphate RNA in this model. This also leaves the title as overstating its case.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study addresses the mechanisms by which mutations in the PURA protein, a regulator of gene transcription and mRNA transport and translation, cause the neurodevelopmental PURA syndrome. Based on convincing evidence from structural biology, molecular dynamics simulation, biochemical, and cell biological analyses, the authors show that the PURA structure is very dynamic, rendering it generally sensitive to structure-altering mutations that affect its folding, DNA-unwinding activity, RNA binding, dimerization, and partitioning into processing bodies. These findings are of substantial importance to cell biology, neurogenetics, and neurology alike, because they provide first insights into how very diverse PURA mutations can cause similar and penetrant molecular, cellular, and clinical defects.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein, TIPE, regulates aerobic glycolysis to promote tumor growth in melanoma. Data using multiple independent approaches provide new insights into the molecular mechanisms underpinning aerobic glycolysis, also known as the Warburg Effect, in melanoma cells. The claims of the authors are solid, although more in-depth metabolic assays as well as the inclusion of melanoma patient survival analysis in TIPE high and low tumors would strengthen the study. The work will be of interest to biomedical researchers working in cancer and metabolism.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a cellular automaton model to study the dynamics of virus-induced signalling and innate host defense against viruses such as SARS-CoV-2 in epithelial tissue. The data presented are convincing and represent a valuable contribution that would be of interest to researchers studying the dynamics of viral propogation. The significance of the study might be further elevated with more details on the reduction of expression data to the model rules discussed.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable finding that a testis-enriched gene is essential for normal formation and function of the sperm flagellum, motility, and male fertility in mice. The data on phenotypic characterization are solid, but the evidence supporting the direct role of this protein in preventing RNP granule formation in the sperm flagellum appears insufficient. This work will be of interest to biomedical researchers who work on testicular biology and male fertility.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides a detailed evaluation of how HIV evades nascent immune pressure from people living with HIV followed nearly immediately after infection. There is convincing evidence that H173 mutations in the V2 loop was a key determinant of selection pressure and escape. These data are congruent with protection in the RV144 clinical trial, the only trial that showed protection from infection. Overall, this study is valuable to the field.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this valuable study, the authors investigate the transcriptional landscape of tuberculous meningitis, revealing key molecular differences contributed by HIV co-infection. Whilst some of the evidence presented is compelling, the bioinformatics analysis is limited to a descriptive narrative of gene-level functional annotations, which are somewhat basic and fail to define aspects of biology very precisely. Whilst the work will be of broad interest to the infectious disease community, validation of the data is critical for future utility.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This current revision builds on observations in validated conditional double KO (cDKO) mice for LRRK1 and LRRK2 that will be useful for the field, given that LRRK2 is widely expressed in the brain and periphery, and many divergent phenotypes have been attributed previously to LRRK2 expression. The manuscript presents solid data demonstrating that it is the loss of LRRK1 and LRRK2 expression within the SNpc DA cells that is not well tolerated, as it was previously unclear from past work whether neurodegeneration in the LRRK double Knock Out (DKO) was cell autonomous or the result of loss of LRRK1/LRRK2 expression in other types of cells. Future studies may pursue the biochemical mechanisms underlying the reason for the apoptotic cells noted in this study, as here, the LRRK1/LRRK2 KO mice did not replicate the dramatic increase in the number of autophagic vacuoles previously noted in germline global LRRK1/LRRK2 KO mice.
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eLife assessment
This important study presents interesting findings that suggest that the UPR and immune regulators can act as evaluators of nutritional quality in C. elegans. Convincing evidence expands our understanding both of physiological food evaluation systems and of the known roles of stress response pathways in organismal physiology. However, there is limited mechanistic exploration in the study, and in some cases, the effect size is small and statistical significance questionable.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable paper presents a thoroughly detailed methodology for mesoscale-imaging of extensive areas of the cortex, either from a top or lateral perspective, in behaving mice. While the examples of scientific results to be derived with this method are in the preliminary stages, they offer promising and stimulating insights. Overall, the method and results presented are convincing and will be of interest to neuroscientists focused on cortical processing in rodents.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study reports a valuable new mechanism through which the TGF-beta signaling pathway promotes contacts between oocytes and their surrounding somatic cells via regulating the number of transzonal projections (TZPs) in mice. The evidence supporting the major conclusions is solid, although further assessments of the physiological significance of SMAD4-dependent formation of transzonal projection networks would have strengthened the study. The work will be of interest to biomedical researchers who work on ovarian biology and female fertility.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this manuscript, the authors investigate the properties of prokaryotic NADPH oxidases (NOX) and discuss the implications for NOX regulation and function. The structure of the S. pneumoniae Nox protein is an important step forward in our understanding of procaryotic NOX enzymes and the characterization and interpretation are convincing. The results will be of interest to structural biologists as well as biochemists focusing on enzymatic functions.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper presents an important finding: that Styxl2, a poorly characterized pseudo-phosphatase, plays a role in the sarcomere assembly by promoting the degradation of non-muscle myosins. The genetic evidence supporting the conclusions is compelling, although future work will be needed to elucidate the functional role and biochemical mechanism of autophagic degradation of non-muscle myosins. This work will be of interest to biologists studying muscle development, cell biology, and proteolysis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
CCL2 is a chemokine known to have relevant immune cell chemoattractant properties, and it is believed to play a role in several chronic inflammatory diseases. The RNA-binding protein HuR controls the stability and translation of CCL2 mRNA. This paper presents solid evidence that a relatively common genetic variant tied to several disease phenotypes affects the interaction between the mRNA of CCL2 and the RNA-binding protein HuR. As CCL2 is believed to be relevant for leukocyte migration in various conditions, including chronic inflammation and cancer, this is an important finding that may be relevant to a broad audience.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study addresses how protein synthesis in activated lymphocytes keeps up with their rapid division, with important findings that are of significance to cell biologists and immunologists endeavouring to understand the 'economy' of the immune system. The work is supported by solid data. Because it proposes non-conventional mechanisms, the study sets the scene for further work in this area.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The effect of Vitamin D supplementation in reducing asthma via anti-inflammatory mechanisms is a topic of wide interest, with somewhat conflicting published data. Here, bioinformatic approaches help to identify a role of VDR in inducing the expression of the key regulator Ikzf3, which possibly suppresses the IL-2/STAT5 axis, consequently blunting the Th2 response and mitigating allergic airway inflammation. These are important findings based on convincing evidence.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript utilizes a Drosophila explant system and modeling to provide important insights into the mechanism of microtubule aster positioning. Although the intellectual framework of aster positioning has been worked out by the same authors in their previous work, this study provides additional solid evidence to solidify their model.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important report studies the recovery of genome-reduced bacterial cells in laboratory evolution experiments to understand how they regain their fitness. Through the analysis of gene expression and a series of tests, the authors discover distinct molecular changes in the evolved bacterial strains and propose that various mechanisms are employed to offset the effects of a reduced genome. While the findings have intriguing implications for understanding genome evolution, it is crucial to note that the evidence supporting these claims is incomplete due to insufficient experimental tests and statistical analysis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important work by Hann et al. advances our understanding of the role of the survival motor neuron (SMN) protein in coordinating pathogenesis of the spinal muscular atrophy (SMA). The authors addressed many concerns raised by the reviewers, providing convincing evidence in terms of skeletal analyses not being able to satisfactorily elucidate SMN regulation of bone development.
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eLife assessment
This important work combines DNA contact analysis and controlled genome rearrangements to investigate the processes that organize the E. coli chromosome, with a particular focus on how the SMC-related complex MukBEF is regulated. The evidence supporting the conclusions is compelling, with time-resolved experiments and analysis of mutant strains. The work will be of broad interest to chromosome biologists and bacterial cell biologists.
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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 used by researchers across a number of fields including analysts, modelers, 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.medrxiv.org www.medrxiv.org
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eLife assessment
This is a methodologically state-of-the-art systematic review and meta-analysis of studies that addressed the question of whether the administration of multiple antibiotics simultaneously prevents antibiotic resistance development in individuals. The findings are solid. Rather than providing a precise answer, the synthesis of studies eligible for analysis leads to the conclusion that "our analysis could not identify any benefit or harm of using a higher or a lower number of antibiotics regarding within-patient resistance development." This article is important as it articulates the existing knowledge gap, but also serves as an example to careful future use of the meta-analysis methodology, when existing data just don't allow conclusions.
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www.medrxiv.org www.medrxiv.org
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eLife assessment
This very interesting study by Vuond and colleagues reports on the kinetics of viremia in a large set of individuals from Vietnam. In the large cohort, all 4 dengue serotypes are represented and the authors try to correlate viraemia measured at various days from illness onset with thrombocytopaenia and severe dengue, according to the WHO 2009 classification scheme. These are fundamental findings and provide compelling evidence of the importance of measuring viremia early in the phase of the disease. These data will help to inform the design of studies of antiviral drugs against dengue.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This solid study investigates the transdifferentiation of chicken embryonic fibroblasts into muscle and fat cells in 3D to create whole-cut meat mimics. The study is important and provides a method to control muscle, fat, and collagen content within the 3D meat mimics and thus provides a new avenue for customized cultured meat production. Limitations of this study include the use of transgene for transdifferentiation and thus the creation of GMO food.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The study provides useful data supporting prior findings that mitochondria in cultured cells maintain a temperature that is up to 15°C above the external temperature at which cultured cells are maintained. The evidence supporting the hypothesis is solid, although direct measures of temperature in isolated mitochondria or comparison with other cellular compartments would have strengthened the ability to interpret the relevance of the findings. Nevertheless, the bioenergetic implications of the work will be of interest to cell biologists, biochemists, and physiologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The study provides valuable data supporting prior findings that mitochondria in cultured cells maintain a temperature that is up to 15°C above the external temperature at which cells are cultured. The evidence supporting the hypothesis is incomplete at this stage, and additional benchmarking of temperature probes and inclusion of outcome measures beyond mitochondrial temperature will strengthen the ability to interpret the relevance of the findings. Nevertheless, the bioenergetic implications of the work will be of interest to cell biologists, biochemists, and physiologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents the useful observation that repetitive Transcranial Magnetic Stimulation (rTMS) over the medial prefrontal cortex (mPFC) is associated with immediate dampening effects of conditioned responses and generalization of these responses to similar cues. Additionally, the effects were still present one week later, in the absence of any stimulation. However, the evidence supporting the claims of the authors is incomplete. The main outcome data (skin conductance response) have been normalized and standardized in suboptimal ways and, most critically, no comparisons are being made with the strength of conditioned responses during acquisition. If the observations hold, when based on within-subject comparisons, the work will be of interest to psychologists and neuroscientists working on interventions into aberrant emotional memories.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Large populations of neurons are capable of entering pathological synchronous oscillations under a variety of conditions and work over many decades has found ways to disrupt such oscillations using stimulation in both open loop and closed loop configurations. This study adds useful results and methodology to this line of research, by providing solid evidence that delayed feedback control via electrical stimulation can, under certain conditions, terminate network level oscillations in cultured cortical neurons. The study provides analyses and simulation results that shed light on why some networks respond to such feedback control while others do not.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study demonstrates that the transcription factor TEAD1 is required for the function of Yap/Taz in Schwann cells, with conditional mouse mutants having very similar dysmyelinated phenotypes. Convincing histological evidence is shown for the role of TEAD1 itself, leaving open the function of other TEAD proteins in this system. This study will nevertheless be of great interest to researchers in the field of peripheral nerve development.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study examines an interplay between synaptic mitochondria and glutamate receptor exocytosis in C. elegans. Collectively, the solid results support the idea that mitochondrial function influences receptor dynamics at postsynaptic sites. This is important because tight control of synaptic function likely integrates several mitochondrial functions: energy production, calcium buffering, and (here) reactive oxygen species signaling.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This convincing manuscript represents a valuable advance in understanding the role of MCT1 – a transporter for lactate and other organic anions – in hepatocytes and hepatic stellate cells in the liver. The authors also generate exciting new tools to investigate hepatic stellate cell biology, and these may have much broader applications, but future studies are required to validate these new tools.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study extends insights on NAFLD and NASH regarding the role of plasma lactate levels using mice haplo-insufficient for the gene encoding lactate transporter MCT-1. While the evidence is largely convincing and the work significantly advances our understanding of the roles of distinct hepatic cell types in steatosis, a number of issues require attention and would best be solved by further experimentation.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Payne et al. present a novel model that predicts the sites and directions of plasticity within the vestibular cerebellum to explain the basis for learned adjustments to reflexive eye movements in monkeys. The work is solid; the model is well constrained by prior biological observations and makes an important prediction about the level of feedback available to the cerebellar cortex post-learning. Overall, a number of exciting and testable experiments will likely be motivated by this study.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a useful characterization of the biochemical consequences of a disease-associated point mutation in a nonmuscle actin. The study uses solid and well-characterized in vitro assays to explore function. In some cases the statistical analyses are inadequate and several key in vitro assays are not employed.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents an advance in efforts to use histone post-translational modification (PTM) data to model gene expression and predict epigenetic editing activity. Such models are broadly useful to the research community, especially ones that can model epigenetic editing activity, which is novel. However, whereas the authors have nicely integrated datasets across cell types into their model, the work is incomplete in two key areas: (1) a lack of comparisons to existing models that predict gene expression from PTM data makes it unclear what advantages the current model offers, and (2) more rigorous experimental evidence for dCas9-based perturbations is needed to rigorously assess how well the model predicts epigenetic editing outcomes.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study uses population and functional genomics to examine long non-coding RNAs (lncRNAs) in the context of human evolution. Computational prediction of human-specific lncRNAs and their DNA binding sites and analyses of these loci lead to the development of hypotheses regarding the potential roles of these genetic elements in human biology. The evidence supporting the conclusions is, however, still incomplete, as key details regarding the methodology and analyses are lacking.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study addresses two questions: (i) how danger signaling is altered for people with childhood adversities, and (ii) how this differs across different operationalizations of adversity. The latter is of particularly broad interest to multiple fields, given that childhood adversity is operationalized very differently across the literature, but the strength of evidence is incomplete because the statistical techniques used do not sufficiently account for between-subjects covariates. These data will be of interest to scientists and clinicians interested in early life adversity, statistical approaches for quantifying stress exposure, or aversive learning.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study poses a provocative mechanism of channel activation of the mechanically activated ion channel TREK-1. The data provide solid evidence that the application of shear to cells causes a redistribution of both TREK-1 and an associated enzyme, PhospholipaseD2 in the membrane that increases the enzyme activity. The work offers a new mechanism, but note that this is only one possible method of channel activation, and mechanisms independent of PLD2 are also probable.
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eLife assessment
Miyano et al. study the impact of RIM-BP2 deletion at mossy fiber synapses, using direct electrophysiological recordings from mossy terminals and STED super-resolution microscopy. The paper addresses an important question in the field of synaptic transmission and provides compelling evidence demonstrating reduced calcium channel abundance in mossy terminals upon RIM-BP2 removal.
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eLife assessment
This study represents a useful description of a third interaction site between melanophilin and myosin-5a which has a role in regulating the distribution of pigment granules in melanocytes. While much of the data forms a solid case for this interaction, the inclusion of key controls for the cellular studies and measurement of interaction affinities would have been helpful.
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eLife assessment
This study presents fundamental findings on the role of transcription readout and intron retention in transposon expression during aging in mammals. The evidence supporting the claims of the authors is compelling, strongly supporting the authors' claims. The work will be of interest to scientists studying aging, transcription regulation, and epigenetics.
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eLife assessment
Receptor tyrosine kinases such as ALK play critical roles during appropriate development and behaviour and are nodal in many disease conditions, through molecular mechanisms that weren't completely understood. This manuscript identifies a previously unknown neuropeptide precursor as a downstream transcriptional target of Alk signalling in Clock neurons in the Drosophila brain. The experiments are well designed with attention to detail, the data are solid, and the findings will be useful to those interested in events downstream of signalling by receptor tyrosine kinases.
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eLife assessment
This valuable study reports novel active learning batch selection methods that have been applied to optimization tasks related to ADMET and affinity properties relevant within the drug discovery field. While the evidence is solid, the paper could have benefited from a clearer and deeper description of methods as well as interpretation of the obtained models, and a wider comparison to existing methods. The article will be of general interest to scientist working in the field of drug discovery and, in general, to researchers within the fields of machine learning and data analysis.
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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 specific methodological and analytical approaches taken should be considered for further interpretation.
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eLife assessment
This solid manuscript describes a preclinical model to assess different methods of infusion of organoids for clinical applications. This is an important and timely study with practical implications beyond a single subfield. The methods described, including the analysis, broadly support the claims although there are some areas for improvement.
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eLife assessment
This important study reports a new mutant mouse line with compromised function of a DNA damage response protein. The evidence supporting the conclusion that the mutants display defective maintenance of meiotic sex chromosome inactivation is solid. This work is of interest to biomedical researchers working on meiosis and meiotic sex chromosome inactivation.
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eLife assessment
In this important study, a mathematical model to predict biological age by leveraging physiological traits across multiple organ systems is developed. The results presented are convincing, utilizing comprehensive data-driven approaches, although additional external validation would further strengthen its generalizability. The model provides a way to identify environmental and genetic factors impacting aging and lifespan, revealing new factors potentially affecting aging and it also shows promise for evaluating therapeutics aimed at prolonging a healthy lifespan.
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eLife assessment
This study documents important findings on three variants in SNAP25 that are associated with developmental and epileptic encephalopathy. The thorough characterization of synaptic release and in vitro vesicle fusion phenotypes provides interesting information about the nature of the SNAP25 variants. The evidence supporting the claims is compelling, and this work will be of interest to neuroscientists working on SNAP25, SNAP25-associated encephalopathy, and synaptic vesicle exocytosis.
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eLife assessment
The authors use human intracranial recordings to investigate the relationship between the power of brain oscillations and the latency and strength of cortico-cortical couplings. In the current version, the authors provide a valuable finding that the delay between nearby electrodes in ECoG data is correlated with the amplitude of power, differently so for high and low frequencies. The findings of this study will interest investigators in the wider field of systems neurophysiology; however, editors and reviewers perceived headroom for improving clarity in the presentation of analyses and results, and the strength of evidence for some of the claims as currently presented was viewed as incomplete.
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eLife assessment
This important study examines the relationship between expiratory airflow and vocal pitch in adult mice during the production of ultrasonic vocalizations and also identifies a molecularly defined population of brainstem neurons that regulates mouse vocal production across development. The evidence supporting the study's conclusions that expiratory airflow shapes vocal pitch and that these brainstem neurons preferentially regulate expiratory airflow is incomplete and would benefit from the inclusion of additional analyses and discussion. This work will be of interest to neuroscientists working on mechanisms and brainstem circuits that regulate vocal production and vocal-respiratory coordination.
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eLife assessment
This study presents a valuable exploration of the complex relationship between structure and function in the developing human brain using a large-scale imaging dataset from the Human Connectome Project in Development and gene expression profiles from the Allen Brain Atlas. The evidence supporting the claims of the authors is convincing, although the inclusion of more systematic analyses of structural and functional connectivity with respect to myelin measures and oligodendrocyte-related genes, and also more details regarding the imaging analyses, cognitive scores, and design and validation strategies, would have strengthened the paper. The work will be of interest to developmental biologists and neuroscientists seeking to elucidate structure-function relationships in the human brain.
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eLife assessment
The authors investigated the requirement and function of Blimp1/Prdm1 in murine natural killer (NK) cells and the ILC1 lineage of innate lymphoid cells, using a conditional knockout model. The single-cell mRNA-seq data provided here represent a valuable resource for the community, but the lack of mechanistic investigations leaves the study incomplete. The work will be of interest to the fields of innate lymphoid cell biology and tissue immunology.
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eLife assessment
This fundamental study evaluates the evolutionary significance of variations in the accuracy of the intron-splicing process across vertebrates and insects. Using a powerful combination of comparative and population genomics approaches, the authors present convincing evidence that species with lower effective population size tend to exhibit higher rates of alternative splicing, a key prediction of the drift-barrier hypothesis. The analysis is carefully conducted and all observations fit with this hypothesis, but focusing on a greater diversity of metazoan lineages would make these results even more broadly relevant. This study will strongly appeal to anyone interested in the evolution of genome architecture and the optimisation of genetic systems.
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eLife assessment
This important study advances our understanding of sperm motility regulation during fertilization by uncovering the midpiece/mitochondria contraction associated with motility cessation and structural changes in the midpiece actin network as its mode of action by using various advanced microscopic techniques. The evidence supporting the association is solid, but the evidence to support the causality of contraction and motility cessation is incomplete and would benefit from time-resolved imaging monitoring contraction, motility, and cell viability simultaneously. With the causality part strengthened, the work will be significant and of broad interest to cell biologists working on the cytoskeleton, mitochondria, cell fusion, and fertilization.
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eLife assessment
This important study provides solid evidence for a non-genomic action of progesterone in Xenopus oocyte activation. The findings demonstrate that two non-genomic progesterone receptors, ABHD2 and mPRb, function as a novel progesterone-stimulated phospholipase A2. However, the findings are reliant on high concentrations of inhibitor drugs, and mechanistic details about the molecular interaction and respective functions of ABHD2 and mPRb are incomplete. The findings will be of broad interest to reproductive endocrinologists and physiologists.
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eLife assessment
The authors present a valuable observation that challenges existing knowledge about DNA methylation dynamics in pre-implantation mammalian development. Their findings suggest a novel role for a well-studied epigenetic mark, with potential implications for gene expression regulation in early embryonic stages. However, the evidence provided is incomplete and only partially supports the main claims.
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eLife assessment
The manuscript describes important findings regarding the significance of CHD2 in ovarian folliculogenesis. Overall, the results lead to convincing conclusions, with minimal concerns raised by the reviewers. Both the results and conclusions are well discussed. This work will be of interest to ovarian biologists and physicians working on female fertility.
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eLife assessment
Using state-of-the-art fate-mapping models and genetic and pharmacological targeting approaches, this study provides valuable findings on the distinct functions exerted by resident and recruited macrophages during cardiac healing after myocardial ischemia. The evidence supporting the conclusions is solid with the use of the FIRE mouse model in combination with fate-mapping to target fetal-derived macrophages. This study will be of interest for the macrophage biologists working in the heart but also in other tissues in the context of inflammation.
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eLife assessment
Toll like receptor 2 (TLR2) signaling has traditionally been viewed a surface protein that induces innate immune responses and improves acquired immunity. Here, the authors suggest a different role for TLR2 in the hair cycle. By using a Cre reporter that is largely, but not solely active in hair follicle stem cells, the authors conditionally delete Tlr2 in mice and report that BMP signaling is sustained and hair cycle entry is delayed. Delving further, the authors identify CEP (2-ω-carboxyethyl pyrrole) as an endogenous ligand of TLR2 in hair follicle stem cell regulation. Although a role for TLR2 signaling in hair follicle stem cells is potentially novel and important, the reviewers remain in consensus that evidence presented in two significant areas continues to be incomplete: 1) where TLR2 and CEP are expressed and how specific is their expression to the hair follicle stem cells; 2) whether as the authors suggest, TLR2 functions by regulating BMP signaling in the stem cell niche of the hair follicle.
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eLife assessment:
The authors report a novel hepatic lncRNA FincoR regulating FXR with therapeutic implications in the treatment of MASH. The findings are important and use an appropriate methodology in line with the current state-of-the-art, with convincing support for the claims.
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eLife assessment
This study presents a valuable finding that serum androstenedione levels may provide a new biomarker for early detection and progression of glaucoma, although a single biomarker is unlikely to be singularly predictive due to the etiological heterogeneity of the disease. The strength of the evidence presented is solid, supported by multiple lines of evidence.
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eLife assessment
This fundamental study examines the effects of herbivory-induced maize volatiles on neighbouring plants and their responses over time. Measurements of volatile compound classes and gene expression in receiver plants exposed to these volatiles led to the conclusion that the delayed emission of certain terpenes in receiver plants after the onset of light may be a result of stress memory, highlighting the role of priming and induction in plant defences triggered by herbivore-induced plant volatiles. The evidence supporting the conclusions is compelling, with rigorous chemical assays of and state-of-the-art high throughput real time mass spectrometry. The work will be of broad interest to plant biologists and chemical ecologists.
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eLife assessment
This useful study asks how the architecture of gene expression differences relates to the development of two alternative morphs in a marine annelid species. The dataset will be of value to the field and the work has the potential to substantially advance our understanding of life history evolution. However, in its current form, the lack of details for some methods and analyses makes the strength of the evidence incomplete. If suitably improved, the work would be of interest to anyone studying the evolution of development and life histories.
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eLife assessment
This is an important paper as it is the first to use a reconstituted translation system to study competition among mRNAs for the initiation machinery. Understanding the principles of the biochemistry of mRNA competition for initiation factors cannot be achieved without such a system. The authors provide compelling evidence that Ded1 is required for efficient initiation in highly structured RNAs. A highly significant finding that validates the in vitro reconstituted system indeed recapitulates the effects of in-vivo perturbations of translation initiation.
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eLife assessment
The study presents valuable findings on how the hypoxia response pathway senses and responds to changes in the homeostasis of the amino acid cysteine and other sulfur-containing molecules. By providing a compelling, rigorous genetic analysis of the pathway, the study adds to a growing body of literature showing that prolyl hydroxylation is not the only mechanism by which the hypoxia response pathway can act. Although the paper does not reveal new biochemical insight into the mechanism, it opens up new areas of investigation that will be of interest to cell biologists and biomedical researchers studying the many pathologies involving hypoxia and/or cysteine metabolism.
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eLife assessment
This useful study aimed to examine the relationship of spatial frequency selectivity of single macaque inferotemporal (IT) neurons to category selectivity. There are some interesting findings in this report but some of these findings were difficult to evaluate because several critical details of the analysis are incomplete. The conclusion that single-unit spatial frequency selectivity can predict object coding needs further evidence to confirm.
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eLife assessment
This fundamental study reveals the major role of calcium-binding proteins (CaBP1 and CaBP2) in sustained exocytosis from mouse inner hair cell ribbon synapses. Compelling data and analysis from CaBP1/2 double-knockout mice show enhanced calcium channel (CaV1.3) inactivation, slowed recovery from inactivation, and reduced synaptic vesicle exocytosis as assayed by membrane capacitance measurements, as well as greatly reduced in vivo spontaneous and sound-evoked spikes from the postsynaptic spiral ganglion neurons. Importantly, transgenic expression of CaBP2 led to the rescue of hearing capabilities. The continuous transmission of sound-evoked signals from auditory hair cells thus depends on the expression of both CaBP1 and CaBP2 and their suppression of CaV1.3 inactivation.
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eLife assessment
Given a great need for novel human model systems to study small cell lung cancer (SCLC), the authors describe an important pre-clinical model with broad potential for the study of how genetic perturbations or drug treatments alter SCLC tumor growth, metastasis, and response to therapy. For the major finding, the authors provide convincing evidence that RB/TP53 suppression coupled with MYC overexpression in an ES cell-derived model system results in aggressive and metastatic SCLC. However, comparisons of the RB/TP53-suppressed, MYC overexpressing model with RB/TP53-suppressed cells in supporting the minor conclusion that MYC overexpression increases the neuroendocrine compartment are incomplete, and the impact of the work would have been increased with the inclusion of a broader set of genetic perturbations, such as over-expression of MYCL, to better model major SCLC phenotypes. The new model described will be of significant interest to researchers studying lung cancer.
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eLife assessment
This study presents valuable insights into the potential role of a general transcription factor in MYCN-dependent regulation of transcription. The study presents solid evidence that TFIIIC and MYCN interact to control transcription. The methods, data, and analyses broadly support the claims with minor weaknesses, yet the logic can be improved, and several specific issues should be addressed. The paper would be of interest to molecular biologists working on MYCN-dependent regulation of gene expression.
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eLife assessment
This important work substantially advances our understanding of osteoblast migration to the sites of bone formation and regeneration. The evidence supporting the conclusion is convincing, with rigorous in vitro assays for cellular and biochemical aspects and with appropriate in vivo models. The work will be of broad interest to developmental biologists and bone biologists.
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eLife assessment
To investigate the evolutionary relationship between the RNAi pathway and innate immunity, this study uses biochemistry and structural biology to investigate the trimeric complex of Dicer-1, DRH-1 (a RIGI homologue), and RDE-4, which exists in C. elegans. The results described include rigorous kinetic analysis of the enzymatic activity of the complex and a moderate resolution cryo-EM structure. The results are convincing and valuable to the broader understanding of the evolution of antiviral defense.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study shows that eliminating a large portion of the principal neurons in the mammalian olfactory bulb does not affect the initial establishment of the circuit but has an impact on its maintenance. The strength of the paper is that the anatomical changes induced by genetic ablation of neurons are clear-cut. There is a solid description of the structural and behavioral effects of ablating the majority of M/T neurons; however, the conclusions are incompletely supported by the findings.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This paper describes valuable results from studies investigating circuits in the brain that underlie behavioral responses in fearful situations. The authors identified a role for a class of neurons that are sufficient to cause these stereotyped behaviors including freezing behaviors. These solid studies increase our understanding of brain pathways regulating these types of behaviors.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important work provides a robust yet simple protocol to isolate small extracellular vesicles from small volumes of plasma. The evidence supporting the conclusions is convincing, although a more thorough statistical comparison of the different techniques and technique combinations explored in the study would have been appreciated. The work will be of broad interest to cell biologists and biochemists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study compares gene expression patterns among different autonomic ganglia and will be of interest to developmental neuroscientists and neurophysiologists. The study expands the database of genes expressed by subpopulations of autonomic neurons in ganglia, a key step in decoding their developmental origins and physiological functions. The evidence supporting the alternative view that the pelvic ganglionic neurons are actually modified sympathetic neurons is incomplete and may cause confusion, given the enrichment of cholinergic neurons, as well as the large number of molecular and functional differences known to be present between cranial and sacral neurons.
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eLife assessment
This useful study compares gene expression patterns among different autonomic ganglia and will be of interest to developmental neuroscientists and neurophysiologists. The study expands the database of genes expressed by subpopulations of autonomic neurons in ganglia, a key step in decoding their developmental origins and physiological functions. The alternative view that the pelvic ganglionic neurons are actually modified sympathetic neurons is incompletely demonstrated given the large number of molecular and functional differences known to be present between cranial and sacral neurons.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study explores how Ebola virus evades human immune responses. The study reports a potential new mechanism wherein Ebola virus traps human IRF3, a key transcription factor involved in immune signaling, into virus-produced "inclusion bodies". The topic is important, the paper has many merits, and the biochemical assays are solid. However, the current data do not clearly explain the relationship between the VP35 protein and IRF3.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a potentially valuable discovery which indicates that activation of the P2RX7 pathway by the small molecule HEI3090 can reduce lung fibrosis after its establishment by inflammatory damage. If confirmed, the study could clarify the role of specific immune networks in the establishment and progression of lung fibrosis. The presented data and analyses showing the efficacy of HEI3090 small molecule acting via the P2RX7 pathway in reducing lung fibrosis are solid. The studies also show that genetic deletion of P2RX7 itself can reduce the extent of fibrosis. P2RX7 can thus have distinct effects in various phases of the development of lung fibrosis. There is a need for additional definitive studies that specifically identify the discrete phases of when inflammasome activation via P2RX7 signaling can worsen fibrosis versus when the same signaling can be beneficial. It also needs to be established whether distinct immune cell populations mediate the detrimental and beneficial effects of P2RX7 activation in lung fibrosis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors develop a novel genetic strategy for specific and comprehensive labeling of axo-axonic cells, also referred to as Chandelier cells, in the mouse brain. The approach and analysis are rigorous such that the data convincingly support the key conclusions, including the expanded distribution of axo-axonic cells throughout the brain. This study provides valuable new information about the distribution of this neuronal cell type, as well as new tools for future studies. This work will be of broad interest to neuroscientists who work on the anatomical and functional organization of neural circuits.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The manuscript addresses a fundamental question: are IDRs responsible for subnuclear clustering of transcription factors? A screen of 75 IDRs yielded convincing evidence that IDRs are rarely sufficient for subnuclear clustering, while the experimental design and data analysis provided limited evidence for the authors' claims regarding transcription factor clustering.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This is an important paper that combines methods ranging from agronomy and plant breeding to Arabidopsis functional genetics, to argue that polymorphism in a single gene affects crop yield in pearl millet by affecting root cell elongation and drought stress resilience in a poorly studied crop. The overall argument is plausible but whether the solid evidence generated with Arabidopsis experiments can be extended to pearl millet itself is unclear.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this valuable contribution, the authors demonstrate that the infusion of NAD+ may prevent death and reduce disease severity from lethal experimental bacterial sepsis, possibly through inflammasome inhibition, without reducing bacterial load. They provide solid evidence for these protective effects of NAD+, though the precise mechanisms involved remain unclear and need further support and elucidation. The core findings may well have clinical implications but, in addition to mechanistic clarifications, contextualised interpretation as metabolic adaptation to sepsis would create wider interest.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This detailed and well powered manuscript explores auditory perception of modulated noise in the presence of transcranial alternating-current stimulation (tACS) and shows valuable results suggesting that there are subject-specific effects when the phase of 2-Hz tACS varies relative to the phase of the noise modulation. The strength of the evidence is mixed. There is convincing evidence that tACS alters perception significantly in individuals; however, the effects are inconsistent across subjects and even across sessions, frustrating attempts to draw conclusions about the underlying mechanisms of the idiosyncratic effects. Despite these limitations, the paper will be of great interest to researchers interested in determining when and how tACS influences neural processes, especially those interested in neural entrainment and its relationship to perception.
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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 compelling, 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 a valuable method to visualize the location of the cell types discovered through single-cell RNA sequencing. The evidence supporting the claims is solid, but the inclusion of a larger number of samples would strengthen the study. It would also be helpful to have the methods explained in more detail. The work will be of interest to those seeking to identify new cell types from scRNA-seq and snRNA-seq data.
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mongoosejs.com mongoosejs.com
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Instance methods Instances of Models are documents. Documents have many of their own built-in instance methods. We may also define our own custom document instance methods. // define a schema const animalSchema = new Schema({ name: String, type: String }, { // Assign a function to the "methods" object of our animalSchema through schema options. // By following this approach, there is no need to create a separate TS type to define the type of the instance functions. methods: { findSimilarTypes(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); } } }); // Or, assign a function to the "methods" object of our animalSchema animalSchema.methods.findSimilarTypes = function(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); }; Now all of our animal instances have a findSimilarTypes method available to them. const Animal = mongoose.model('Animal', animalSchema); const dog = new Animal({ type: 'dog' }); dog.findSimilarTypes((err, dogs) => { console.log(dogs); // woof }); Overwriting a default mongoose document method may lead to unpredictable results. See this for more details. The example above uses the Schema.methods object directly to save an instance method. You can also use the Schema.method() helper as described here. Do not declare methods using ES6 arrow functions (=>). Arrow functions explicitly prevent binding this, so your method will not have access to the document and the above examples will not work.
Certainly! Let's break down the provided code snippets:
1. What is it and why is it used?
In Mongoose, a schema is a blueprint for defining the structure of documents within a collection. When you define a schema, you can also attach methods to it. These methods become instance methods, meaning they are available on the individual documents (instances) created from that schema.
Instance methods are useful for encapsulating functionality related to a specific document or model instance. They allow you to define custom behavior that can be executed on a specific document. In the given example, the
findSimilarTypes
method is added to instances of theAnimal
model, making it easy to find other animals of the same type.2. Syntax:
Using
methods
object directly in the schema options:javascript const animalSchema = new Schema( { name: String, type: String }, { methods: { findSimilarTypes(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); } } } );
Using
methods
object directly in the schema:javascript animalSchema.methods.findSimilarTypes = function(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); };
Using
Schema.method()
helper:javascript animalSchema.method('findSimilarTypes', function(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); });
3. Explanation in Simple Words with Examples:
Why it's Used:
Imagine you have a collection of animals in your database, and you want to find other animals of the same type. Instead of writing the same logic repeatedly, you can define a method that can be called on each animal instance to find similar types. This helps in keeping your code DRY (Don't Repeat Yourself) and makes it easier to maintain.
Example:
```javascript const mongoose = require('mongoose'); const { Schema } = mongoose;
// Define a schema with a custom instance method const animalSchema = new Schema({ name: String, type: String });
// Add a custom instance method to find similar types animalSchema.methods.findSimilarTypes = function(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); };
// Create the Animal model using the schema const Animal = mongoose.model('Animal', animalSchema);
// Create an instance of Animal const dog = new Animal({ type: 'dog', name: 'Buddy' });
// Use the custom method to find similar types dog.findSimilarTypes((err, similarAnimals) => { console.log(similarAnimals); }); ```
In this example,
findSimilarTypes
is a custom instance method added to theAnimal
schema. When you create an instance of theAnimal
model (e.g., a dog), you can then callfindSimilarTypes
on that instance to find other animals with the same type. The method uses thethis.type
property, which refers to the type of the current animal instance. This allows you to easily reuse the logic for finding similar types across different instances of theAnimal
model.
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Evaluation statement (10 January 2024)
Driggers et al. is an elegant study that reports the structure of an open KATP channel complex formed from the Q52R diabetes mutation of the pore-forming subunit Kir 6.2, the sulfonylurea receptor (SUR1), and long-chain phosphatidylinositol 4,5-bisphosphate (PIP2) – a key lipid that stabilizes the open state of the channel and regulates inhibition by intracellular ATP. The structure reveals one PIP2 site related to that seen in other Kir channels as well as a second unanticipated one where the lipid snuggles into the interface between Kir6.2 and a region of SUR1 previously implicated in promoting the open state of KATP. This important finding helps to explain how PIP2 exerts such a profound regulatory influence on KATP.
Biophysics Colab considers this to be a convincing study and recommends it to scientists working on KATP and other membrane proteins regulated by PIP2.
(This evaluation by Biophysics Colab refers to version 2 of this preprint, which has been revised in response to peer review of version 1.)
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable manuscript follows up on previous findings from the same lab supporting the idea that deficits in learning due to enhanced synaptic plasticity are due to saturation effects. Convincing evidence is presented that behavioral learning deficits associated with enhanced synaptic plasticity in a transgenic mouse model can be rescued by manipulations designed to reverse the saturation of synaptic plasticity. In particular, the finding that a previously FDA-approved therapeutic can rescue learning could provide new insights for biologists, psychologists, and others studying learning and neurodevelopment.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this important study, Gaikwad and colleagues employed ribosome profiling in conjunction with standard biochemical approaches to investigate the role of eIF2A in translation initiation in yeast under optimal growth conditions or stress. The authors provide convincing data that eIF2A is not implicated in translation initiation in yeast, a finding that is anticipated to inspire future investigations to identify the cellular role(s) of eIF2A in yeast. Considering the broad scope of cellular functions attributed to eIF2A, this study should be of interest to a wide spectrum of biomedical researchers ranging from those studying mechanisms of translation regulation to virologists and cancer biologists.
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www.researchsquare.com www.researchsquare.com
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eLife assessment
This fundamental study presents a method to restore muscle innervations in ALS mouse models using optogenetics. It is convincing that embryonic stem cell derived motor neurons can be transplanted into and applied to reinnervate the muscles in an ALS mouse model. The work will be of broad interest to researchers and medical biologists to develop new strategies for the treatment of neurodegenerative disorders resulting from denervated skeletal muscles.
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eLife assessment
This is a valuable paper that might contribute new insight into the role of GABA in semantic memory, which is a significant question in higher cognition. However, the empirical support for the main claims is incomplete, with some results not fully coherent and robust – the paper would benefit from more rigorous analyses. These results, once strengthened, will be of interest to broad readers of the neuroscience and cognitive neuroscience community.
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eLife assessment
This important study combines experiments with optogenetic actuation and theory to understand how signalling proteins control the switch between cell protrusion and retraction, two processes in single-cell migration. The authors examine the role of a guanine exchange factor (GEF) on the downstream effectors RhoA and Cdc42, which trigger retraction and protrusion, respectively. The experimental and theoretical evidence provides a convincing explanation for why and how a single signalling protein – here, a GEF of RhoA – can control both protrusion and retraction.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In this valuable study, the authors characterize the role of splicing factor SRSF1 during spermatogenesis with a conditional knockout of Srsf1 in male germ cells. The phenotype and molecular role of SRSF1 in regulating alternative splicing in precursor spermatogonial stem cells in juvenile testes are convincingly supported. The paper also provides convincing evidence that the mRNA encoding Tial, a factor relevant to spermatogonial maintenance and male fertility, is alternatively spliced in testis and that this splicing is regulated by SRSF1. The work will be of interest to the fields of reproductive biology, stem cell biology, and alternative splicing.
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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 convincing 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 results and conclusions of the study.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a useful set of tools to perform tissue clearing and labeling on large-scale formalin-fixed paraffin-embedded brain specimens. This has the potential for the use of archival pathology specimens in modern research. Whilst the evidence supporting the validity of the method is convincing, the method development and protocol description are still incomplete and would benefit from a more comprehensive analysis. This paper would be of interest to neuroscientists and pathologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study by Jeong and Choi studied neural activity in the medial prefrontal cortex (mPFC) while rats performed a foraging paradigm in which they forage for rewards in the absence or presence of a threatening object (Lobsterbot). The authors conclude that the mPFC population activity switches between distinct functional modes conveying distinct task variables such as the distance to the reward location and types of threat-avoidance behaviors depending on the location of the animal. The reviewers appreciated the use of the naturalistic paradigm but thought that the evidence was incomplete as the authors could not exclude the possibility that there are separate populations of neurons encoding different task variables, and in addition, various confounding factors such as specific movements have not been dissociated from the activity encoding the above variables.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study reports important findings that intermediate states exist in epithelial-mesenchymal transition (EMT) during natural development and differentiation of mammalian neural crest cells, similar to recent reports in cancer. The authors convincingly determined that there were at least two paths to delamination and migration - one that occurs during S-phase of cell cycle and another during G2/M phase, and that the process of delamination is not restricted to cell fate. Finally, the authors showed that expression of Dlc1 may be used to identify cells in an intermediate state of EMT as well as their spatial location in the mouse embryo. The work will be of interest to developmental biologists, neurobiologists and cancer researchers.
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www.biorxiv.org www.biorxiv.org
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eLife Assessment
This important study demonstrates the use of the mammalian Musashi-1 (MSI-1) RNA-binding protein as a tool for regulating gene expression in Escherichia coli. The authors provide convincing evidence that MSI-1 functions as an effective repressor of translation, and that MSI-1 can be allosterically controlled by oleic acid. This work establishes MSI-1 as a potential tool for synthetic biology applications, and the system developed here can be used for mechanistic studies of MSI-1.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors used an appropriate micro-engineered experimental model of angiogenesis coupled to mathematical model to study the early steps of the angiogenic sprouting. To this end, the authors developed a convincing model to predict how VEGF activates Delta-Notch signaling. The work affords important new insight into the complex processes involved in the onset of angiogenesis.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable paper examines the Bithorax complex in several butterfly species, in which the complex is contiguous and not split, as it is in the well-studied fruit fly Drosophila. Based on genetic screens and genetic manipulations of a boundary element involved in segment-specific regulation of Ubx, the authors provide convincing evidence for their conclusions, which could be strengthened by additional data and analyses in the future. The data presented are relevant for those interested in the evolution and function of Hox genes and of gene regulation in general.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents an important tool for tracking the connectivity of neurons in mouse and potentially other mammals using a combined approach of barcoded rabies virus libraries and spatial transcriptomics. The data supporting the technique are convincing, the validation against known anatomical knowledge is rigorous, and the authors advance the techniques by combing them in vivo. Overall, this is a very good paper describing a technique for tracking neural circuits.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This fundamental study advances our understanding of TRAIL-induced apoptosis by defining how Heparan triggers this pathway at the molecular level. The evidence supporting the conclusions is compelling, with rigorous binding assays, structural methods, and cellular studies. The work will be of broad interest to cell biologists and biochemists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides continuous maps of human brain gene expression and explores their relationship with a large variety of microscopic and macroscopic aspects of brain organisation. The authors provide convincing evidence for a relationship between gene expression maps with various aspects of the anatomy of adult brains, during development, and in the case of mental disorders. The data and methods introduced can be an important tool for neuroimaging research.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The manuscript describes the synergy among PI3Kbeta activators, providing compelling results concerning the mechanism of their activation. The particular strengths of the work arise to a great extend from the reconstitution system better mimicking the natural environment of the plasma membrane than previous setups have. The study will be a landmark contribution to the signaling field.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study describes how PhoP regulates cyclic-AMP production in the human pathogen Mycobacterium tuberculosis. The authors provide convincing evidence that PhoP acts as a repressor of the cyclic-AMP-specific phosphodiesterase, Rv0805, which can degrade cyclic-AMP. The work requires substantive revision to clarify the presentation of the data, together with appending conclusions, and will be of interest to bacteriologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study offers important insights into the transcriptional regulatory networks driving female gametocyte maturation in rodent malaria parasites. The work is based on solid methodology and shows how two female-specific transcription factors, AP2-FG and PFG (aka Fd2), co-operate to up-regulate the expression of genes required for development after fertilization occurs in the mosquito midgut. This study will be of interest to scientists working on sexual differentiation and gene regulation in Plasmodium and other apicomplexan parasites.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors have developed a compelling coarse-grained simulation approach for nucleosome-nucleosome interactions within a chromatin array. The data presented are solid and provide new insights that allow for predictions of how chromatin interactions might occur in vivo. The tools presented herein will be valuable for the chromosome biology field.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable paper builds on a method, previously conceptualized and validated, of genetic control for insect populations. The method, called pgSIT, uses integrated CRISPR-Cas9 based constructs to generate, in certain combinations of genotypes, mutations that cause both male sterility and female inviability. Release of such genotypes in sufficiently large numbers can lead to an inundation of a local insect population with sterile males and this can lead to localised population suppression, which represents an effective method of control for problematic insect populations. The data are convincing and will be of interest to anyone working on vector control strategies.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study uses genomically-engineered glypican alleles (Dally and Dally-like) to determine the role of these proteins on the Dpp/BMP morphogen gradient in the wing disc of Drosophila melanogaster. The new glypican null and tagged add-back alleles, as well as a Dpp mutant that cannot bind heparin sulfate moieties in glypicans, provide solid results that support the model in which Dally but not Dally-like stabilizes Dpp on the cell surface by counteracting receptor-mediated Dpp internalization. This paper would be of interest to developmental biologists working on morphogens.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The manuscript explores the interplay between cytoskeletal bactofilins and cell wall hydrolases in bacterial morphogenesis, utilizing a range of methodologies from bacteriological to biochemical. The study provides important insights into bactofilin polymers' control over peptidoglycan synthesis and the identification of LdmC, supported by a comprehensive array of genetic, bioinformatic, biochemical, and biophysical tools. These convincing findings propose a conserved module governing bacterial morphogenesis, emphasizing the direct association of cell wall remodeling enzymes with a dynamic cytoskeleton, akin to mechanisms observed in other cellular processes such as cell growth and division.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This useful study presents 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 solid.
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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 important study advances our understanding of the machinery that couples DNA synthesis with the deposition of histone proteins onto newly synthesized DNA. A convincing 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 valuable study presents convincing evidence for an association between PARP-1 and H4K20me1 in transcriptional regulation, supported by biochemical and ChIP-seq analyses, but further validation and attempts to obtain mechanistic insights are warranted along with discussion of recent findings by others in this area.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
For decades it has been accepted that only the growth-arrested "stumpy" form of Trypanosoma brucei can infect the arthropod vector, the Tsetse fly, but this was recently challenged by a demonstration that - under artificial conditions that are known to enhance infectivity - the proliferative "slender" form can also establish Tsetse infections. The infectiousness of the two forms is a fundamental question in trypanosome biology and epidemiology, concerning both infection dynamics and parasite differentiation. The authors of the current study provide compelling evidence that without artificial enhancement, the "stumpy" form is indeed much more infective for Tsetse than the slender form; they suggest that this is probably also true in the wild. Since the authors of this paper did not themselves test the effect of enhancing conditions, the precise reason for the discrepancy in results between the two laboratories has not been demonstrated conclusively.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The authors introduce a useful machine-learning model for predicting binding sites of diverse ligands, including DNA, RNA, peptides, proteins, ATP, HEM, and metal ions, on proteins. The method is freely accessible and user-friendly. The authors have conducted thorough benchmarking and ablation studies, providing solid evidence of the model's overall performance, but the comparisons to other methods are incomplete, due to the lack of consistency between training methods and data.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
In Drosophila melanogaster, the SOCE channel Orai is required for the development of flight promoting dopaminergic neurons. The Hasan laboratory has previously shown that disabling Orai function impairs Drosophila flight due to aberrant neuronal development at the pupal stage. In this fundamental study, Mitra et al show that SOCE drives a transcriptional feedback loop via the homeobox transcription factor, 'Trithorax-like' (Trl), and histone modifiers, Set2 and E(z), to regulate the expression of key genes required for the function of dopaminergic flight neurons, including the muscarinic acetylcholine receptor and the inositol 1,4,5-trisphosphate receptor. This solid study is carefully performed with validated methodology and most of the analyses are rigorous.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study aims to identify pioneer transcription factors, which are defined as transcription factors that compete with nucleosomes for DNA binding. The authors provide methods for identifying pioneer transcription factors on a cell type basis, using nucleosome positioning and motif information across different cell lines. The evidence to support the claims is largely solid. This work will be of interest to computational and molecular biologists working on transcription factors.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents a valuable syngeneic zebrafish model for studying glioblastoma and will be of interest to neuro-oncologists and cancer biologists. Using a feasible in vivo model to study the tumour microenvironment, cell/cell interaction, and immunity, the data are compelling, although the study can benefit from the additional characterization of tumours, as well as non-tumour cells in the niche including microglia/macrophage population.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
The work described in this manuscript is timely and useful in that it builds on prior research investigating the neural basis of abstract and concrete concepts by examining how these concepts are processed for a naturalistic stimulus - movie watching. The authors provide incomplete evidence that the varying strength of the relationship between a word and a particular visual scene is associated with a change in the similarity between the brain regions active for concrete and abstract words. This work makes a contribution that will be of general interest within the field despite some limitations in how the authors chose to define context, highlighting both the inherent challenge of quantifying context in a multimodal stimulus and the need to move towards brain imaging paradigms that capture context better than isolated word or sentence paradigms do.
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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 and the work will likely spark interest in further examining the proposed channel-channel interaction in neuronal cell membranes.
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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-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. This paper may be of interest to preclinical and clinical scientists working with anesthetic and dissociative drugs.
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www.researchsquare.com www.researchsquare.com
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eLife assessment
In this manuscript, the authors present a wealth of fMRI data at both 3T and 7T to identify a scene-selective region of the intraparietal gyrus ("PIGS") that appears to have some responsivity to characteristics of ego-motion. In a series of experiments, they delineate the anatomical location of PIGS and functionally differentiate it from nearby V6 and OPA. Evidence for these valuable findings is solid, but further (a) consideration of whether this region overlaps with others reported previously and (b) support for, or tempering of, the ego-motion claim may be warranted.
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eLife assessment
This important study provides evidence supporting the idea that visual experience plays a role in shaping the patterns of functional connectivity between extrastriate visual cortex and prefrontal regions during development, by comparing neonates, blind and sighted adults. The evidence supporting the authors' claim is solid, although control analyses could strengthen the conclusions and possibly offer additional mechanistic insights. This study will be of significant interest to neuroscientists and neuroimaging researchers working on vision, plasticity, and development.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Songbirds provide a tractable model system to study mechanisms of vocal production and sequencing, and past work showed that the lesions to LMAN, the output of a basal ganglia thalamocortical loop, reduced vocal variability, consistent with a role in motor exploration. In this important work, the authors examined how lesions to an understudied neighboring region, MMAN, part of a parallel basal ganglia loop, affect singing in Bengalese finches, whose songs exhibit complex sequential transitions. They provide convincing evidence that MMAN lesions cause increased sequential variability, showing that distinct frontal systems can have distinct functions for producing and sequencing song syllables.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides a valuable contribution to our understanding of causal inference in visual perception. The evidence provided through multiple well-designed psychophysical experiments is solid. However, the conclusions drawn on the implementation of causal inference in general are too broad to be properly supported by the current results given their narrow focus on visual launch events.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This valuable study reports on the characteristics of premotor cortical population activity during the execution and observation of a moderately complex reaching and grasping task. By using new variants of well-established techniques to analyse neural population activity, the authors provide solid evidence that while the geometry of neural population activity changes between execution and observation, their dynamics are largely preserved. While these observations are novel and robust barring the need for additional controls, the authors should do additional work to define the functional implications of their findings.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents important findings about synaptic connectivity among subsets of unipolar brush cells (UBCs), a specialized interneuron primarily located in the vestibular lobules of the cerebellar cortex. The evidence supporting the claims are interesting and solid. The work will be of interest to cerebellar neuroscientists as well as those focussed on synaptic properties and mechanisms. Although several compelling pieces of data were presented, some in vivo work remains to be conducted in order to test if the hypothesis and predictions translate into the behaving animal and how it would impact the processing of feedback or feedforward activity that would be required to promote behavior.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides direct evidence showing that Kv1.8 channels underly several potassium currents in the two types of sensory hair cells found in the mouse vestibular system. This is an important finding because the nature of the channels underpinning the unusual potassium conductance gK,L in type I hair cells has been under scrutiny for many years. Although most of the experimental evidence is compelling and the analysis is rigorous, the evidence supporting some of the claims related to Kv1.4 channels is incomplete. The study will be of interest to cell and molecular biologists and auditory neuroscientists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This manuscript presents valuable findings on the identification of epigenetically mediated control for the recognition of dihydropyrimidine dehydrogenase (DPYD) gene expression that is linked with cancer treatment resistance using 5-fluorouracil. The evidence is compelling, supported by data from patient-derived specimens and direct assessment of 5-fluorouracil sensitivity, which provides confidence in the proposed mechanisms. The model is additionally supported by genome data from a population with high "compromised allele frequency". This work will interest those studying drug resistance in cancer therapy.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important study using engineered mouse models provides a first compelling demonstration of a pathogenic phenotype associated with lack of expression of p53AS, an isoform of the p53 protein with a different C-terminus as canonical p53. The work also offers correlative evidence that Ackr4, differentially expressed in this mouse model, may be a male-specific prognostic factor in a specific type of B-cell lymphomas. Direct functional evidence testing the links proposed would better support the major findings of the study.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study offers valuable insights into the remarkable resistance of tardigrades to ionizing radiation by showing that radiation treatment induces a suite of DNA repair proteins. They identify a strongly induced tardigrade-specific DNA-binding protein that can reduce the number of double-strand breaks in human cancer-derived cells. The evidence of upregulation of repair proteins is compelling and the case for a role of the newly identified protein in repair can be strengthened as genetic tools for tardigrades become better developed. The results will be of interest the fields of DNA repair and radiobiology as well as tardigrade biologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides a valuable theoretical exploration of non-enzymatic sustained replication of RNA systems, in the parabolic growth regime of the evolution of putative primordial replicators. It provides solid evidence that parabolic growth mitigates the error threshold catastrophe, thus demonstrating another way in which this regime contributes to the maintenance of genetic diversity, although the justification of modeling choices and of parameter values is sometimes incomplete. The findings shed light on relevant evolutionary regimes of primordial replicators, with potential applicability to our understanding of the origin of life.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
Based on a technological advance which couples onboard calcium imaging with in vivo electrophysiology in freely behaving mice, this important work presents data about the modulation of some long range brain activity correlations during social interactions. Solid evidence shows that neural activity across cerebellum and cingulate cortex is more correlated during social behaviors than during non-social epochs. This study is of interest for a broad range of neurophysiologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This important manuscript focuses on the mechanisms by which food signals and food ingestion modulate animal foraging. The authors provide convincing support for the interesting idea that chemosensory and interoceptive signals converge on transcriptional regulation of the TGF-beta ligand DAF-7 in a single pair of C. elegans chemosensory neurons (ASJ) to regulate behavior. Their studies implicate a conserved signaling molecule, ALK, in this regulation, suggesting a conserved link between food cues and the neuroendocrine control of foraging behavior.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This work advances on two Aso et al 2014 eLife papers to describe further resources that are valuable for the field. This paper identified and contributes additional MBON split-Gal4s, convincingly describing their anatomy, connectivity and function.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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eLife assessment
This valuable study shows that auxin exposure perturbs feeding behavior, survival rates, lipid metabolism, and gene expression patterns in adult Drosophila flies. The results are solid with proper methods and data analyses, and the evidence broadly supports the conclusions with only minor weaknesses. This work is relevant for fly geneticists who are interested in using the auxin-inducible gene expression system for inducing target protein degradation acutely.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study provides important findings on the evolution and function of the X-linked miR-506 miRNA cluster. The evidence supporting the conclusions is convincing, including the generation and characterization of an impressive number of the miRNA deletion mutants. This work will be of interest to RNA biologists, evolution biologists and reproductive biologists.
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www.biorxiv.org www.biorxiv.org
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eLife assessment
This study presents new data highlighting the importance of appropriate coenzyme A handling in the mitochondria for maintaining appropriate energy production capacity. Several findings regarding the role of a key metabolic enzyme in how skeletal muscle cells use different substrates for energy production are valuable and supported by solid evidence, but there are concerns whether the data support the conclusion that ACOT2 regulates mitochondrial matrix acyl-CoA levels in white skeletal muscle to facilitate fatty acid oxidation β-oxidation.
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