eLife assessment

This important study reconstructs the evolutionary history of Heliconius butterflies, a well-established model system for understanding speciation in the presence of gene flow between species. Using a convincing statistical phylogenetic approach that relies on the multispecies coalescent, the authors reconstruct the evolution of the lineage, including the timing of speciation events and the history of gene flow. The new phylogeny will be of interest to all researchers working on Heliconius butterflies, and the phylogenetic approach to investigators aiming to understand the history of lineages that have experienced extensive gene flow.

eLife assessment

This important study reports a new mutant mouse with compromised function of one of the BRCT repeats of TOPBP1, a DNA damage response protein. Mutant mice are viable but males are sterile, owing to the lack of spermatocytes beyond the late pachynema stage of the first meiotic prophase. Using immunofluorescence, phospho-proteomics and single-cell sequencing of cells in the testis, the authors provide solid evidence that the animals are defective in the maintenance (but not the initiation) of sex chromosome inactivation in pachynema. The report is of interest to researchers in the fields of meiosis as well as gene silencing/sex chromosome inactivation.

eLife assessment

The manuscript by Kahraman et al. describes the use of a fluorescent dye for purifying and analyzing human islet alpha cells. The study provides solid evidence that the alpha cells can be purified using this method and the cells remained viable and functional after culturing for several days. The significance of the study is access to a new tool that will be useful for islet biologists and researchers studying diabetes mechanisms.

eLife assessment

This study presents valuable findings that could be utilized for the identification of women at risk for preeclampsia prior to the onset of the disease. The novel aspect of this study lies in the utilization of exosomes with two different sizes. However, the data is incomplete: the patient population has not been well-defined, and the study only measured the proteins at a single time point.

eLife assessment

This important study describes how the composition and stabilization of nanodomains in the plasma membrane are an integral part of plant defence against viruses, with a focus on the calcium-dependent kinase CPK3 and its apparent interaction with a plasma-membrane nano domain scaffold protein from the remorin family. While the evidence for a specific role of CPK3 in limiting viral spread is convincing, the claims regarding the CPK3-remorin interaction would be strengthened by additional experimental support. The work, which will be of interest to plant cell biologists and plant virology, opens new avenues for understanding the role of plasma membrane nanodomains in limiting viral spread.

eLife assessment

This study has uncovered some important initial findings about cellular responses to aneuploidy through analysis of gene expression in a set of donated human embryos. While the study's findings are in general solid, some experiments lack statistical power due to small sample sizes. The authors should try to get much more insight with their data highlighting the novel findings.

eLife assessment

This study has uncovered some interesting findings about the fungal composition and its interaction with bacteria in Caesarean section scar diverticulum (CSD). While the study's findings are valuable and with translation possibilities, the strength of the conclusions obtained is incomplete due to the small sample size and methodological issues indicated by the reviewers such as the lack of controls and the location of samples analyzed.

eLife assessment

This valuable study describes engineered dengue virus variants that can be used to dissect epitope specificities in polyclonal sera, and to design candidate vaccine antigens that dampen antibody responses against undesirable epitopes. While the major claims are supported by solid evidence, experiments to distinguish the impact on antibody binding from neutralizing activities would have strengthened the study. This work will be of interest to virologists and structural biologists working on antibody responses to flaviviruses.

eLife assessment

This important study explores numerous lines of evidence for the surprisingly diverse diets of a group of toothed birds that lived over 100 million years ago. The large amount of data the authors collected forms a solid dataset for their statistical analyses. The methods are, to various extents, extensible to other limbed vertebrates. The conclusions in the article itself will be of interest to anyone who studies ecological evolution in birds or dinosaurs more generally, as well as to anyone who studies the impact of the mass extinction event 66 million years ago on ecology and evolution.

eLife assessment

This study describes an important bioinformatics tool for normalizing gene copy number from metagenomic assemblies. The tool is used in a meta-analysis of data from inflammatory bowel disease (IBD) patients and healthy controls. While some of the evidence for the power of the method is compelling, other evidence seems incomplete. The inclusion of additional computational and/or experimental validation would markedly strengthen the study. This paper will likely be of broad interest to researchers studying the role of complex microbial communities in host health and disease.

eLife assessment

This important work provides a comprehensive study of how different cell types of the lateral and dorsomedial hypothalamus are affected by an Influenza H1N1 infection. The evidence presented here is solid; the methodological approach is state-of-the-art, however, the theoretical analysis can be strengthened by further reanalysis of the datasets. This work is of interest to virologists and neurobiologists as the results are promising and open a new door to understanding the effect of respiratory viruses on the physiology of the central nervous system.

eLife assessment

In this valuable paper, the authors analyze the functions of the five C-terminal repeat sequences in the Dux embryonic transcription factor and their role in recruiting cofactors for gene regulation. The evidence is solid and the work is carefully done, although additional experiments could strengthen the overall conclusions of the manuscript.

eLife assessment

This study provides important imaging evidence for the connectopic mapping of the locus coeruleus (LC) and links a rostro-caudal gradient to heterogeneous functional organisation of this structure. Using a well-established gradient approach applied to large 3T and 7T fMRI datasets, the study demonstrates a change in LC functional gradients with increasing age. Overall, the study provides solid evidence and highlights the importance of using more specific spatial definitions of the LC based on distinct connectivity patterns in future studies.

eLife assessment

The role of CRB3A/B in ciliogenesis was discovered several years ago in epithelial cells and in vivo, but the mechanism by which CRB3A/B regulates ciliogenesis has been unknown. Here, the authors confirm the requirement of CRB3A/B expression for primary ciliogenesis in both mouse and human cells and propose a mechanism by which CRB3A/B promotes ciliogenesis. The results are useful but currently incomplete: further experimentation and data analysis are needed to support some of the authors' central claims.

eLife assessment

This study presents valuable insights into the circuit mechanisms of how the fly nervous system modulates ingestive behaviors in response to metabolic conditions. The authors present convincing findings on how downstream neurons connected to Interoceptive Subesophageal zone Neurons modulate nutrient and/or water ingestion in Drosophila melanogaster.

eLife assessment

There is a tremendous need to increase agricultural productivity with means that are both practical and efficient. Drawing on data from variable field environments, this important study provides a theoretical framework for the identification of new factors with presumed relevance for crop growth. This framework can be applied in the context of both agricultural and ecological studies. There is solid evidence for several of the authors' claims, but the impact of the study is limited due to missing functional validation of candidate species in the field. Plant biologists and ecologists working in agricultural and natural environments will find the work interesting.

eLife assessment

There is a tremendous need to find practical and efficient means in order to increase agricultural productivity. Drawing on data from variable field environments, this study provides a valuable theoretical framework to identify new factors that could increase agricultural production. There is solid evidence to support the authors' claims, though following the fate of candidate species after introduction into rice fields would have strengthened the study. Plant biologists and ecologists working in nature and fields will find the work interesting.

eLife assessment

This fundamental study provides a framework for leveraging systems genetics data to dissect mechanisms of gut physiology. The authors provide compelling analyses to highlight diverse modes of interrogating intestinal inflammation, dietary response, and consequent impacts on IBD. As a resource, it will have great utility for linking genetic variation and diet to gut-related pathophysiologies.

eLife assessment

This valuable study contributes to understanding how retinal activity shapes the response properties of excitatory and inhibitory neurons in a major visual target, the superior colliculus. The evidence supporting the claim is convincing: the work is technically excellent yet the interpretation of these results assumes an unbiased sampling and integration of the RGC axon in the SC, a caveat pointed out by the authors. Overall, this study provides insights into the integration of visual information from the eye to the brain, and this work will be of interest to visual neuroscientists.

eLife assessment

This fundamental study leverages natural genetic diversity in mice to discover candidate genes for insulin sensitivity, followed by experimental identification of compounds that can modulate insulin sensitivity, and finally initial mechanistic investigation of the mode of action. The generalized approach presented here – the integration of systems genetics data with drug discovery – supported by compelling evidence, will be a guide for others who seek to translate insights from mammalian genetics to drug discovery.

eLife assessment

This important study leverages natural genetic diversity in mice to discover candidate genes for insulin sensitivity, followed by experimental identification of compounds that can modulate insulin sensitivity, and finally initial mechanistic investigation of the mode of action. The generalized approach presented here – the integration of systems genetics data with drug discovery – supported by convincing evidence, will be a guide for others who seek to translate insights from mammalian genetics to drug discovery.

eLife assessment

This valuable manuscript attempts to identify the brain regions and cell types involved in habituation to dark flash stimuli in larval zebrafish. Habituation being a form of learning widespread in the animal kingdom, the investigation of neural mechanisms underlying it is a worthwhile endeavor. The authors use a combination of behavioral analysis, neural activity imaging, and pharmacological manipulation to investigate brain-wide mechanisms of habituation. However, the data presented are incomplete and do not show a robust causative link between pharmacological manipulations, neural activity patterns, and behavioral outcomes.

eLife assessment

This study presents fundamental new insight into the regulatory apparatus of PI3Kgamma, a crucial kinase in signaling pathways that control the immune response and cancer. A suite of biophysical and biochemical approaches provide convincing evidence for new sites of allosteric control over enzyme activity. The rigorous findings provide structure and dynamic information that may be exploited in efforts to control PI3Kgamma activity in a therapeutic setting.

eLife assessment

This paper demonstrates valuable evidence for genetic redundancy of the COUPTF transcription factors in hippocampal development by creating conditional compound knockouts in combination. Authors aim to demonstrate specific and complementary roles of the two COUPTF homologues. The paper uses convincing methods that includes both anatomic and behavioral studies for the roles of these factors. However, the strength of evidence was incomplete, due to the use of a Cre line that was not adequately described, and lack of concordance with expression domains of the COUPTF factors with the published literature dampened enthusiasm. This concern is expressed by reviewers in the interpretation of some of the finding that may require additional experiments in the future.

eLife assessment:

This valuable study, of interest for students of the biology of genomes, uses simulations in combination with published data to examine how many TADs remain after cohesin depletion. The authors suggest that a significant subset of chromosome conformations do not require cohesin, and that knowledge of specific epigenetic states can be used to identify regions of the genome that still interact in the absence of cohesin. The theoretical approaches and quantitative analysis are state-of-the-art, and the data quality and strength of the conclusions are solid. However, because "physical boundaries (of domains?)" in the model appear to be a consequence of preserved TADs, rather than the other way around, the functional insights are limited.

eLife assessment

This valuable study presents a novel analysis of a large human intracranial electrophysiological recording dataset. The study challenges the traditional view that neural responses to word lists exhibit smoothly drifting contexts over time, showing that items just after a boundary have a characteristic response that occurs repeatedly. The evidence is incomplete, however, leaving open the possibility for alternative explanations.

eLife assessment

This convincing study, which is based on a survey of researchers, finds that women are less likely than men to submit articles to elite journals. It also finds that there is no relation between gender and reported desk rejection. The study is an important contribution to work on gender bias in the scientific literature.

eLife assessment

This study, of interest to cell biologists, presents valuable findings on the positioning mechanics of microtubule asters in Drosophila embryo explants. While the experimental setting is artificial (centrosomes are detached from nuclei and the cell cycle is arrested in interphase in these explants), it extends the framework of aster positioning from recently published work. The authors reach the conclusion that asters interact via pushing forces, an interesting conclusion supported by solid evidence. The identification of motors and MAPs functioning in the aster positioning mechanism would further strengthen the study.

eLife assessment

This important study identifies a short amino acid sequence that, when fused in multimeric form to the amino termini of luminal ER proteins, initiates proteasomal degradation via the Hrd1 ER quality control ubiquitin ligase complex. The authors provide solid evidence that this sequence functions as a "degron" for ER proteins. Future work is required to get a more detailed view of the properties of this degron, the mechanisms underlying its recognition by ER-resident and cytoplasmic factors, and the in vivo relevance of the findings.

eLife assessment

This study presents a useful inventory of the joint effects of genetic and environmental factors on psychotic-like experiences, and identifies cognitive ability as a potential underlying mediating pathway. The data were analyzed using solid and validated methodology based on a large, multi-center dataset. The claim that these findings are of relevance to psychosis risk and have implications for policy changes are partially supported by the results.

eLife assessment

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

eLife assessment

This important study combines extensive phenotyping of genome-wide deletion mutants and machine learning-based prediction to generate a large scale resource for understanding the functions of thousands of fission yeast protein-coding genes. This resource is supported by convincing phenotyping data and state-of-the-art bioinformatic analyses and will be of interest to many geneticists.

eLife assessment

This important study advances our understanding of the functions and regulation of the Drosophila transcriptional regulator Bonus, an ortholog of mammalian TIF1 family members. Solid evidence, leveraging both in vivo and in vitro studies, reveals the molecular requirements for Bonus' function as a transcriptional repressor, including a key role for sumoylation.

eLife assessment

This important study expands on current knowledge of allosteric diversity in the human kinome by C-terminal splicing variants using as a paradigm DCLK1. The authors provide convincing evolutionary and some mechanistic evidence how C-terminal isoform specific variants generated by alternative splicing can regulate catalytic activity by means of coupling specific phosphorylation sites to dynamical and conformational changes controlling active site and substrate pocket occupancy, as well as protein-protein interactions. The data will be of interest to researchers in the kinase and signal transduction field.

eLife assessment

This important study in the protozoan parasite Toxoplasma gondii significantly advances our understanding of calcium signaling mediated by the kinase CDPK1 in this species. The authors' conclusions are supported by convincing evidence, with rigorous biochemical experiments and microscopy analysis. The work will be of broad interest to researchers in the fields of signal transduction and protozoan biology.

eLife assessment

This work presents important insights regarding the mechanism underlying the assembly, maintenance, and disassembly of a very stable microtubule-based structure, termed quiescent-cell nuclear microtubule (Q-nMT) bundle, formed in quiescent yeast cells to ensure cell survival and viability. Some of the evidence is solid, but some of the major claims are only incompletely supported and require additional analyses using state-of-the-art methodology and more precise descriptions.

eLife assessment

This study provides a clearly presented and thoughtfully analyzed single cell-resolution dataset of gene expression in wildtype and mutant zebrafish skin. These data are used by the authors to develop and test hypotheses about cell lineage relationships and signaling interactions between cell types in the skin, allowing them to identify roles for several signaling pathways and the hypodermis in scale and pigment cell development. These findings constitute a fundamental contribution to the field, and the rigor of the analyses make this manuscript compelling.

eLife assessment

This study presents valuable findings on genetic risk factors for type 1 diabetes and celiac disease using a large cohort from the Environmental Determinants of Diabetes in the Young (TEDDY) study. The evidence supporting the claims of the authors is solid, although the inclusion of the genetic effect of this locus on individuals with different genetic backgrounds would have strengthened the study. The work will be of interest to population geneticists working on diabetes and celiac disease.

eLife assessment

This study presents a valuable set of experiments to test whether Bombus terrestris bumblebees can detect lethal-level doses of a series of pesticides in nectar-mimicking sugary solutions. Behavioural essays were coupled with electrophysiological measurements to show that B. terrestris mouthparts cannot detect high levels of the tested pesticides. If confirmed using pesticide formulas, and other bumblebee species, the study will be of general interest in environmental science research. Most experimental data are compelling, and the conclusions are solid, but the write-up would benefit from being more to the point and less overgeneralizing.

eLife assessment

The findings of this work on the protective role of Leucine in LPS-induced cytokine release syndrome by modulating macrophage polarization are potentially valuable in establishing the link between metabolic regulation of macrophage function and inflammatory responses. The evidence supporting the conclusions that the mTORC1/LXRa axis but not the STAT6 pathway mediates Leucine-promoted M2 polarization are is solid. The manuscript is well written, but the mechanistic studies are incomplete, hence should be improved.

eLife assessment

This convincing study demonstrates a potentially important role for the factor Numb in skeletal muscle excitation-contraction coupling. Numb knockout reduced contractile force. The authors thus demonstrate a novel role for Numb in calcium release in skeletal muscle.

eLife assessment

This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. While of significant interest to those working on the immune biology of urothelial cancer and drug discovery, this work does not provide any mechanistic insights into the role of DUX4 and immune suppression and the assessment on clinical samples forms the discovery part of a biomarker program, requiring further cohorts for validation.

eLife assessment

The authors have made important contributions to our understanding of the pathogenesis of erectile dysfunction (ED) in diabetic patients. They have identified the gene Lbh, expressed in pericytes of the penis and decreased in diabetic animals. Overexpression of Lbh appears to counteract ED in these animals. The authors also confirm Lbh as a potential marker in cavernous tissues in both humans and mice. While solid evidence supports Lbh's functional role as a marker gene, further research is needed to elucidate the specific mechanisms by which it exerts its effects. This work is of interest to those working in the fields of ED and angiogenesis.

eLife assessment

This manuscript presents a useful method for a comprehensive numerical simulation to systematically characterise the effect of heterogeneity in either the initial conditions or the biophysical parameters on the dynamic behaviour of protein signalling networks. Nevertheless, the presentation and detail of their model appear incomplete to fully support the main claims of the manuscript.

eLife assessment

The authors set out to study the development of high altitude polycythemia, which affects mice in a hypoxia chamber and humans staying at a hypoxic atmosphere at high altitude. The findings are useful both for initiating the discussion of the hypothesis that splenic red pulp macrophages, central to red cell survival, are impacted by hypoxia, and for providing some data that partially supports this hypothesis. However, the current data are inadequate to fully support the authors' conclusions that RPM are inefficient during hypoxia, reducing erythrophagocytosis, and new data provides evidence of the opposite conclusion, given that RBC lifespan is decreased (rather than increased) in response to hypoxia, suggesting that RPM are more efficient at erythrophagocytosis.

eLife assessment

The authors generate a new formulation built upon a previous nanoparticle platform to generate a new system termed bicontinuous nanospheres (BCN), allowing for the dual incorporation of lipid and protein antigens. The authors generate mycolic acid (MA)-loaded BCN and perform a series of characterization studies to demonstrate the superior performance of this new formulation relative to the original one in terms of antigen persistence, a quality needed to sustain responses after vaccination. This work provides important new insights relevant to the TB vaccine field and it suggests that alternative antigens to proteins could be used in TB vaccine formulations. The data are convincing and will be of interest to individuals working on tuberculosis, vaccines and basic immunology.

eLife assessment

This work is useful as it highlights the importance of data analysis strategies in influencing outcomes during differential gene expression testing. While the manuscript has the potential to enhance awareness regarding data analysis choices in the community, its value could be further enhanced by providing a more comprehensive comparison of alternative methods and discussing the potential differences in preprocessing, such as scFLOW. The current analysis, although insightful, appears incomplete in addressing these aspects.

eLife assessment

This valuable study illuminates molecular movements of acid-sensing ion channels by combining compelling advanced chemical biology and biophysical techniques. The evidence for the main claim, lack of interaction of molecular termini, is solid and challenges prior models. Some other claims warrant further evidence. This work will pique interest in the ion channel signaling field, providing a fresh perspective.

eLife assessment

This work provides useful data related to vomeronasal sensory neuron tuning to urine from different sexes, inbred strains, and wild mice, as well as a catalog of nonvolatile molecules and proteins that are present in these urine sources, as assessed by mass spectrometry. Evidence linking specific nonvolatile molecules or proteins to vomeronasal neural activity is incomplete; specific candidate ligands derived from urine, or fractions thereof, are not directly tested on the vomeronasal sensory neurons. A large category of vomeronasal ligands that are known to be present in urine (small nonvolatiles) were not evaluated. This work provides a foundation for future research that will determine which molecules drive sex- and strain-specific vomeronasal responses.

eLife assessment

This intracranial EEG study presents important neural evidence supporting the high spatial specificity (receptive field) of visually-driven alpha-band oscillation in human brains and its potential role in exogenous cuing attention. The evidence supporting the claims is solid, although more control analyses to exclude other explanations could further strengthen the conclusion. The work challenges the predominant view about the role of alpha-band oscillation in visual attention and advocates that stimulus-driven alpha suppression is precisely tuned and might contribute to exogenous spatial attention.

eLife assessment

In this useful study, the authors use a computational model to investigate how recurrent connections influence the firing patterns of grid cells, which are thought to play a role in encoding an animal's position in space. The work suggests that a one-dimensional network architecture may be sufficient to generate the hexagonal firing patterns of grid cells, a possible alternative to attractor models based on recurrent connectivity between grid cells. However, the support for this proposal was incomplete, as the model was inconsistent with certain key features of grid cell organization.

eLife assessment

This study provided a valuable finding demonstrating the spatial relationship between dendritic spines and mitochondria. The authors combined the analysis of ultra-structure data and functional data, which gives an excellent spatial and functional resolution to understand how mitochondria positioning is correlated to synaptic function and response in an in vivo model. Specifically, the authors provided convincing evidence and showed that dendritic mitochondria are positioned in spines with a diversity of orientation tuning, spines that display heterogeneous responses, and in areas of low local calcium activity.

eLife assessment

The manuscript offers useful descriptive insights into the potential influence of whole-brain lactate and pH levels on the manifestation of behavioral phenotypes seen in diverse animal models of neuropsychiatric disorders. However, reviewers have raised concerns about the potential loss of specificity in capturing regional and cell-type-specific effects when relying solely on whole-brain analysis methods. While the evidence supporting the conclusions is largely solid, the robustness of these conclusions could be enhanced by the inclusion of additional data and further analysis.

eLife assessment

This important study uses a range of technical approaches to investigate the responses of zona incerta neurons to movement and sensory stimuli. The majority of neurons exhibited movement-related activity but only a small propotion were modulated by whisker deflections. The major conclusion of the study is that the zona incerta distributes a general motor signal. The evidence supporting this claim is solid, although the study would be improved by greater transparency and discussion of experimental methods and histological verification of recording sites, viral spread, and which territories of the zona incerta were investigated. The work will be of interest to behavioral and physiological neuroscientists.

eLife assessment

This study provides potentially important, new insights about the combination of information from the two eyes in humans. The data includes frequency tagging of each eye's inputs and measures reflecting both cortical (EEG) and sub-cortical processes (pupillometry). The strength of supporting evidence is solid, suggesting that temporal modulations are combined differently than spatial modulations, with additional differences between subcortical and cortical pathways. However, questions remain as to exactly how information is combined, how the findings relate to the extant literature and more broadly, to the interests of vision scientists at large.

eLife assessment:

This work advances on two Aso et al 2014 eLife papers to describe further resources valuable for the field. This paper adds more MBON split-Gal4s convincingly describing their anatomy, connectivity and function.

eLife assessment

This important study reports the physiological role of ZMYND21 in the regulation of sperm flagellar development and male fertility. The data supporting the conclusion are solid, although the inclusion of more patients and ultrastructural studies would have further strengthened the study. This work will be of interest to clinicians and researchers who work on either sperm biology or ciliopathy due to cilial defects.

eLife assessment

This work is a valuable advance in our understanding of a very interesting biological phenomenon: the role of trophic eggs in ant caste determination. The evidence supporting the unexpected finding that feeding larvae trophic eggs promotes the development of the non-reproductive caste is compelling. However, even though there is a description of how trophic and fertile eggs differ in composition, the evidence of its significance for caste determination is incomplete.

eLife assessment

The manuscript describes valuable theoretical calculations focusing on the structural changes in the photosynthetic reaction center postulated by others based on time-resolved crystallography using X-ray free-electron laser (XFEL) (Dods et al., Nature, 2021). The authors provide solid arguments that calculated changes in redox potential Em and deformations using the XEFL structures may reflect experimental errors rather than real structural changes.

eLife assessment

This important study identifies the gene Bm-mamo as a new regulator of pigmentation in the silkworm Bombyx mori, a function that was previously unsuspected because the extensively studied Drosophila mamo gene is involved in gamete production. The evidence supporting the role of Bm-nano in pigmentation is convincing, including high-resolution linkage mapping of two mutant strains, expression profiling, and reproduction of the mutant phenotypes with state-of-the-art RNAi and CRISPR knock-out assays. The part of the work that concerns potential effector genes that Bm-mamo may regulate relies on in vitro and in silico analysis and can be used as a starting point for future in vivo studies. The work will be of interest to evolutionary biologists and geneticists interested in color patterns and in evolution of gene networks in general.

eLife assessment

This work presents convincing evidence for the presence of wooly mammoth/rhinoceros ancient environmental DNA (aeDNA) far from the time likely to host living individuals: what is effectively a genetic version of a geological inclusion. These are important findings that will have ramifications for the interpretation and conclusions extracted from aeDNA more generally.

eLife assessment

This manuscript describes a useful tool for quantitative assessment of sarcomere structures in healthy and perturbed cardiomyocytes grown in vitro. The work is solid, and the methods, data and analyses broadly support the claims with only minor weaknesses. The tool will be relevant to biologists working on and interested in obtaining quantitative information on sarcomere structure, function and development.

eLife assessment

This study addresses an important question in sensory neuroscience: how the olfactory system distinguishes decreases in stimulus intensity from decreases in neural responses due to adaptation. Based on a combination of electrophysiological and behavioral analyses, solid evidence establishes that neural coding changes differently between intensity reductions and adaptation. Intriguingly, behavioral responses tend to increase as the neural responses decrease, suggesting that core features of the odor response persist through adaptation. While the experimental results are convincing overall, the conclusions would be strengthened by more refined statistical analysis and data quantification.

Evaluation statement (24 May 2023)

Yang et al. present valuable information about ligand interactions with the serotonin transporter SERT, innovatively purified from pig brain using Fab fragments. The approach of using natively expressed SERT is notable for its potential insight into binding of endogenous membrane components such as lipids. Data distinguishing binding of the psychostimulants methamphetamine and cocaine add to our knowledge of substrate and inhibitor interactions with SERT and allow direct comparison with the closely related dopamine transporter DAT. The authors carefully state the limitations of their findings, including the possibility that the monomeric transporter stable in detergent micelles might exist in a multimeric state in native membranes.

Biophysics Colab considers this to be a convincing study and recommends it to scientists interested in the structure, mechanism and ligand interactions of neurotransmitter transporters.

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

Evaluation statement (22 August 2023)

Bansal et al. present an atomistic view of the transition cascade of the class F GPCR Smoothened (Smo). The extensive long-range molecular dynamics simulations together with stochastic modelling provide theoretical insight into Smo activation and how this is modulated by different ligands. The work identifies testable hypotheses for functional studies of Smo and other class F GPCRs. Future simulations of regions beyond the seven-transmembrane bundle, particularly the cysteine-rich domain, will afford a more complete understanding of receptor activation.

Biophysics Colab considers this to be a convincing computational study and recommends it to scientists interested in the conformational dynamics of class F GPCRs.

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

eLife assessment

This important study uses the brain endocast of a ~1.9-million-year-old hominin fossil from Kenya, attributed to genus Homo, to show that the organization of the Broca's area in members of early Homo was primitive. Specifically, the prefrontal sulcal pattern in this early Homo specimen more closely resembles that of chimpanzees than of modern humans. Because Broca's area is associated with speech function, the compelling evidence from this study is relevant for understanding the timing and trajectory of evolution of speech related traits in our genus. Coupled with its potential implications for taxonomic classification, this study will be of interest to paleoanthropologists, paleontologists, archaeologists, and neuroscientists.

eLife assessment

This fundamental study advances the analytic toolset and understanding of long-term series of biological (freshwater) communities, and the impact of humans on these. The authors highlight the value of including not only spatiotemporal scales in biodiversity assessments but also some of the possible drivers of biodiversity loss. Analyzing their joint contribution as environmental stressors, the authors provide compelling evidence that ecosystem assessment methods currently used by environmental regulators throughout Europe are not fit-for-purpose, and they identify several alternatives, more robust indicators of freshwater ecosystem health. The work is timely and will be of interest to ecologists, modelers and global warming scientists in general.

eLife assessment

This valuable study presents an exhaustive structural analysis of a complete tripartite HipBST toxin-antitoxin system of the Enteropathogenic E. coli O127:H6, which represents a fascinating variation on the well-studied HipAB toxin-antitoxin system. The convincing data show that major features of the canonical HipAB system have been rerouted to form the tripartite HipBST, revealing a new mode of inhibition of a toxin kinase.

eLife assessment:

This study reports a meta-analysis of published data to address an issue that is topical and potentially useful for understanding how the sites of initiation of DNA replication are specified in human chromosomes. The work focuses on the role of the Origin Recognition Complex (ORC) and the Mini-Chromosome Maintenance (MCM2-7) complex in localizing origins of DNA replication in human cells. While some aspects of the paper are of interest, the analysis of published data is in parts inadequate to allow for the broad conclusion that, in contrast to multiple observations with other species, sites in the human genome for binding sites for ORC and MCM2-7 do not have extensive overlap with the location of origins of DNA replication.

eLife assessment

This important study combines experiments and mathematical modelling to enhance our understanding of the interplay between the two flight muscles in birds during slow flight. The evidence for the findings is compelling, deriving from a combination of novel methods for measuring wing shape and force production, and validated methods in muscle physiology. This work will be of broad interest to comparative biomechanists.

eLife assessment

This fundamental work substantially advances our understanding of animals' foraging behaviour, by monitoring the movement and body posture of barn owls in high resolution, in addition to assessing their foraging success. With a large dataset, the evidence supporting the main conclusions is convincing. This work provides new evidence for motion-induced sound camouflage and has broad implications for understanding predator-prey interactions.

eLife assessment

This study shows important evidence of the correlation between social tolerance and communicative complexity in a comparison of three macaque species. Notably, the authors use an innovative, detailed methodology for quantifying facial expressions during social interactions. The results are convincing regarding a positive association between social complexity and facial behaviour, which should stimulate further comparative research in this field.

eLife assessment

This important study makes use of AlphaFold2 to predict the models of tens of cohesin subcomplexes from different species. The models, which are in most cases consistent with published cohesin mutants with defects in cohesin function in vitro and in vivo, provide convincing evidence that leads to testable hypotheses of cohesin dynamics and regulation. More broadly, this study serves as an example of how to use AlphaFold2 to build models of protein complexes that involve the docking of flexible regions to globular domains.

eLife assessment

This important study reveals for the first time that ferroptotic stress may play critical roles in regulating tooth germ development. While the evidence presented is solid, it insufficiently supports several of the claims, due to a lack of in-depth analysis.

eLife assessment

Trypanosoma brucei evades mammalian humoral immunity through the expression of different variant surface glycoprotein genes. In this fundamental paper, the authors extend previous observations that TbRAP1 both interacts with PIP5Pase and binds PI(3,4,5)P3, indicating a role for PI(3,4,5)P3 binding and suggesting that antigen switching is signal dependent. While much of the evidence is compelling, the work would benefit from further controls to rule out that any of the observed effects come from the protein tags used.

eLife assessment

This valuable study provides an experimental paradigm and state-of-the-art analysis method to study the existence of call types and transition differences among Mongolian gerbil families in a naturalistic environment. While the evidence supporting the authors' claims is solid, the conclusions would be significantly strengthened by additional analyses and a larger number of families and pup generations. The work will likely be of interest to the auditory neuroscience and vocal neuroethology communities.

eLife assessment

This valuable paper examines the role of the WRNIP1 AAA+ ATPase in regulating R-loop formation, which induces a conflict with active replication forks and transcription. The authors provide convincing evidence to support a role of the ubiquitin-binding UBZ domain of WRNIP1 in R-loop suppression generated by this conflict. The work is of interest to researchers who work on genome stability/instability.

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.

eLife assessment

This important study provides convincing evidence that the low-cost, user-friendly, and open-hardware UC2 wide-field microscopy framework can be expanded to enable single-molecule localization microscopy. Because the approach offers a simple and cost-effective alternative to commercially available microscopes, which are often expensive, this setup will be important for anyone seeking affordable solutions for single molecule localization microscopy and single particle tracking. While the information and data are openly accessible, the documentation could be expanded and better structured to (further) facilitate implementation in practice.

eLife assessment

This study provides important insights into how the brain constructs categorical neural representations during a difficult auditory target detection task. Through simultaneous recordings from primary and secondary auditory areas, compelling evidence is provided that categorical neural representations emerge in a secondary auditory area, i.e., PEG. The study is of interests to neuroscientists and can also potentially shed light on human psychological studies

eLife assessment

This study presents an important finding on the implicit and automatic emotion perception from biological motion (BM). The evidence supporting the claims of the authors is solid, although inclusion of a larger number of samples and more evidence for the discrepancy between Intact and local emotional BMs would have strengthened the study. The work will be of broad interest to perceptual and cognitive neuroscience.

eLife assessment

This study presents a valuable finding on the functional significance of protocadherin gamma (PCDHg) isoforms in establishing or maintaining functional synaptic connectivity. The authors used sophisticated methods such as single-cell sequencing and whole-cell patch-clamp recordings and obtained solid results that suggest that the neurons expressing the same PCDHg isoforms are less likely to be synaptically connected to each other. These results are largely consistent with previous results using morphological criteria.

eLife assessment

This study presents an important finding on the anatomical connectivity and functional roles of the previously uncharacterized neuronal populations in the nucleus incertus. The evidence supporting the conclusions is convincing, with imaging and manipulations of the genetically targeted populations of neurons. The work presents an important milestone for future mechanistic studies of the nucleus incertus.

eLife assessment

This study provides useful initial information on how humans represent two-dimensional abstract spaces in relation to the social traits of warmth and competence. While the study poses an interesting question, the evidence for a grid-like code at present is incomplete. This study will be of interest to researchers working in the field of spatial navigation as well as the navigation of conceptual abstract space.

eLife assessment

This study presents a valuable contribution to cardiac arrhythmia research by demonstrating long noncoding RNA Dachshund homolog 1 (lncDACH1) tunes sodium channel functional expression and affects cardiac action potential conduction and rhythms. Whereas the evidence for functional impact of lncDACH1 expression on cardiac sodium currents and rhythms is convincing, biochemical experiments addressing the mechanism of changes in sodium channel expression and subcellular localization are incomplete.

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.

eLife assessment

This important study was designed to examine the bypass of Ras/Erk signaling defects that enable limited regeneration in a mouse model of hepatic regeneration. This hepatocyte proliferation is associated with the expression by groups of cells of mRNA-loaded CD133+ intracellular vesicles that mediate an intercellular signaling pathway that supports proliferation. These are new observations, supported by convincing data, that have broad significance to the fields of regeneration and cancer.

eLife assessment

This important work significantly advances our comprehension of the molecular events occurring during germline stem cell differentiation in the Drosophila melanogaster ovary. The conclusions are strongly supported by compelling evidence, including rigorous data sets and complementary whole-genome analyses. As a result, this research holds substantial interest for developmental and stem cell biologists alike.

eLife assessment

The manuscript by Paine and coworkers provides a fundamental improvement on how the enzymatic activity of CALPAIN7 (a Cys protease) influences cytokinesis mediated by the ESCRT (endosomal sorting complexes required for transport) pathway. The authors provide a convincing molecular and cellular basis for one of the several key steps involved in membrane fission during the separation of dividing eukaryotic cells. These findings should be of interest to a wide scientific audience including biochemists, structural biologists, and cell biologists.

eLife assessment

This important work advances our understanding of the generation of a main organizer of the vertebrate brain, the cortical hem. The authors convincingly show the contribution of multiple downstream effectors, each involved in specific processes regulated by the master gene, Lmx1a. This study has broader implications for how secondary organizers are created in the embryo and will be of interest to a wide readership.

eLife assessment

This important study deepens our understanding of macrophage phenotypes in pathological contexts and identifies a new macrophage state associated with tissue fibrosis, as well as putative drivers of this cellular state. The authors provide convincing evidence and performed a well-thought-out and thoroughly described computational analysis of single-cell RNA-sequencing data. This work will be of broad interest to the fields of tissue inflammation, fibrosis, macrophage biology, and immunology.

eLife assessment

The manuscript by Salloum and colleagues shows that cholesterol-lowering statins can reduce mitochondrial cholesterol and impact epigenetic programs in macrophages. The findings could be valuable for understanding statin-mediated anti-inflammatory functions in macrophages. The major claims describing new mechanisms by which statins may regulate macrophage function via epigenetic programming are partially supported by the data presented.

eLife assessment

This current study provides a new model of lung agenesis to explore the generation of the ability of blastocyst complementation to generate an entire organ. These studies will provide new avenues for organ bioengineering and additional insight into early contribution of mesoendoderm to lung development.

eLife assessment

In this study, Yang et al. have shown that SIRT2 has adverse effects on the heart in response to injury. Further, they demonstrate that deletion of Sirt2 is protective through stabilization and increased nuclear translocation of NRF2, which leads to increased expression of antioxidant genes. They also show that pharmacological inhibition of SIRT2 protects the heart against the development of cardiac hypertrophy.

eLife assessment

The authors attempted to show that syntaxin 6 (Stx6) delays PrP fibril formation and in presence of Stx6, PrP forms amorphous aggregates which are more toxic to neuronal cells, indicative of Stx6's anti-chaperone activity. This useful study has potential to provide important understanding of the molecular mechanism of PrP aggregation and neurotoxicity. However, the evidence supporting the physiological relevance and robustness of the assays is incomplete.

eLife assessment

Plant intracellular ion channels are poorly understood. In this important manuscript, patch-clamp is used to define functional differences between two cation channels present in the vacuole of different plants. The authors find a calcium-biding site whose absence or presence modulate activation at lower voltages and is responsible for increased excitability in the vacuole of the faba bean plant. The experimental evidence presented is convincing and findings have practical implications for the field of plant electrophysiology and channel biophysics.

eLife assessment

This is an important study that investigates the role of commensal microbes and molecules in the antigen presentation pathway in the development and phenotype of an unusual population of T lymphocytes. The authors provide convincing evidence to identify a population of unconventional T cells that exist in the small intestine epithelium, which appear to depend on commensal microbes, and show that a single commensal microbe (that encodes an antigen capable of weakly stimulating these cells) is sufficient to maintain the T cell population.

eLife assessment

This important study combines experiments on human mutation and making a mouse model lacking IQCH and the functional consequences on spermatogenesis. The mouse model is compelling but some of the analysis is indirect and incomplete and would benefit from more rigorous direct approaches. With the experimental evidence that supports direct interaction between IQCH and potential RNA binding proteins strengthened, this paper would be of interest to cell biologists and male reproductive biologists working on the sperm flagellar cytoskeleton and mitochondrial structure.

eLife assessment

This fundamental study describes the mechanisms for regulation of the phosphate starvation response in baker's yeast, clarifies the interpretations of prior data, and suggests a unifying mechanism across eukaryotes. The study provides compelling data, based on biochemical analyses, protein localization by fluorescence, and genetic approaches that 1,5-InsP8 is the phosphate nutrient messenger in yeast.

eLife assessment

This important study advances the understanding of physiological mechanisms in deep-sea Planctomycetes bacteria, revealing unique characteristics such as the only known Phycisphaerae using a budding mode of division, extensive involvement in nitrate assimilation and release phage particles without cell death. The study uses convincing evidence, based on experiments using growth assays, phylogenetics, transcriptomics, and gene expression data. The work will be of interest to bacteriologists and microbiologists in general.

eLife assessment

This is a valuable paper demonstrating the validity of a novel task that could advance the field of reinforcement learning to better incorporate threat processing in approach-avoidance-conflict. A compelling methodology includes the use of online samples and computational modelling, psychometrics, discovery/replication and pre-registration. This work provides a foundation for future work, which is required to address potential confounds and establish this task as relevant to psychopathology and treatment.

eLife assessment

This valuable study presents a screening pipeline (SPICE) for detecting DNA motif spacing preferences between TF partners. SPICE predicts previously known composite elements, but experiments to elucidate the nature of the predicted novel interaction between JUN and IKZF1 are incomplete. These experiments would benefit from more rigorous approaches using other databases to explore additional relevant data. The work will be of broad interest to those involved in dissecting the regulatory logic of mammalian enhancers and promoters.

eLife assessment

This valuable study reports multi-scale molecular dynamics simulations to investigate a class of highly potent antibodies that simultaneously engage with the HIV-1 Envelope trimer and the viral membrane. The work provides insights into how broadly neutralizing antibodies associate with lipids proximal to membrane-associated epitopes to drive neutralization. However, the evidence for rules for lipid recognition in antibodies is still incomplete. In addition, the text would benefit from clearer subsections that delineate discrete mechanistic discoveries.

eLife assessment

This important study examines the effects of herbivory-induced maize volatiles on neighboring 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 defenses triggered by herbivore-induced plant volatiles (HIPVs). Most experimental data are compelling but additional experiments and accurate quantifications of the compounds would be required to confirm some of the main claims.

eLife assessment

This useful study has the potential to reveal insights into how calcineurin influences C. elegans lifespan through its role in controlling the defecation motor program. Currently, the evidence in support of the conclusions is still incomplete, largely due to concerns about partial gene inactivation by RNAi. The inclusion of experiments using a tax-6 null allele would mitigate these concerns.

eLife assessment

This is a useful study for scientists interested in cell polarity, epithelial morphogenesis, cancer, and primary cilia. The authors investigate the role of CRB3 in regulating these processes by using a combination of a mammary epithelial cell-specific conditional Crb3 knockout mouse model, and cellular, molecular and biochemical approaches. The results, which are solid, supporting and extending previous findings, suggest that CRB3 affects ciliogenesis by a mechanism involving Rab11 and gamma-TuRC.

eLife assessment

This valuable paper examines gene expression differences between male and female individuals over the course of flower development in the dioecious angiosperm Trichosantes pilosa. The authors show that male-biased genes evolve faster than female-biased and unbiased genes, 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 reviewers found the evidence to be 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.

eLife assessment

The increased risk of fracture without decreased bone density in type 2 diabetes (T2D), the so-called "diabetic bone paradox", is mainly attributed to the limitation of assessing risk of fracture based on bone density alone in the current practice. Now we have learnt that poor bone quality and increased risk of falling due to concomitant co-morbidities partially explains it. This study this presents useful findings that clinical risk factors (though not genetic factors) related to T2D are associated with risk of fracture in T2D patients. The new approach of using Mendelian randomization to explain the relationship of two complex conditions is solid, and the discovery of 10 loci shared between T2D and fracture risk is intriguing. However, including clinically more relevant risk factors for fracture risk in T2D patients in their observational analysis would have strengthened the study.

eLife assessment

This study reports the fundamental finding of differential expression of key genes in full-term placenta between Tibetans and Han Chinese at high elevations, which are more pronounced in the placentas of male fetuses than in female ones. If confirmed, these results will help us understand how human populations adapt to high elevation by mitigating the negative effects of low oxygen on fetal growth. However, although the differential gene expression reported is solid, the downstream analyses offer only incomplete support for its connection to hypoxia-specific responses, adaptive genetic variation, and pregnancy outcomes.

eLife assessment

This work presents valuable information about the specificity and promiscuity of toxic effector and immunity protein pairs. The evidence supporting the claims of the authors is currently incomplete, as there is concern about the methodology used to analyze protein interactions, which did not take potential differences in expression levels, protein folding, and/or transient interaction into account. Other methods to measure the strength of interactions and structural predictions would improve the study. The work will be of interest to microbiologists and biochemists working with toxin-antitoxin and effector-immunity proteins.

eLife assessment

This valuable study is focused on the requirement for the photoreceptor-specific tetraspanins, ROM1 and PRPH2, in the formation of the light-sensitive membrane discs. The evidence supporting the claim that deficiency in one of the proteins can be compensated by the other is convincing, with both established and modern techniques yielding results that will be of interest to those studying photoreceptor development and membrane curvature.

eLife assessment

This is a valuable paper demonstrating validity of a novel task that could advance the field of reinforcement learning to better incorporate threat processing in approach-avoidance-conflict. A compelling methodology includes the use of online samples and computational modelling, psychometrics, discovery/replication and pre-registration. This work provides a foundation for future work, which is required to address potential confounds and establish this task as relevant to psychopathology and treatment.

eLife assessment

This study provides a useful catalog of the cardiac proteome and transcriptome in response to intermittent fasting. Although mechanistic integration is limited, the technical aspects have been executed in a solid way, and sufficient evidence is provided to support the main conclusions. Future work can build on this study to expand our understanding of the relationship between dietary perturbations and cardiac function.

eLife assessment

This valuable study uses adult and neonatal murine models, together with genetic approaches, to propose that vitamin D, via Ikfz3/Aiolos, suppresses IL-2 signalling and reduces IL-2 signalling in Th2 cells. While vitamin D has been previously thought to modulate both effector and regulatory T-cell populations via the control of IL-2 signalling, this study provides solid new data of interest to immunologists as well as asthma researchers.

eLife assessment

The study highlights an important role of key fatty-acid synthesis enzyme, acetyl-coA-carboxylase 1 (ACC1) in development and homeostasis of invariant natural killer T (iNKT cells), as well as its significance in asthma etiology. The work defines novel mechanisms driving metabolic regulation of iNKT cells and its role in allergic asthma. The data reported in the manuscript are convincing, and the work adds to our understanding of the metabolic regulation of iNKT cells.

eLife assessment

This manuscript uses genetic mouse modeling to delve deeper into a rare human disease of aging. The targeted approaches employed lend greater pathophysiologic insight and makes this paper valuable to the field art large. Additionally, the approaches used are rigorous and solid in supporting their conclusions. Some minor weaknesses were noted along with suggestions to add greater clarity.