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

The manuscript describes a valuable theoretical calculation 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.

eLife assessment

This is an important study that tries to shed light on why the deer mouse is host to many diverse pathogens. The results are convincing and rely on state of the art transcriptomic analysis. The findings will be of interest to the biologists, ecologists and infectious disease researchers.

eLife assessment

This important paper provides insights into the role of the inflammasomes in the control of Salmonella replication within human macrophages. Solid evidence is provided that in the absence of inflammasome signaling that Salmonella replicated in the macrophage cytosol. This paper will be of broad interest to cell biologists, immunologists and microbiologists.

eLife assessment

The reviewers have found the work to be valuable to the field of immunotherapy in the treatment of cancer. The data supporting the role of PDLIM2 as a tumor suppressor, and more immediately, as a strategy to improve the efficacy of immunotherapy treatment, was viewed as compelling. However, the results are lacking a completed mechanism, which would substantially expand the impact of the work.

eLife assessment

This study describes a potential role for mechanical stimulation on non-small cell lung cancer (NSCLC) development. The findings are important and their observations are interesting, as models to study exercise in a mouse cancer setting would have practical implications beyond lung cancer, and biological roles of osteocytes in bone metastatic cancer is an area of great interest for potential therapy development. However, the methods and data interpretation are incomplete and the claims of osteocytes inducing tumor dormancy are overstated. The mechanism by which osteocytes affect tumor cells is not clear and the authors' theory on this remains unproven since much of the data are correlative rather than causative, and adequate controls, data quantification, and confirmation with secondary cell lines are often lacking.

eLife assessment

This study presents a valuable finding that YAP/TAZ promotes the formation of P-bodies for tumor progression via inhibiting PNRC1 which is a critical suppressor of P-body formation. The evidence supporting the claims of the authors is solid, although the inclusion of the mechanistic link between P-body formation and oncogenesis would have strengthened the study. The work will be of interest to cancer biologists or scientists working in the field of Hippo signaling.

eLife assessment

This valuable paper describes a web-based tool for curated association mapping results from the Drosophila genome reference panel. With this tool, one can visualize and view association results for various phenotypes, and the authors provide examples for the use of the resource, including study summary statistics. The evidence for the tool working as advertised is solid, but further improvements to the tool would increase its value for the community.

eLife assessment

This structural and biochemical study of the mouse homolog of acidic mammalian chitinase (AMCase) enhances our understanding of the pH-dependent activity and catalytic properties of mouse AMCase and sheds light on its adaptation to different physiological pH environments. The methods and analysis of data are solid, providing several lines of evidence to support a development of mechanistic hypotheses. While the findings and interpretation will be valuable to those studying AMCase in mice, the broader significance, including extension of the results to other species including human, remain unclear.

eLife assessment

The work is a useful contribution to understanding the mechanism of nuclear export of tRNA in budding yeast. The authors report that Dbp5 functions in parallel with Los1 in tRNA export, in a manner dependent on Gle1 and requiring the ATPase cycle of Dbp5, but independent of Mex67, Dbp5's partner in mRNA export. The evidence for this conclusion is still incomplete, as is the biochemical evidence that Dbp5 interacts directly with tRNA in vitro with Gle1 and co-factor InsP6 triggering Dbp5 ATPase activity in the Dbp5-tRNA complex. The evidence that Dbp5 interacts with tRNA in cells independently of Los1, Msn5 and Mex67 is, however, solid.

eLife assessment

This valuable study reports a new method based on batch active learning to optimize the biological and pharmaceutical properties of small molecules of pharmaceutical interest. The new method seems compelling, but the theoretical analysis is incomplete and the reproducibility and impact of the article would benefit from disclosing the code and datasets used in the study. With these aspects strengthened, this paper would be of interest to computational and medicinal chemists and scientists working in the drug discovery field.

eLife assessment

This important study advances existing approaches for demographic inference by incorporating rapidly mutating markers such as switches in methylation state. The authors provide a solid comparison of their approach to existing methods, although the work would benefit from some additional consideration of the challenges in the empirical use of methylation data. The work will be of broad interest to population geneticists, both in terms of the novel approach and the statistical inference proposed.

eLife assessment

This important study combines in vitro and in vivo experiments to investigate the reciprocal regulation between mitochondria-associated membranes and Notch signaling in skeletal muscle atrophy, with implications beyond the single subfield of muscle atrophy. The methods, data, and analyses convincingly support most of the claims. There are minor weaknesses, with the analysis of gene and protein expression in some parts being incomplete.

eLife assessment

This important study makes a bold step towards understanding what fraction of DNA that is liberated from different tissues in a healthy human is found in circulation as cell-free DNA. Unfortunately, the evidence for the conclusions is presently incomplete, but with additional controls, this could become a major achievement for reference in understanding changes in cell-free DNA in disease states.

eLife assessment

This study provides valuable findings on a causative relationship between LRRC23 mutations and male infertility due to asthenozoospermia. The evidence supporting the conclusions is solid despite a lack of analyses of the effects of the mutations detected on the flagellar structure of human sperm. This work will be of interest to biomedical researchers who work on sperm biology and non-hormonal male contraceptive development.

eLife assessment

The authors provide the first investigation of the role of the lateral habenula in vocal learning in the songbird. This study provides important insights into the conserved connectivity of the lateral habenula with dopaminergic reinforcement circuits and presents a potential role of this circuit in zebra finch song learning. The results stem from a careful anatomical and functional mapping and from a rigorous behavior analysis that, together, implicate a previously undescribed analog between mammals and songbirds. Although many aspects of the manuscript - like the analysis of song behavior - are exceptional, the evidence linking behavior to selective lesions of the lateral habenula is, at this point, incomplete, leaving the interpretation of key results difficult.

eLife assessment:

This important study sheds light on several apparent discrepancies observed across animal studies examining neuroimaging biomarkers of functional recovery following focal ischemia. Using 2-photon imaging of calcium activity in awake mice, the authors show solid evidence that deficits in neuronal activity and functional connectivity after photothrombosis occur within a very small distance from the infarct (<750 microns) whereas these measures were relatively unaltered more distally, even those typically implicated with functional remapping of the forelimb representation in anaesthetized animals. These findings reveal a complex spatiotemporal relationship between perilesional neuronal network function and behavioral recovery that is more nuanced than previously reported, and motivates the need for better criteria for what is considered remapping.

eLife assessment

In this work, the authors make a valuable contribution based on convincing evidence that children 6-to-7-years-old improve in 2 years of development towards utilising more optimal value-based decision-making strategies while performing a reinforcement learning task. They found that delayed feedback learning was associated with volume in the hippocampus while immediate feedback learning was not. Striatal volume was associated with both forms of learning, in contrast to prior research funding in adults. Brain-behaviour correlations were stable across the 2-year period, despite the hippocampus increasing in volume and striatal volume remaining stable.

eLife assessment

This study presents useful findings regarding how a particular class of neurons within a brain region respond to threatening stimuli and their role in fear processing in male and female mice; these results are solid as they uncover the role functional of this brain region (BNST) in this particular type of processing and expand this knowledge by highlighting the function of a specific class of neurons (CRF) showing that their role in fear depends on the sex of the animal. However, the analysis is incomplete and can certainly benefit from additional (for example locomotor) controls and from clarifying interpretability issues with respect to sex differences in fear expression and to a precise role of these neurons. The work will be of interest to neuroscientists studying the biological basis of fear processing.

eLife assessment

This important study identifies and characterizes a broad peptidergic network that coordinates nutrient-specific consumption needs for food or water. Using state-of-the-art methodology the authors combine a well-balanced set of exploratory anatomical analyses with rigorous functional experimental approaches to examine how ingestion is regulated based on internal needs. These significant and convincing new findings are of broad interest to the neuroscience field.

eLife assessment

In this potentially useful study, the authors employ concepts and algorithms associated with induced subgraph in graph theory to automate several key but non-trivial steps in the development of coarse-grained models. These developments can help to model complex biomolecular systems at the coarse-grained level., but given the limited number of examples explicitly discussed, the demonstration of the general applicability of the approach to biomolecular systems is considered incomplete.

eLife assessment

This valuable study presents reports on the role of the transcription factor BATF and its target PD1 in lipid metabolism including a model of nonalcoholic fatty liver disease (NAFLD). Overall, the evidence supporting the conclusions is convincing. The work will be of interest to medical biologists working on NAFLD.

eLife assessment

This paper introduces the python software package Pynapple and a separate package of more advanced routines (Pynacollada) to the Neuroscience/Neural Engineering community. Pynapple provides a set of data objects and methods that have the potential to simplify data analysis for neural and behavioral data types. This represents a valuable contribution to the field. With more examples and as a live coding notebook, the evidence was judged to be compelling.

eLife assessment

This study reports useful information on the limits of the organotypic culture of neonatal mouse testes, which has been regarded as an experimental strategy that can be extended to humans in the clinical setting for the conservation and subsequent re-use of testicular tissue. The evidence that the culture of testicular fragments of 6.5-day-old mouse testes does not allow optimal differentiation of steroidogenic cells is compelling and would be useful to the scientific community in the field for further optimizations.

eLife assessment

This paper conducts human and rodent experiments of non-invasive diffusion MRI estimates of axon diameter with the aim to establish whether these estimates provide biologically specific markers of axonal degeneration in MS. It will be of interest to researchers developing quantitative MRI methods and scientists studying neurodegeneration. The experiments provide evidence for the sensitivity of these markers, but do not directly validate axon diameter and do not reflect common pathological mechanisms across rodents and humans.

eLife assessment

The authors have improved a method to differentiate human iPSC-derived microglial cells with immune responses and phagocytic abilities; and through transplantation into the adult mouse retina, the authors further demonstrated their integration and occupation of native microglial cell space, and functional response to retinal injuries. The study is important for potential microglial replacement therapy to treat retinal and CNS diseases. Overall, the data are solid, but there is a need to improve writing, figure-making, and data interpretation.

eLife assessment

This valuable study informs whether diminishing BDNF expression or alterations in the activity of BDNF-containing neurons in the paraventricular nucleus of the hypothalamus contributes to metabolic alterations in individuals with reduced RAI1 function, including those afflicted with Smith-Magenis syndrome (SMS). The evidence supporting the conclusions is compelling in that RAI1 deficits in BDNF-containing neurons partly contribute, with prominent effects on glycemic control and modest effects on feeding and body weight regulation, however, the histological analyses of BDNF and TrkB expressions are inadequate. This study would be of interest to neuroscientists and medical biologists working on metabolic disorders such as obesity and diabetes, as the findings in this study further links SMS-associated obesity with reduced Bdnf gene expression in the PVH and shed light on the role of the Rai1 gene in the PVH Bdnf neurons and offer a basis for future therapeutic strategies for managing obesity in SMS.

eLife assessment

This study has the potential to provide valuable insights that connect the way humans and non-human primates (Rhesus monkeys) perform visuomotor control for a simplified, virtual task that involves stabilizing an unstable system (analogous to pole balancing). Thus, the paper provides the potential, in future studies, to make new discoveries in the neural mechanisms that underly behavior. However, the evidence (including inferring control strategies on a single-trial basis) was incomplete. Overall, the question and approach are potentially valuable in informing future studies, but more evidence is needed to support the primary claims of the paper.

eLife assessment

In this potentially useful study, the authors attempt to use comparative meta-analysis to advance our understanding of life history evolution. Unfortunately, both the meta-analysis and the theoretical model is inadequate and proper statistical and mechanistic descriptions of the simulations are lacking. Specifically, the interpretation overlooks the effect of well-characterised complexities in the relationship between clutch size and fitness in birds.

eLife assessment

This paper represents a valuable single-cell level analysis of tendon enthesis development. It will allow further understanding of this specific process with clinical implications. Specifically, the authors provided convincing evidence for the heterogeneity of postnatal enthesis growth and the molecular dynamics and signaling networks during enthesis formation.

eLife assessment

The authors make the case that the assembly of MreB from Geobacillus, a Gram-positive organism differs substantially from MreB from the Gram-negative model organism, Escherichia coli. Although the conclusion of this valuable study would represent a major advance if correct, the evidence is currently incomplete, and significant additional work is necessary to ensure both rigor and impact.

eLife assessment

This fundamental study addresses the role of miRNA-218 in circuit development, seizure susceptibility, and behavior. The supporting experimental evidence provided by the authors is solid, although more mechanistic insight into how miRNA-218 controls neuronal cell type function during circuit development to then impact seizures and behavior would have strengthened the study. This work has broad implications for researchers working on the role of neuronal microRNA in neurodevelopmental and neurological diseases.

eLife assessment

The authors use a previously described technology of designing soluble transmembrane-targeting peptides, to interfere with the receptor function of the T cell receptor (TCR), which provides useful insights into the molecular mechanism of T cell activation. The designed PITCR peptide has functional effects, but the evidence for the proposed mechanism is still incomplete. With further data to support the conclusion, results from this study will be of interest to those studying the TCR as well as those seeking to use the TCR or its derivatives in synthetic biology studies and immunotherapy.

eLife assessment

This important research uses complementary CRISPR screening strategies to reveal novel pathways that prevent T cells from killing tumor cells. The evidence presented to support the claims is solid, although some additional assays defining the features of these novel pathways and their clinical relevance are still required. Overall, this work will be of broad interest to immunologists, cancer biologists, and those interested in cell adhesion and cell-cell communication.

eLife assessment

This useful paper examines changes (or lack thereof) in birds' fear response to humans as a result of COVID-19 lockdowns. The evidence supporting the primary conclusion is currently inadequate, because the model used does not properly account for many potentially confounding factors that could influence the study's outcomes. If the analytic approach were improved, the findings would be of interest to urban ecologists, behavioral biologists and ecologists, and researchers interested in understanding the effects of COVID-19 lockdowns on animals.

eLife assessment

The study presents important findings on the timing and movement of crops in the Near East. The authors provide convincing data supporting a predominant contribution of Roman Agricultural Diffusion to the spread of a number of cultigens in the region. The work will be of interest to those thinking about the timing and movement of the diffusion of agricultural crops post-domestication.

eLife assessment

The present study shows that the expression of some inhibitory receptors (IRGs) on CD8 T cells is increased in people living with HIV (PLWH) and remain elevated even after years of viral suppression by antiretroviral therapy. The authors further report that inhibition of TGIT partially restores the ability of CD8 T cells to produce CD107a but not the other functions. Altogether, the results provide some valuable insights into our understanding of inhibitory receptor expression in the HIV infected individuals but some evidence seems incomplete.

eLife assessment

This important study combines experiments and computational approaches to understand the effects of influenza H1N1 infection on hypothalamic cells. The methodology and analysis are solid and raise questions around how a respiratory virus affects the central nervous system.

eLife assessment

This valuable study provides high-quality epigenome data in Drosophila testes and purified germ cells. The analyses are solid and will help to understand and appreciate the dramatic chromatin structure change during spermatogenesis in Drosophila. The work will be of interest to students of epigenetic modifications and reproductive biologists.

eLife assessment

This is an important study using 3D mapping of neuronal activation throughout the brain after pair-bonding in the monogamous vole, which can be broadly applied to other species and behaviors. The authors provide compelling evidence that there is some synchrony in the male and female partners in a pair bond and that number of ejaculations is the most important variable. Same-sex pairs are also examined and found to have activation in the same brain regions. An overall low level of sex differences is observed, which was unexpected.

eLife assessment

This useful study tests the hypothesis that Mycobacterium tuberculosis infection increases glycolysis in monocytes, which alters their capacity to migrate to lymph nodes as monocyte-derived dendritic cells. The authors conclude that infected monocytes are metabolically pre-conditioned to differentiate, with reduced expression of Hif1a and a glycolytically exhaustive phenotype, resulting in low migratory and immunologic potential. Unfortunately, the evidence for the conclusions is currently incomplete, as the use of dead mycobacteria will affect bioenergetic readouts. The study will be of interest to microbiologists and infectious disease scientists.

eLife assessment

This valuable study presents a modification of earlier imputation methods for clinical data, effectively addressing missing values with a slight improvement over previous techniques. The methodology and results for the classical case are solid, although the evidence for the claim of a practical advantage in 'next generation' quantum computers is not validated. This work will be of value to scientists dealing with datasets involving imputation for classification tasks, particularly in clinical studies.