eLife assessment

The significance of this manuscript is that is provides useful information for the field of hepatology and endocrinology on the regulatory mechanisms of cholesterol homeostasis by melanocortin. The authors provide solid evidence utilizing both in vivo and in vitro molecular, cellular, and biochemical approaches to support their claims.

eLife assessment

This important work advances our understanding of the import of clonal heterogeneity in cancers in immune response to individual antigens. The evidence supporting the conclusions is convincing, and uses interesting tools, although the mechanistic basis of the observations is unclear. The work will be of broad interest to immunologists including cancer immunologists.

eLife assessment

This is an important study describing the mechanism of Spermidine modulation of Src kinase, identifying the interacting amino acids and the effect on indoleamine 2,3-dioxygenase 1 (IDO1) activation based on solid evidence. Considering the important role of IDO1 in the immune response this study could provide important information for the design of allosteric modulators capable of turning SRC on/off.

eLife assessment

This work examines a role for altered splicing in pancreatic tumorigenesis by interrogating effects of a specific mutation in the Sf3b splicing factor in pancreatic organoid and cell line growth primarily, with some in vivo work also performed. There is significant potential in the study but there is a concern about the lack of in vivo validation of claims that are most relevant to metastatic progression and the focus on one specific mechanism at the expense of other possible effects on splicing of factors important for disease progression.

eLife assessment:

This fundamental study provides compelling evidence that long-range resection is important for recombination between distal, but not proximal, homologous sequences. It is thus proposed that a major role of long resection of a double-strand break mediated by Sgs1 and Exo1 is to activate the DNA damage checkpoint to allow the chromosomal mobility needed for the DNA ends to find a distant homologous sequence with which repair via homologous recombination, adding a new biological meaning to the role of long DNA resection in homologous recombination.

eLife assessment

The mechanisms underlying mirror neurons are a topic of wide interest for all who study the workings of the brain. The authors use an elegant decoding approach to test whether mirror neurons encode action categories in the same framework regardless of whether actions are executed in the dark or observed in the light. This new approach identifies only a small subset of mirror neurons with fully matched coding among a larger set showing partial matches. The thought-provoking study opens up new principled avenues to probe the mechanics of matching action and perception.

eLife assessment

Using C. elegans as a model organism, the study hones in on the role of ether lipid biosynthesis as an effector of metformin--a process previously implicated in extending lifespan in response to diet--, TOR signalling, and mitochondrial interventions. The data in this paper are compelling, and a better understanding of biguanide impact on metabolism is highly important in the field.

eLife assessment

This study presents valuable insights into the circuits that are common for innate and learned threat. The evidence supporting the author's conclusions is solid, but the specificity of the circuit targeting methods requires further histological assessment and clarification. Deeper interpretation of novel mechanistic insights that are gained would benefit the study.

eLife assessment

This valuable study advances our knowledge of the effects of anxiety/depression treatment on metacognition, demonstrating that treatment increases metacognitive confidence alongside improving symptoms. The authors provide convincing evidence for the state-dependency of metacognitive confidence, based on a large longitudinal treatment dataset. However, it is unclear to what extent this effect is truly specific to treatment, as changes in metacognitive confidence in the group receiving online therapy were not statistically different from those in the control group.

eLife assessment

This fundamental study substantially advances our physical understanding of the sharp increase and saturation of the viscosity of non-confluent tissues with increasing cell density. Through the analysis of a simplified model this study provides compelling evidence that polydispersity in cell size and the softness of cells together can lead to this phenomenon. The work will be of general interest to biologists and biophysicists working on development.

eLife assessment

This study presents a valuable finding on the impact of metformin-induced shifts in gut microbial community structure and metabolite levels for drug efficacy in a mouse model of liver injury. The current evidence supporting the claims of the authors is incomplete, although inclusion of additional controls and a revision to clarify the reviewer's methodological concerns could strengthen the study. This paper could be of broad interest to researchers across multiple disciplines, including the study of the microbiome, liver disease, and pharmacology.

eLife assessment

This manuscript provides important evidence on the association between sleep regularity and mortality in the UK Biobank, which is a popular topic in recent sleep and circadian research in population-based studies. The study is based on a large accelerometer study with validated follow-up of incident diseases and deaths, and the data quality and large sample size strengthen the credibility of the conclusion. Overall, the analyses are appropriately done, the manuscript is clearly written, and the strength of the evidence is convincing.

eLife assessment

This study presents valuable findings describing how two brain regions, the midbrain periaqueductal gray matter and basolateral amygdala, communicate when a robotic predator threat is detected. While the experimental design and data collection methods are solid, the main claims are only partially supported by the data and would benefit from more rigorous anatomical approaches as well as functional validation of the role of the paraventricular nucleus of the thalamus as the critical connection between the periaqueductal gray and basolateral amygdala. The study will appeal to a broad audience, including basic scientists interested in neural circuits, basic and clinical researchers interested in fear, and behavioral ecologists interested in foraging.

eLife assessment

This potentially important study used single-cell whole-brain imaging of the immediate early gene Fos to identify the brain areas recruited by two anesthetics, ketamine and isoflurane. The results suggest these anesthetics might induce anesthesia via different brain regions and pathways. However, the support for the primary conclusions is incomplete owing to differences in route of administration between the drugs, lack of a dose response curve and behavioral/physiological measures of the depth of anesthesia, and statistical analysis that does not correct for multiple comparisons. With these issues addressed, this paper would be of interest to preclinical and clinical scientists working with anesthetic and dissociative drugs.

eLife assessment

This study provides an important investigation of the role that alpha-band activity modulations play in the generation of the P300. The data offer solid evidence in favour of such a role although further analyses may be required to determine whether the observed relationships may be driven by inter-individual differences in factors that may modulate both signals in tandem such as skull thickness.

eLife assessment

This important study dissects the interplay between internal energy homeostasis, food intake and food-related memories, focusing on the role played in Drosophila by Octopamine, a monoamine functionally related to noradrenalin. This work will help interpret previously published work on the function of Octopamine, and should be of interest to the growing community of biologists interested in how internal state shapes behavior, including decision making processes, learning and memory. The experimental evidence is solid, but additional evidence using, for instance, tissue-specific and effector-specific manipulation, and a unifying model would strengthen the present study.

eLife assessment

This study provides useful information on the evolution of gene expression levels and plasticity in tissues impacted by hypoxia during colonization of a high-altitude environment. Unfortunately, the evidence for the conclusions is incomplete because of the low sample size available.

eLife assessment

This fundamental study advances our understanding of seabird responses to environmental conditions, with implications for movement ecology, flight biomechanics, animal foraging and bio-energetics. Animal-borne data-loggers are used to generate a compelling high quality dataset on animal movement and environmental conditions. The study will interest ornithologists, comparative bio-mechanists, ocean ecologists and those interested in technological advances in animal sensors.

eLife assessment

This work presents valuable findings on the non-breeding itinerant behavior of a migratory raptor. With its extensive dataset and solid analytical framework, this work will be of broad interest to researchers investigating the ecological drivers of bird migration. However, the main claim on a novel migration pattern (so-called 'fox-trot migration') is incomplete in light of current knowledge on bird migratory behavior.

eLife assessment

Wang et al present a useful manuscript that builds modestly on the group's previous publication on KLF1 (EKLF) K47R mice focused on understanding how Eklf mutation confers anticancer and longevity advantages in vivo (Shyu et al., Adv Sci (Weinh). 2022). The data demonstrates that Eklf (K74R) imparts these advantages in a background, age, and gender independent manner, not the consequence of the specific amino acid substitution, and transferable by BMT. However, the authors overstate the meaning of these results and the strength of evidence is incomplete, since only a melanoma model of cancer is used, it is unclear why only homozygous mutation is needed when only a small fraction of cells during BMT confer benefit, they do not show EKLF expression in any cells analyzed, and the PD-1 and PDL-1 experiments are not conclusive. The definitive mechanism relative to the prior publication from this group on this topic remains unclear.

eLife assessment

The authors analyze a comprehensive cohort of human plasma samples to identify an extracellular vesicles protein signature for earlier diagnosis of pancreatic cancer. Application of liquid biopsies is valuable, and it addresses a significant clinical problem as pancreas cancer is often diagnosed in late stage with standard biopsies often nondiagnostic. The strength of evidence is largely solid; however, certain aspects of the data were deemed incomplete, given the broad manuscript claims. This work supports the use of extracellular vesicles in clinical settings, with potential interest to scientists and clinicians.

eLife assessment

This important study reports that a long non-coding RNA disrupts the activity of the tumor suppressor p53 to contribute to the growth and therapeutic response of glioblastoma. Most evidence supporting the claims of the authors is solid, but the conclusions would benefit from more rigorous approaches. The work will be of interest to biologists working on the non-coding RNA and brain tumors.

eLife assessment

This represents an important study that demonstrates a high degree of heterogeneity within trailblazer cells in clusters that participate in collective migration. Solid methods highlight this heterogeneity and show that in TNBC cancers, trailblazer cells are defined by vimentin (and not Keratin 14) and are dependent on both TGFbeta and EGFR signaling.

eLife assessment

This important manuscript presents several structures of the Kv1.2 voltage-gated potassium channel, based on state-of-the-art cryoEM techniques and algorithms. The authors present solid evidence for structures of DTX-bound Kv1.2 and of Kv1.2 in potassium-free solution (with presumably sodium ions bound within the selectivity filter). These structures advance our knowledge of the molecular basis of the channel inactivation process.

eLife assessment

This valuable study adds to our understanding of the DNA replication origin selection process in budding yeast. The authors provide convincing evidence that the number of possible origins of replication is much higher than previously appreciated, although many of the newly identified origins probably direct replication initiation only very rarely. This work will be of interest to those studying DNA replication and investigating protein-DNA interactions across the genome.

eLife assessment

This important work substantially advances our understanding of the interplay between genetic variation, chromatin, and genes within topologically associated domains and how this interplay regulates gene expression. The evidence supporting the conclusions is convincing, with appropriate and validated methodology in line with current state-of-the-art genomic and epigenomic techniques. The work will be of broad interest to geneticists and those working to understand the basic mechanisms of gene expression.

eLife assessment

This study presents valuable findings regarding 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

The mechanisms that determine when neural stem cells should stop dividing after having generated their full repertoire of progeny remain not completely understood. The authors present useful findings on how Notch activity regulates the termination of neurogenesis in central brain of Drosophila. The evidence supporting the claims of the author is solid, although other complementary approaches could have been used to probe more deeply into the underlying molecular mechanisms. This work will be of interest to developmental neurobiologists.

eLife assessment

This is a useful investigation of the changes in gene expression and some of the physiological consequences of sublethal exposures to the neonicotinoid insecticide imidacloprid in honeybee larvae. While the study adds to our understanding of how this insecticide impacts development and growth of honeybees, the evidence supporting the major claims is incomplete. The study would benefit from a more thorough mechanistic characterization of the phenotypes to substantiate the conclusions.

eLife assessment

The manuscript by Eyraud and colleagues examines the role of interactions between fibrocytes and CD8 cells as drivers of disease progression in COPD (chronic obstructive pulmonary disease). The findings that there exist bidirectional interactions between CD8 cells and fibrocytes are supported by solid evidence that combines histology of clinical lung samples, in vitro studies obtained from circulating blood fibrocytes and CD8 cells, as well as a computational model that predicts how bidirectional interactions could promote disease progression over the course of 20 years. The study, which is based on patient samples, thus provides fundamental insights on COPD progression.

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 has 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 important study reports that Foxc2+ cells in the testis represent the quiescent spermatogonial stem cells (SSCs). The data supporting this claim are solid. The finding is of great significance to reproductive and stem-cell biology as male fertility depends on the fine balance between self-renewal and differentiation activities of the male germline stem cells, i.e., SSCs.

eLife assessment

In this valuable study, patients homozygous for both minor frequency alleles of the APOL1 gene are shown to be at significant risk for progression into sepsis after infection. The study has enrolled a significant number of subjects and provides solid results. The study addresses to infectious diseases and critical care experts and one major weakness is the lack of inclusion of non-Black patients.

eLife assessment

This study presents a valuable finding on the putative molecular patterns underlying characteristic morphological regions observed in colorectal cancer (CRC) and the extent to which morphotype heterogeneity impedes prognostic and predictive expression-based classifiers. The evidence supporting the claims of the authors is solid, although clarity in terms of patient selection and subtype definition would have strengthened the study. The work will be of interest to medical biologists working on colorectal cancer (CRC).

eLife assessment

This study follows the career trajectories of the winners of an early-career funding award in the United States, and finds that researchers with greater mobility, men, and those hired at well-funded institutions experience greater subsequent funding success. Using data on K99/R00 awards from the National Institutes of Health's grants management database, the authors provide convincing evidence documenting the inequalities that shape faculty funding opportunities and career pathways, and show that these inequalities disproportionately impact women and faculty working at particular institutions, including historically black colleges and universities. Overall, the article is an important addition to the literature examining inequality in biomedical research in the United States.

eLife assessment

This paper contributes to the field of hippocampal registration by introducing a novel surface-based approach that utilizes the topological and morphological features of the hippocampus for anatomical registration across individuals, rather than volumetric-based methods commonly used in the literature. The study provides compelling evidence for the efficacy of this approach using histological samples from three different datasets and offers validation of the method through comparison with traditional volumetric registration. This is important work given the large number of studies that examine hippocampal shape, thickness, and function in large cohorts, providing strong support for the use of hippocampal unfolding methods in future studies.

eLife assessment

This important study provides a panoramic view of the spectrum of natural variation in C. elegans egglaying behavior, begins to illuminate molecular and genetic influences underlying this variation, and reveals how distinct egglaying behaviors might impact maternal and offspring fitness in diverse environmental conditions. The evidence supporting the authors' conclusions is convincing. This work establishes intraspecific variation in C. elegans egglaying behavior as a model for elucidating the genetic basis for evolutionary transitions between oviparity and viviparity. As such, it will be of interest to evolutionary biologists studying molecular mechanisms underlying fitness tradeoffs between parent and offspring that influence adaptation to changing environments.

eLife assessment

Scheer and Bargmann provide an important behavioral genetics study on how behavioral context affects decision making of C. elegans. The results and interpretations are overall convincing; the behavioral analysis at multiple time scales combined with genetic and neuronal manipulations revealed how arousal states affect decision making. However, alternative interpretations should be considered and statistical methods should be justified. This work will be of interest to both neuroscientists and ecologists.

eLife assessment

This important work reports the identification of a list of proteins that may participate in the clearance of paternal mitochondria during fertilization, which is known as essential for normal fertilization and embryonic and fetal development. The main method used is state-of-the-art and the supporting data are solid. This work will be of interest to developmental and reproductive biologists working on fertilization.

eLife assessment

Boyle et al identify Npy-expressing dorsal horn neurons as powerfully inhibiting pain and itch under normal and pathological conditions. The valuable data are convincing, and the effect sizes are robust and directly challenge previous work.

eLife assessment

This manuscript describes a compelling study demonstrating an important mechanistic role for zinc fluctuations during fertilization. The results show strong evidence that zinc availability modulates inositol triphosphate receptor and that the cytosolic zinc concentration is critical for calcium oscillations that are required for egg activation and fertilization.

eLife assessment

This work describes the generation of a mouse reporter line dedicated to the visualization and study of the axon initial segment (AIS). This reporter line could be a valuable tool for molecular and cellular studies in neuroscience. In this work, the authors have made an exhaustive characterization of the structural and electrophysiological properties of the labelled neurons and convincingly show that they are unaffected by the expression of the reporter protein.

eLife assessment

This is an important study examining the behavioural and neural profile of weak and strong fear memories. The data presented provide solid evidence in support of the conclusion that weak but not strong fear memories are more easily modified using behavioural and pharmacological approaches potentially as a result of differential connectivity with the amygdala showing greater connectivity through the brain in weak compared to strong memories. This conclusion would be strengthened if the possible effect of extinction during training was eliminated. This paper is of interest to behavioural and neuroscience researchers studying learning, memory, and neural networks.

eLife assessment

This important study correlates the size of various prefrontal brain regions in primate species with socioecological variables like foraging distance and population density. The evidence presented in solid but needs to be strengthened with additional analyses that show the robustness of the results to delineation of the brain regions as well as including confounding variables like brain mass. Further the authors should clarify how this approach would generalize to lissencephalic primates which do not have the clear anatomical landmarks used in this study.

eLife assessment

This important study reports vastly different object recognition performance in rats and humans using comparable and rigorous behavioural testing, showing that rats performance is driven by low-level visual features whereas human performance is driven by more complex features. The evidence in support of these claims is intriguing but incomplete, and additional analyses are needed to elucidate the visual features that drive these differences and investigate inter-individual variability. The authors also need to acknowledge and discuss other factors such as visual acuity and training paradigm (extensive training on only two objects) that could have led to these different patterns of performance.

eLife assessment

This study presents valuable findings on the impact of C-natriuretic peptide (CNP) treatment in vivo on the fertility of aged mice. Solid data indicate CNP induces the cAMP-PKA pathway, causing reduced recruitment of Parkin protein to mitochondria in oocytes, resulting in reduced mitophagy which may be significant for increased mitochondrial bioenergetics and improved cytoplasmic and nuclear maturation. The authors make additional claims regarding the mechanisms by which CNP impacts oocyte quality in vivo for which the evidence is incomplete. This work will be of interest to reproductive biologists and clinical infertility specialists.

eLife assessment

This study explores how Ebola virus evades human immune responses. The study reports a potential new mechanism wherein Ebola virus traps human IRF3, a key transcription factor involved in immune signaling, into virus-produced "inclusion bodies." While overall the topic is important and the paper has many merits, readers should note that the reviewers identified some flaws in the experimentation, analyses, and description of methods, which means the strength of evidence is currently incomplete.

eLife assessment

The presence or absence of a surrounding envelope, previously a clear distinguishing feature of different viruses, has been blurred by the recent recognition that many so-called 'nonenveloped' viruses are released from cells as quasi-enveloped virions cloaked in host cell membranes. This mechanism of viral egress allows for non-lytic infection, and has potentially important implications for pathogenesis. In this manuscript, Jassey and colleagues provide solid evidence that the protein deacetylase SIRT-1 is required for the non-lytic release of enteroviruses in extracellular vesicles.

eLife assessment:

Autosomal dominant optic atrophy (DOA) in humans is associated with mutations in OPA1, a mitochondrial dynamin like GTPase. This study uses Drosophila as a model to recapitulate some aspects of the disease phenotype, and it supports and extends previously published data to provide valuable findings that have theoretical or practical implications in the field of rare retinal diseases. The approaches used are solid and allow to investigate differences between mutations that are supposed to be loss-of-function or acting as dominant negative with consequences in the optic system or in a version of DOA, in which other tissues are also affected. However, the main claims are only partially supported and additional information in the materials and methods and several figure legends is needed to complete the study.

eLife assessment

This study presents convincing evidence that metabolite levels in Escherichia coli bacteria from a long-term evolution experiment have changed in consistent ways, which in turn can be explained by recurrent mutations in regulatory genes that affect enzyme expression levels. The use of high-resolution mass spectrometry measuring bulk metabolite levels, in combination with existing gene expression and DNA sequencing datasets provides valuable information linking changes in an organism's genome, transcriptome, and metabolome.

eLife assessment

This study presents a computational model to explore how neurostimulation could impact hippocampal theta oscillations. The computational model combines a detailed physiologically realistic hippocampus model and an abstract theta oscillator. If confirmed, the study could be a useful tool that provides useful predictions on pathological changes in this network. The modelling is based on solid approaches that could be significantly improved with experimental validation.

eLife assessment

This important paper provides new insight into how asexual reproduction can arise in interspecific hybrids, an empirical example of the "extended speciation continuum." The molecular cytogenetic evidence supporting the conclusions is solid, but additional replicates within each species would strengthen the overall findings. By highlighting the potential for asexuality to evolve in hybrids during a narrow window of species divergence, this work will be of broad interest to evolutionary biologists.

eLife assessment

This valuable offers insight into the relationship between floral and reproductive phenotypes and gene expression in allopolyploids. This well-reasoned experimental setup uses thorough statistical analyses to provide compelling insights into the mechanisms driving both phenotypic and gene expression evolution in allopolyploids. The work will be of interest to researchers working in plant speciation and genomics, as well as those more broadly in the effects of ploidy on phenotypic and expression evolution.

eLife assessment

This manuscript presents a valuable analysis of allosteric communication in the CFTR protein using a coarse-grained dynamic model and characterized the role of disease-causing mutations. Some of the results are convincing and make a contribution to understanding the mechanism of CFTR, the discussion of the allostery mechanism is incomplete. Further discussion and validation of the computational approach will help strengthen the manuscript.

eLife assessment

This study presents findings on changes in brain network asymmetry in infants with congenital hearing loss. The findings are valuable but the evidence supporting the claims is incomplete and needs more appropriate and strict statistical analyses. The findings will be of interest to psychologists, neuroscientists, and clinicians.

eLife assessment

This paper reports the fundamental discovery of a new function of neutrophil in specifically clearing apoptotic hepatocytes by penetrating the cells rather than engulfing them without causing inflammation as a part of tissue homeostasis. This solid study transforms the way we think about role of neutrophil in pathogenesis of autoimmune liver disease.

eLife assessment

The authors present "MotorNet", a useful software package to train artificial neural networks to control a biomechanical model of an effector. The manuscript provides solid evidence that MotorNet is easy to use and can reproduce past results in the field, both at the neural and behavioural levels. Validation is limited to planar arm-like plants or point-masses, so future work exploring three-dimensional movements and other types of plants would strengthen the impact of the tool.

eLife assessment

This study presents a valuable set of findings on how prior expectations modulate tactile sensory processing. The neuroimaging evidence supporting the main conclusions is solid, although the nature of the experimental task somewhat limits the interpretation of the findings. This work will be of interest to neuroscientists working on sensory processing and perception.

eLife assessment

This useful study investigated the appearance of a "new-type" ultrasonic vocalization around 44 kHz that occurs in response to prolonged fear conditioning in rats. While the descriptive approach applied may be of interest to some researchers, evidence in support of the conclusions is incomplete.

eLife assessment

Using sophisticated reinforcement learning modeling, authors provide a valuable and convincing result that acute ketamine reduces the strength of the impact of losses vs neutral/gains on performance of a token-based matching-pennies task. However, authors provide incomplete evidence that this interesting acute effect may be a mechanism whereby ketamine is a rapid-acting antidepressant.

eLife assessment

This study involves a valuable investigation of habit-learning in obsessive-compulsive disorder versus controls with participants engaging in a month of motor-sequence task practice administered via a smartphone app. Currently the results are inadequate to support the authors' key claims as not all of the criteria were met to establish that habit learning occurred.

eLife assessment

This study provides a valuable contribution to the study of eye-movements in reading, revealing that attention-weights from a deep neural network show a statistically reliable fit to the word-level reading patterns of humans. Its evidence is solid and strengthens a line of research arguing that attention in reading reflects task optimization, although the work may further benefit from a more specific attribution of the predictive power of the models. The work would be of interest to psychologists, neuroscientists, and machine learning researchers.

eLife assessment

This useful study identifies several gain-of-function division protein variants that can suppress the lethality caused by depletion of Aeg1/AdvA in Acinetobacter baumannii, but characterization and description of AdvA in its localization patterns and interactions with other divisome proteins are inadequate. Since a role of AdvA in cell division has been shown before, the claim that a "novel cell division protein" has been identified is incorrect. The evidence provided also does not support the claim that AdvA plays a critical role in the assembly of the A. baumannii divisome.

eLife assessment

This study has uncovered some important initial findings about how certain extracellular vehicles (EVs) from the mother might impact the energy usage of an embryo. While the study's findings are in general solid, some experiments lack statistical power due to small sample sizes. The study's title might be a bit too assertive as the evidence linking maternal mtDNA transmission to changes in embryo energy use is still correlative.

eLife assessment

This study presents a valuable finding on variations within the RNA synthesis protein of SARS-CoV-2, the virus that is responsible for COVID 19. The evidence supporting the claims of the authors is solid, although a more in-depth analysis of the structures and simulations would have strengthened the conclusions of the work. This work has implications for drug design and will be of broad interest to the general biophysics and structural biology community.

eLife assessment

In this valuable paper, the authors use an existing theoretical framework relying on information theory and maximum entropy inference in order to quantify how much information single cells can carry, taking into account their internal state. They reanalyze experimental data in this light. Despite some limitations of the data, the study convincingly highlights the difference between single-cell and population channel capacities. This result should be of interest to the quantitative biology community, as it contributes to explaining why channel capacities are apparently low in cells.

eLife assessment

This study presents a novel fluorescence based imaging strategy to investigate the folding status of RNA-binding proteins (RBPs) and their association with molecular chaperones under stress. It provides fundamental findings that will potentially advance our understanding in the folding and aggregation status of RBPs in nuclear stress bodies in a significant manner. However, there is also the concern that the evidence regarding protein fate is incomplete and additional controls are needed to fully support the conclusion. The imaging methodology can be adapted to study many other proteins that undergo liquid-liquid phase separation under specific cellular conditions.

eLife assessment

This study assesses homeostatic plasticity mechanisms driven by inhibitory GABAergic synapses in cultured cortical neurons. The authors report that up- or down-regulation of GABAergic synaptic strength, rather than excitatory glutamatergic synaptic strength, is critical for homeostatic regulation of neuronal firing rates. The reviewers noted that the findings are potentially important, but they also raised questions. In particular, the evidence supporting the findings is currently incomplete and demonstration of independent regulation of mEPSCs and mIPSCs is a necessary experiment to support the major claims of the study.

eLife assessment

The manuscript represents an important study on the pathogenesis of rubella virus tropism and neuropathology in human microglia-containing human stem cell derived organoids and human fetal brain slices. The strength of evidence is compelling, employing two different human-relevant models. The findings will be of broad interest to virologists and infectious disease experts, as well as neurodevelopmental biologists. The findings could also be of interest to pediatrics and obstetrics clinical colleagues.

eLife assessment

This manuscript describes important findings that will impact our understanding of nuclear pore complex (NPC)-genome interactions and how nuclear pore proteins (nucleoporins) impact super enhancer function. The authors develop a clever new approach termed NPC-DamID to map chromatin-NPC interactions that has several important advantages over existing techniques and may be used in contexts that are incompatible with genetic manipulation. The authors provide compelling evidence that nucleoporins interact with super enhancers in multiple cell types and also suggest that the phase separation behavior of nucleoporins contributes to the hierarchical organization of super enhancers, which is exciting and will stimulate additional work.

eLife assessment

This study addresses the long-standing question as to how different functional pools of synaptic vesicles are organized in presynaptic terminals to mediate different modes of neurotransmitter release. Based on imaging of active synapses with recycling synaptic vesicles labeled by FM-styryl dyes, the authors provide data that are compatible with the hypothesis that two separate reserve pools of vesicles - slowly vs. rapidly mobilizing - feed two distinct releasable pools - reluctantly vs. rapidly releasing. Overall, this study represents a valuable contribution to the field of synapse biology, specifically to presynaptic dynamics and plasticity. However, the authors' methodological approach of using bulk FM-styryl dye destaining as a readout of precise vesicle arrangements and pools in a population of functionally very diverse synapses has limitations. Consequently, the evidence that directly supports the authors' two-pool-interpretation of their data is incomplete, and alternative interpretations of the data remain possible.

eLife assessment

This is an important study that demonstrates a role of the murine thalamus in ocular dominance plasticity. The evidence supporting the authors' claims is solid, although the inclusion of a conditional KO in which synaptic inhibition was only interfered with in adulthood could better support the authors' conclusions. This work will interest those in the field of ocular dominance plasticity in the visual system as well as scientists investigating the function of synaptic plasticity in the brain.

eLife assessment

This important study examines whether synaptic cell adhesion molecules neuroligin 1-3 resident on astrocytes, rather than neurons, exert effect on synaptic structure and function. With convincing evidence, the authors report that deletion of neuroligins 1-3 specifically in astrocytes does not alter synapse formation or astrocyte morphology in the hippocampus or visual cortex. This study highlights the specific role of neuronal neuroligins rather than their astrocytic counterparts in synaptogenesis.

eLife assessment

This valuable study investigates how hierarchies are processed in the brain, using a paradigm that intends to bridge disparate domains (e.g., language/music and memory). The main findings are that hippocampus and medial prefrontal cortex are sensitive to hierarchy position, while the response in inferior frontal gyrus seems to vary with amount of experience with the hierarchy. Evidence supporting these claims is solid, and would be strengthened by additional methodological clarifications (e.g., as to why the particular analyses are most appropriate for the research question) and further discussion of limitations related to the study design (e.g., the possibility that the task does not require hierarchical representations).

eLife assessment

This manuscript describes a fundamental strategy for developing isozyme-selective inhibitors of inositol hexakisphosphate kinases. The compelling evidence that subtle changes to the gatekeeper position can sensitize the inositol hexakisphosphate kinase mutant to allosteric inhibitors will undoubtedly inspire other analog-sensitive inhibitor studies. This manuscript will be of interest to researchers focusing on kinase regulation and inhibitor design.

eLife assessment

The paper, which investigates mechanisms regulating the F-actin cytoskeleton in the B cell synapse, is an Important contribution to the study of B cell immunology and cell biology. The evidence provided for a key role of N-WASP regulation of F-actin proximal to the B cell receptor is solid, with parts of it being compelling.

eLife assessment

This study presents valuable findings on the role of transcription readout and intron retention in transposon expression during aging in mammals. While the findings are interesting, the evidence supporting the claims of the authors is incomplete, and additional analysis would be required to strengthen the study. The work will be of interest to scientists studying aging, transcription regulation, and epigenetics.

eLife assessment

The manuscript represents an important study on the pathogenesis of rubella virus tropism and neuropathology in human microglia-containing human stem cell derived organoids and human fetal brain slices. The strength of evidence is compelling, using state-of-the-art multimodal technologies. The findings will be of interest to neuroscientists, virologists, and epidemiologists, presenting novel hypotheses and generally helpful tools.

eLife assessment

This important study advances our understanding of the potential mechanisms of deep-sea adaptation and sheds light on the evolutionary history of hadal snailfish. Through comparative genomic analysis, the authors provide convincing evidence and propose hypotheses on the timing of trench colonization, population structure, and adaptations to the hadal snailfish genome in response to their environment.

eLife assessment

The authors pair single-cell sequencing technology with the LoopSeq synthetic long-read method to examine samples of hepatocellular carcinoma and benign liver, with the goal of identifying mutations and fusion transcripts specific to cancer cells. The authors present a valuable resource, but the overall support for the major claims remains incomplete. In particular, the authors could have provided stronger support for the combination of technologies and interpretation regarding cancer-associated genomic changes.

eLife assessment

The authors present valuable findings on how to determine the genetic architecture of extreme phenotype values by using data on sibling pairs. While the authors' derivations of the method are correct, the scenarios considered are incomplete, making it difficult to have confidence in the interpretation of the results as demonstrating the influence of de-novo or Mendelian (rare, penetrant-variant) architectures. The method shows nevertheless promise and will be of interest to researchers studying complex trait genetics.

eLife assessment

In this study, the authors discuss the relevance of the tumor mutational burden (TMB) as an appropriate predictive biomarker for the effectiveness of immunotherapy. The study offers important findings that will contribute to current dialogues around the biomarkers used for therapy in cancer (and perhaps, other diseases). This is an area of substantial controversy, and the authors have gone to great lengths to support their claims with convincing evidence.

eLife assessment

This work presents valuable findings on the cellular and ultrastructural organization of the nervous system in the freshwater polyp Hydra. The authors use adequate methods and present outstanding imaging data with solid evidence to support their claims. The manuscript provides a starting point for further functional in vivo studies. The work will be of interest to developmental biologists and neurobiologists.

eLife assessment

This important study reports on a novel read-out methodology and fabrication strategy to mimic nuclear pore complexes, without the drawbacks of usual techniques, revealing a clear correlation between the size of the nuclear pore complex mimic and its transport selectivity. The methods are compelling, and the data, analyses and interpretation with coarse grained simulations and phenomenological models are solid, supporting the claims with minor weaknesses that would benefit from further clarification. This approach has important potential implications for further understanding of transport by the Nuclear Pore Complex.

eLife assessment

This valuable study examines the effects of different co-stimulatory pathways on gene expression and chromatin accessibility in T cells, in order to link the role of co-stimulatory proteins to genetic variants associated with inflammatory bowl disease (IBD). The work provides valuable insight into the role of alternative co-stimulatory proteins in controlling T cell responses. However, the data presented and the analyses performed are still incomplete and inconclusive with regards to IBD risk factors.

eLife assessment

The authors present a useful analysis of the phenotype of sheep in which the muscle developmental regulator myostatin has been mutated in a FGF5 knockout background. The goal was to produce sheep with a "double-muscled" phenotype, yet the genetically engineered sheep exhibited meat with a smaller cross-sectional area and higher number of muscle fibers. The work extends the extensive body of knowledge already published in this area. The authors provide evidence using in vitro experiments that Fosl1 regulates myogenesis, but the strength of evidence relating to the muscle phenotype and underlying cellular and molecular mechanism is inadequate.

eLife assessment

This important work examines hepatic acetate production via ACOT12/18 in starvation and diabetes. The investigators use solid loss of function strategies in cells, including mouse primary hepatocytes, and in vivo mouse experiments to show that ACOTs are necessary for normal acetate production in the context of fasting and type 1 diabetes. Given that acetate is commonly thought to primarily represent a fermentation product, this study is of interest as it describes hepatic pathways converting fatty acids to acetate.

eLife assessment

This paper will be of interest to scientists in the fields of virology, entomology, ecology and epidemiology as the paper explores the drivers of viral and host composition in natural and disturbed ecosystems. The data are of high quality and have been rigorously assessed.However, important additional information on the transmission ecology of these viruses and their relationship with the environment is lacking, making it difficult to interpret the results from a disease ecology perspective.

eLife assessment

The authors compellingly demonstrate that k-fiber length and dynamics are regulated at the level of individual fibers, even in the absence of focused poles, but that unfocused spindles fail to accurately segregate chromosomes, suggesting that coordination of k-fiber length by pole focusing is important for spindle function. This study provides important new information on spindle scaling, extending in an original manner previous work on this topic.

eLife assessment

This valuable paper uses representative samples of micro-census data from Botswana to describe migration rates over four points in time, from 1981 to 2011. The authors use compelling descriptive data to present migration characteristics where roughly 10% of the population moved in the past year - with equal numbers of men and women, and with migration between districts more common than within districts. Preliminary data indicated migration patterns could have supported HIV diffusion, this can be a starting point for more in-depth analyses. The work will be of interest to those studying human movement and its impact on diseases.

eLife assessment

The authors have established a model for studying p38g/d signaling, which is an important accomplishment given that previous models have been compromised by changes in the TPL2/ERK pathway. Compelling evidence is presented to support the conclusions.

eLife assessment

This manuscript provides important findings and would be of interest to specialists and researchers dealing with polycystic ovarian syndrome. Based on the compelling evidence, the authors present significant results on the role of B cells in immune cell activation in PCOS. However, there are some remarks regarding the statistics and data presentation.

eLife assessment

This important study gives novel insight into the folding diversity of the cerebellum compared to the cerebrum among 56 mammalian species. Based on impressive data, the analyses performed for anatomical descriptions and phylogenetic comparisons are solid, although some issues need to be addressed regarding the choice of statistical models, and the sample size versus the number of explanatory variables. This study will be of interest to neuroscientists, evolutionary and developmental biologists, and physicists interested in biomechanics, as these observations provide a basis for models of brain folding mechanisms.

eLife assessment

This study presents valuable findings that relate the pH pattern along the root surface of the plant Arabidopsis thaliana to the auxin response and gravitropic (changes in growth orientation) response. The evidence supporting the claims of the authors is solid, based on the observation of dynamic responses at a second-to-minute time scale and the systematic correlation between the observed changes in the longitudinal surface pH profile and changes in growth rate. The work will be of interest to a wide range of plant biologists working on plant development and responses to the environment.

eLife assessment

This paper studies color vision in anemonefish. The central conclusion of the paper is that anemonefish use signals from their UV cones to discriminate colors that would not otherwise be distinguishable; this differs from other fish in which UV cones extend the range of wavelengths of sensitivity but do not add a dimension to color vision. The work fits into a rich history of studies investigating how color vision fits into an animal's ecological niche. At the same time, the manuscript needs to more clearly establish and convey the degree to which each conclusion is supported by the data and where the limits of certainty lie.

eLife assessment

This manuscript presents a valuable new microfluidic tool that will allow researchers from different fields to rapidly quantify the chemotactic response of microbes to chemical gradients that have different strengths. Using planktonic bacteria, this paper convincingly shows that a multiplexed microfluidic device produces similar results to previously described microfluidic devices that generate only one gradient at a time. By performing on-chip dilutions, this device allows data for six different gradient strengths to be generated simultaneously, potentially reducing both experimental effort and biological variability.

eLife assessment:

This manuscript uses an innovative combination of spatial profiling with single-cell transcriptomics to define expression profiles of stromal components in proximal tumor regions compared to those in distal regions in pancreatic ductal adenocarcinoma (PDAC). Based on this, the authors claim that the presence of a proximal fibroblast population predicts worse outcomes for PDAC patients than the presence of a distal fibroblast population. While the work provides valuable insight into how different types of tumor stromal fibroblasts may affect PDAC outcomes, the work is currently incomplete and will benefit from more extended use of fibroblast and myeloid cell markers and efforts to better define the transcriptomic data generated.

eLife assessment

This study of human perceptual decision-making provides important insights into the sources of suboptimality in human inference. The authors provide solid evidence by combining psychophysics in an audiovisual causal inference task with detailed modeling of the observed behavior. Additional control analyses should be carried out to validate the identifiability of distinct suboptimalities using the authors' modeling framework, and the generalizability of their findings in other conditions should be tested or discussed more explicitly.

eLife assessment:

This important study convincingly shows that the endopeptidases ECS1 and ECS2 repress the formation of polyspermy-derived triparental offspring and haploid induction by promoting double fertilization. While the underlying mechanisms remain to be further elucidated, the data presented in this study represent a valuable foundation for understanding the regulation of offspring genome size. This study will be of particular interest to the large community of scientists who are interested in plant reproduction and breeding.

eLife assessment

This development of a highly concentrated and potentially clinically valuable antibody formulation for MS-Hu6, a first-in-class FSH-blocking humanized antibody is of potential translational importance in the management of osteoporosis, obesity, and Alzheimer's disease. The meticulous methodology is thorough and compelling in its range of techniques examining the stability and physiochemical properties of the formulated MS-Hu6.

eLife assessment

This study presents valuable structures of a pentameric ligand-gated ion channel from a thermophilic worm that is a homologue of the well-known mammalian nicotinic receptors. Although the function of the worm receptor is unknown, the authors convincingly identify interesting features for this class of receptors including a steroid detergent that is bound in the canonical neurotransmitter site and that induces conformational changes of the extracellular domains. These observations will be of broad interest to the ligand-gated ion channel community, although it is difficult at this moment to relate these observations to channel function as the channel's activating ligand remains unknown.

eLife assessment

This research provides convincing evidence that standard behavioral modeling and EEG-derived signatures of the decision process may not agree on mechanisms underlying changes in decision strategy. The authors make a strong case for the importance of informing behavioral modeling with putative neural signatures of the corresponding decision processes. The assumptions of this neurally-informed modeling approach should be further explored and clarified to highlight not only its benefits but also potential caveats.

eLife assessment

Models of cerebellar function and the coding of inputs in the cerebellum often assume that random stimuli are a reasonable stand-in for real stimuli. However, the important contribution of this paper is that conclusions about optimality and sparseness in these models do not generalize to potentially more realistic sets of stimuli, for example, those drawn from a low-dimensional manifold. While the mathematical modelling and analysis in the paper are convincing, one important limitation of the paper is that the neural dynamics and circuit architecture are not very specific to the cerebellum, and lack important biological detail.

eLife assessment

This manuscript by Combe et al. presents the role of cholinergic modulation in the spike rate adaptation in pyramidal place cells. Using combined electrophysiology, pharmacological, and multi-compartment computational modeling, the authors identify the downstream pathway (e.g. activation of TRPM4 channel) that shapes the firing pattern under the triangular-shaped ramps. The study demonstrates solid evidence, and the findings are important for bridging pyramidal neurons' molecular/channel properties to behavior-level implications (place field firing).

eLife assessment

This important work studies the spontaneous contractions (SC) of the Hydra body wall and presents a mathematical model of nutrient transport to hypothesize the role of SC on maintaining the microbiota. The solid evidence presented yields insights on the functional implications of the SC and the increased nutrient update obtained from mixing the local fluid environment through body wall contractions. The main result represents an important observation about the role of hydrodynamics on organism behavior and its relation to diffusive chemical transport processes.

eLife assessment

The manuscript by Brunetti et al. represents an important contribution where SARS-CoV-2 infection of T-helper cells is implicated and found to be mediated by CD4. The work progressed through a computationally driven hypothesis, by analyzing the interaction partners of SARS-CoV-2 spike glycoprotein (as initially modelled through similar SARS-CoV-1), followed by experimental validations, and further computational and experimental insights on the mechanism of binding. The study identifies the interaction between spike RBD domain and N Terminal domain of CD4 molecule as the specific viral attachment strategy. The evidence supporting the claims of the authors is solid, the results look significant and the data is clear and enough for understanding the manuscript. It also provides a potential usefulness of their approach in future work in understanding how viruses mediate infection of T cells. The work will be of interest to medical biologists working on SARS-CoV-2.

eLife assessment

This fundamental work advances our understanding of the effects of metformin on bone healing in hyperglycemic conditions. The evidence supporting the conclusion is convincing, using three different types of bone fracture models in type-2 diabetes (T2D) mice. This paper is of potential interest to skeletal biologists, orthopaedic surgeons, and endocrinologists who study the effects of metformin on fracture healing.

eLife assessment

In their current study, Detraux D and colleagues provide some evidence suggesting a role for heme biosynthesis on FGF-ERK and TGF beta signalling and exit from naïve pluripotency, and in controlling the 2-cell-like cell state. The observations provided by the authors are interesting and potentially relevant in the field of pluripotent cell state transitions.

eLife assessment

Dhekne et al report a novel pathway for activation of the multi-domain LRRK2 protein kinase by Rab12 GTPase. LRRK2, which is mutated in Parkinson's Disease phosphorylates a subset of Rab proteins involved in intracellular trafficking, and Parkinson's disease-linked mutations increase this phosphorylation. This work adds an important new layer of understanding of this highly complex pathway by revealing that LRRK2's binding to Rab12 enhances its ability to phosphorylate Rab10. This conclusion is supported by compelling evidence from a wide array of rigorous approaches.

eLife assessment

This valuable study reports on the role of transposable elements in gene expression variation in rice and how TE-associated expression changes could have been selected during domestication. The combination of evidence from linkage studies and selection scans for a subset of insertions is convincing, although it is difficult to know in how many cases linkage of TE insertions to other regulatory variants is responsible for altered gene expression and in how many cases the TE insertions themselves are the bona fide cause of altered gene expression. The work will be of interest to colleagues working on the role of transposable elements in adaptation and to biologists working on domestication.

eLife assessment

This manuscript describes a valuable method to study the mechanism of action of essential genes and novel putative drug targets. Evidence for the effectiveness of the system, which is based on engineering pre-validated targets for RNA-mediated knockdown into genes of interest, is compelling, and the method should find use as an orthogonal method for generating gene specific knockdowns.

eLife assessment

This important study demonstrates that the human FUS protein, which is implicated in ALS and related conditions, interacts with RNAs containing GGGGCC repeats and can regulate their translation by altering three-dimensional structures caused by these repeats. The study is carefully executed and the data provide convincing evidence for its major claims. This work will likely be of interest to researchers studying RNA binding proteins, and to those working on ALS and related diseases.

eLife assessment

This important work provides evidence that artificial recurrent neural networks can be used to investigate neural mechanisms underlying reversible remapping of spatial representations. Authors perform convincing state of the art analyses showing how population activity preserves the encoding of spatial position despite remappings due to the tracking of an internal variable. This paper will be of interest to neuroscientists studying contextual computations, neural representation of space and links between artificial neural networks and the brain.

eLife assessment

In this valuable study, the authors report a structural model of full-length kinesin-1, describing its autoinhibitory mechanism using cryo-EM, AlphaFold structural predictions, cross-linking, and mass spectrometry, which together indicate that the previous model for kinesin-1 auto-inhibition using a small motif in the kinesin tail was not adequate. The data offer a convincing model for how kinesin-1 is autoinhibited, although the evidence is in some places still incomplete and would thus benefit from additional analyses. The work will be of significant interest to the research community working on cytoplasmic transport and microtubule motors.

eLife assessment

This important study makes use of AlphaFold2 to predict the models of tens of cohesin subcomplexes from different species. The models are in most cases consistent with published cohesin mutants with defects in cohesin function in vitro and in vivo. The models provide solid 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 study offers a model that is used to interrogate how microscopic epistasis and factors like clonal interference affect evolutionary dynamics. The study offers several important insights that can aid in our understanding of the forces that operate in adaptation. The evidence provided is solid, in the form of models and analytical descriptions that describe how these forces manifest themselves.