Evaluation Summary:

Cancers have frequently been found to show little evidence for purifying selection in their patterns of mutations. The key observation here is that tumors with low mutation burden show compelling evidence of efficient selection, but that tumors with high mutation burden do not. This is an important finding. The broader implication is that high mutation load tumors carry a substantial deleterious mutation load and may use common strategies to tolerate them, possibly providing a therapeutic target. Overall this work makes important observational and conceptual contributions to cancer genomics.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

eLife assessment

The authors use an elegant design to tackle a longstanding question about the extent to which learning social information relies on specialized computational and neural mechanism. They find that learning about ostensible others is more accurate than learning about non-social objects, despite identical statistical information, and that such effects are mediated by the dmPFC and pTPJ - regions previously implicated in social cognition. While likely of interest to a broad range of social, behavioral, and cognitive neuroscientists, the work is not sufficiently framed by relevant previous research. Moreover, the difference between social (faces) and non-social (fruits) stimuli raises concerns about attentional confounds.

eLife assessment

The authors have used state of the art tools to discover and visualize the role of a known ER-localized lipid hydrolase/acyl transferase (which they call Aphyd) in creating lipids that facilitate the localization of proteins required for mitochondrial fission and fusion at nodal points of interaction between the ER and mitochondria. The data are clear, quantitative and compelling in respect to the role of this protein in the processes of mitochondrial constriction, fission and fusion.

eLife assessment

Malaria is still one of the world's most deadly diseases because our bodies cannot make appropriate acquired immunity upon Plasmodium infection (the causative agent of malaria). By using animal models of malaria infection and vaccination, this important work shows that Dendritic cells (DCs) have a lower ability to uptake Plasmodium-infected RBCs (particle antigen). This DC dysfunction could be an important reason behind T cell dysfunction in Plasmodium infection. The data presented here convincingly supports the conclusions.

eLife assessment

Najar et al., present a method for the identification of the emergence of new variants prior to the accompanying surge in cases by examining the trend of accumulated non-synonymous mutations from the original Wuhan 2020 SARS-CoV-2 strain. This is an interesting idea but requires additional evidence to establish this as a robust tool for predictions.

eLife assessment

This interesting manuscript assesses calcium dynamics in the kisspeptin neurons of the arcuate nucleus of the hypothalamus during the estrous cycle and during reproductive aging in female mice. In particular, the authors succeed in tracking arcuate kisspeptin calcium activity in the same mice over 10 months, which is quite impressive and provides novel findings that will be of interest to the field.

eLife assessment

This study makes an important contribution to the function of the iron transporter Ferroportin (Fpn). By using a combination of proteoliposome assays, mutagenesis and structural studies by cryo EM, the authors are able to demonstrate that the H+-driven transporter for Fe2+-efflux is also capable of passive Ca2+ influx. The evidence supporting the conclusions is convincing, but the rate of Ca2+ influx and the physiological relevance of Ca2+ entry is yet to be established. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This study provides convincing evidence supporting the important finding that acoustic and linguistic features contribute to brain responses as people listen to speech. However, the innovation of the methodological advance relative to other papers in the subfield is not entirely clear.

eLife assessment

This is a valuable study of Arabidopsis shoot apical meristem maintenance and organ initiation, defining the expression, interactions and functions of four transcription factors (SHR, SCR, JKD, and SCL23) whose roles were initially described in the root apical meristem. The imaging, genetics and FRET-FLIM evidence supporting the claims of the authors is comprehensive, extensive, and solid, although similar mechanisms, protein interactions, and gene regulatory interactions were previously reported in the root. The work will be of interest and importance for plant developmental biologists.

eLife assessment

This paper will be of interest to researchers in the field of genomic medicine and cancer mutagenesis. It presents predictive models with potential clinical applications that can identify patients with specific gene dysfunction based on characteristic patterns of mutation. The key findings are well supported.

eLife assessment

The authors convincingly demonstrate that, in the absence of any shutdowns, the Danish colorectal cancer screening program experienced only minor decreases in program participation during the COVID-19 pandemic period. This likely ensured ongoing program effectiveness in detecting early colorectal cancers and precancerous polyps. The evidence is solid, as the national screening database was used and only a small proportion of participants were excluded.

eLife assessment

This fundamental work substantially advances our understanding of the kidney interstitium and how it influences kidney development focusing on zebrafish as a model organism. The evidence supporting the conclusions is compelling, using single-cell analysis combined with in vivo zebrafish studies to mechanistically explore the functional importance of the discovery. The work will be of broad interest to cell and developmental biologists as well as the kidney community.

eLife assessment

Tan and colleagues studied synaptic transmission, presynaptic protein levels, and synaptic ultra-structure in hippocampal cultures of mice lacking the key active-zone proteins RIM (1, 2), ELKS (1, 2), and Munc13 (1, 2). Compared to cultures lacking only RIM and ELKS, additional deletion of Munc13 results in a further decrease of synaptic Munc13-1 levels, a similar reduction of the number of docked synaptic vesicles, and a more pronounced decrease of total synaptic vesicle number. At the physiological level, these RIM-ELKS-Munc13 hextuple knockout cultures display a further decrease in the pool of release-ready synaptic vesicles with largely unchanged release probability compared with RIM-ELKS quadruple KO cultures. The results support the conclusion of the nonredundant role of Munc13 in synaptic vesicle priming. On the other hand, while the genetic removal of all six genes involved clearly require the use of conditional KO mice, the resulting outcome of the experimental design is a hypomorphic phenotype, as neurotransmitter release is still detected and this complicates the interpretation of the findings. Overall, this study reinforces the notion that synapse formation is a remarkably resilient process that occurs even under strong perturbation of presynaptic function.

eLife assessment

Overall, this is an interesting paper that explains molecular underpinnings of hair cell reprogramming. This paper could have significant implications for our understanding of how different cellular programs can dictate phenotypic outcomes such as hearing.

eLife assessment

Chemical fixation of cells is ubiquitous in microscopy. However, fixation artifacts can lead the incorrect interpretations of biological processes. In here, Irgen-Gioro et al. show that in the context of liquid condensates formed by liquid-liquid phase separation (LLPS), paraformaldehyde (PFA) fixation can lead to artifacts such as changes in the number, appearance, or disappearance of liquid condensates, when comparing fixed to live cells. This will be of great interest not only for those in the LLPS field but for cell biologists, in general, using fixed samples for microscopy.

eLife assessment

This manuscript makes a major contribution to the study of early visual representation in primates by showing that intermediate cortical areas V2 and V4, as well as primary cortical area V1 (previously shown), contain orthogonal maps of orientation and spatial frequency, which are recursive across the visual field representation. This is a fundamental principle of functional mapping across the two-dimensional cortical surface that ensures and optimizes the complete representation of all combinations across two coding dimensions.

eLife assessment

Auwerx and colleagues take a new approach to mine large datasets of the intermediary molecular data between GWAS and phenotype, touncover molecular mechanisms that lead from a GWAS hit to a phenotypic effect. The approach should be of great use to all (human) geneticists. Revisions are necessary to ensure that the significant findings from this approach are understood by the bioinformatic community and that these methods can be applied generally, given that the paper's main novelty is in its approach to mine large datasets, rather than a specific, key molecular finding.

eLife assessment

In this study, the authors performed mass cytometry (CyTOF) analysis and T cell receptor (TCR) sequencing to study immune cell composition and expansion of joint-derived Tregs and non-Tregs in Juvenile Idiopathic Arthritis (JIA). They studied different joints affected at the same time and found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient. The research design of this study is appropriate and the methods used in this study are adequately described in the manuscript. The study may be potentially beneficial for the JIA treatment.

eLife assessment

This article establishes a model experimental bacterial community to represent the microbiome found in ~1/3 of patients with cystic fibrosis (CF) with the goal of understanding why these infections do not respond to treatments that are effective in single-species infections. The authors show that susceptibility to the most common antibiotic used against the dominant pathogen P. aeruginosa is different when grown in this mixed community, and a mutant of this pathogen (lasR) that frequently occurs during infections alters this sensitivity. This study is significant for producing an experimental resource for the microbiology of CF, and it could be strengthened by more detailed measures of interactions between species and how the phenotypes produced by lasR alter species interactions.

eLife assessment

This competently performed retrospective analysis presents important findings concerning the clinical use of tafenoquine, a drug against Plasmodium vivax malaria. The assembly of the majority of global tafenoquine pharmacology data from clinical treatment studies provides compelling evidence in support of the drug's regimen that includes an increase in dosing, which would lead to a significant enhancement of the drug efficacy, hence a decrease in recurrent parasitemia. The manuscript could benefit from a more detailed analysis and discussion concerning the side effects of the drug affecting more susceptible populations.

eLife Assessment

The paper pushes the known preservation of ancient proteins, and their successful recovery, into the late Miocene. The results of the study also have implications for avian taxonomic classification. The findings reported in the paper are a welcome addition to the field of paleoproteomics and encourage future research on ancient proteins in deep antiquity and across various taxa. The paper will be of great interest to paleoscientists.

eLife assessment

This paper deploys elegant genetic tools to understand how synapses are formed in the Drosophila central nervous system. The synaptic connections between two identified neurons in the Drosophila central nervous system are used as a system to document the role of cell ablation and activity in dendrite growth and circuit wiring. In so doing, they identify a brief window of time that appears critical for these wiring and growth decisions.

eLife assessment

This article shows how the COVID-19 pandemic affected cervical cancer screening participation in the organized screening program of Denmark. Through registry data covering the entire population, the study shows that while short-term (90 days) participation after invitation dropped, long-term (365 days) participation remained stable. These results will be of interest to public health specialists and researchers working on pandemic recovery efforts related to cancer screening worldwide.

eLife assessment

Acute inflammation in mammals activates the hypothalamic pituatary axis leading to increased glucocorticoid release, which is required to restrain the inflammatory response. However, in settings of severe or prolonged inflammation, such as that seen in sepsis, there is reduced adrenal steridogenesis. The studies described in this paper provide a plausible mechanism for adrenal resistance which develops during excessive inflammation.

eLife assessment

Neverov and colleagues analyze patterns of correlated changes of amino acids in the SARS-CoV-2 spike protein to identify networks of interacting positions using an improved version of the previously validated method. Identifying such patterns of co-evolution is important for a better understanding of spike-protein evolution. The evidence for the identified co-evolving pairs is solid, though the degree of certainty varies among the different identified groups of potentially interacting positions.

eLife assessment

This paper is expected to be of interest to systems neuroscientists in the fields of emotion, hippocampal function, and anxiety-related behavior. The authors performed recordings in ventral hippocampus and show that 1) place fields become concentrated near the open areas of a maze, 2) direction-dependent coding decreases in these open areas, and 3) ventral hippocampal population activity in the closed area can be used to predict how mice explore the open area in the immediate future. These valuable findings support a potential role for the ventral hippocampus in the exploration of anxiety-provoking environments, however, the manuscript in its current form is incomplete, with some support for the main findings but also some limitations.

eLife assessment

This is a useful study exploring multi-modality brain age (structural plus resting state MRI) in people in the early stages or at risk of Alzheimer's disease. They found solid evidence that people with cognitive impairment had older-appearing brains and that older-appearing brains were related to Alzheimer's risk factors such as amyloid and tau deposition. They claim to show that the multi-modality brain age model is more accurate than a unimodal structural MRI model, though the evidence for that is incomplete.

eLife assessment

This is an important and fundamental, well-written and easily comprehended quantitative imaging study, analyzing the motion of endo-lysosomal compartments within axons in vivo using simultaneous multiphoton imaging in the mammalian brain. Taken together, this is a significant technical advance with interesting observations that substantively move the field forward.

eLife assessment

Hebart et al., present a new massive multi-model dataset to support the study of visual object representation, including data measured from functional magnetic resonance imaging, magnetoencephalography, and behavioral similarity judgments. The general, condition-rich design, conducted over a thoughtfully curated and sampled set of object concepts will be highly valuable to the cognitive/computational/neuroscience community, yielding data that will be amenable to many empirical questions beyond the field of visual object recognition. The dataset is accompanied by quality control evaluations as well as examples of analyses that the community can re-run and further explore for building new hypotheses that can be tested with such a rich dataset.

eLife assessment

This manuscript from Ramírez-Flandes will be of interest to marine biologists, deep ocean ecologists, conservation biologists, and biogeographers. At times, the comparison of merely a pair of samples or sampling locales can substantially widen our view of biological and ecological systems and processes. In the case of this study, the pattern of metazoan diversity from eDNA samples from across the water columns in comparable series from two deep trench systems (to below 8000 m) is markedly different, including evidence of substantial biological diversity deep in the Atacama Trench (to a much greater extent than observed in the Kermadec Trench), contradicting existing paradigms about biodiversity potential in abyssal-hadal regions.

eLife assessment

This work investigates the cellular and cerebellar origins of trisomy 21 (Down syndrome) phenotypes. One human chromosome 21 gene is Pericentrin (PCNT), encoding a component of the centrosome. The authors use several models with 3 or 4 copies of human chromosome 21 (or mouse equivalents) to reveal how increasing PCNT gene dosage alters ciliogenesis and ciliary signaling.

eLife assessment

McKay, et al. describe development of a new wireless, network-enabled automated feeder system with which diet amount and schedule can be controlled across individually housed killifish. The system is constructed using open-source components and software and is amenable to manufacture by individual research groups and is highly scalable. The authors then use this system to explore dietary restriction effects on killifish lifespan and to develop an associative learning assay, two important goals in the KF /longevity field. The authors demonstrate that precise control of food allows automated investigation of lifespan extension under calorie restriction conditions. Secondly, they show an exciting modification of the system that involves only addition of a simple LED light. This modification allows use of the system in an associative learning / conditioning paradigm. Finally, using this paradigm, they demonstrate an age-dependent decline in learning.

eLife assessment

This study describes a previously unrecognized positive feedback loop between leukemic cells and stromal cells impeding normal hematopoiesis mediated by lymphotoxin produced by cancer cells and its receptor expressed in stromal cells. These valuable findings will guide future research in both basic and clinical medicine. However, additional experimental evidence including more comparator groups would have further substantiated the authors' conclusions.

A good summary of James Carse's book "Finite and Infinite Games"

eLife assessment

This manuscript characterizes the localization and function of two proteins promoting division asymmetry in developing stomata of the grass Brachypodium distachyon. The authors demonstrate that the opposing polarity domains of these proteins are linked to cell division orientation. While both proteins have been studied previously in other systems, there was no prior evidence of cooperative functions in a single cell type, as shown here. With further clarification of some of the localization findings, this study will be of strong interest to plant cell biologists and those interested in asymmetric cell division generally.

eLife assessment

This study provides compelling evidence for the involvement of RAM pathway in the survival of C. neoformans in high CO2 concentrations. The work is important to understand how this fungus adapts to the high CO2 concentrations in host tissues. The experimental approach combines genetic and biochemical approaches to explore a complex topic that is of essential for cryptococcal pathogenesis.

eLife assessment

The authors re-analyzed a previously published dataset and identify patterns suggestive of increased bacterial biodiversity in the gut may creating new niches that lead to gene loss in a focal species and promote generation of more diversity. Two limitations are (i) that sequencing depth may not be sufficient to analyze strain-level diversity and (ii) that the evidence is exclusively based on correlations, and the observed patterns could also be explained by other eco-evolutionary processes. The claims should be supported by a more detailed analysis, and alternative hypotheses that the results do not fully exclude should be discussed. Understanding drivers of diversity in natural microbial communities is an important question that is of central interest to biomedically oriented microbiome scientists, microbial ecologists and evolutionary biologists.

eLife assessment

This paper is of broad interest to infer the causal effect of exposures on outcomes. It proposed an interesting idea for the identification of risk factors amongst highly correlated traits in a Mendelian randomization paradigm. The intuition for this method is clearly presented. However, critical details about implementation are missing and its application is not sufficiently demonstrated in the current form.

eLife assessment

This manuscript is relevant to experimental and theoretical neuroscientists interested in the trade-off between chaos and reliability in the brain, and may also pique the interest of the machine learning community, particularly those seeking to understand the computational capacity of recurrent neural networks. The findings are valuable, with practical and theoretical implications for this subfield. Using a spiking neural network model firmly anchored in experimental data from the turtle brain, the authors examine the reliability and flexibility of spike train sequences and determine the differential roles of strong and weak connections. The results show clearly that strong but sparse connections in a sub-network can produce a highly reliable response to single spikes, with reliability and multiplexing across sub-networks controlled by weak connectivity. The strength of evidence for the claims is convincing, using appropriate and validated methodology in line with current state-of-the-art.

eLife assessment

This report illustrates the marked alteration of red blood cell (RBC) morphology that occurs with COVID-19 infection. Of particular importance is the observation that RBC morphology is dramatically affected whether cells are suspended in plasma from healthy vs COVID-infected blood. The claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous. The results are important for consideration of the broader pathophysiology of COVID-19, particularly with regard to the impact on vascular biology.

eLife assessment

This paper directly estimates the fitness cost of loss-of-function mutations in almost every gene in the human genome, providing an interpretable measure of the severity of mutations. The authors then compare datasets of presumably healthy individuals and individuals affected by severe complex disorders or genetic disorders, finding enrichment of de novo loss-of-function mutations in highly constrained genes among probands alongside other illuminating results. This important study will be useful to researchers interested in interpreting and prioritizing disease-causing mutations and in the process of human evolution. Overall, the approach is elegant and the results are of high quality and compelling.

eLife assessment

In this manuscript, the authors address the variable results and data regarding the role of the FAAH variant (C385A at the nucleotide level and P129T at the protein level) in the control of feeding. The authors hypothesize that the variable results might be due to the environmental context, specifically stress related conditions. They designed studies to address the role of glucocorticoids in regulating feeding and metabolism.

eLife assessment

In this study the authors show that neural tuning for object orientation in IT is unaffected by whole-body tilt, suggesting that neurons are encoding objects relative to the gravitational vertical. However, these observations could also be because IT neurons may encode object orientation relative to cues and not due to gravity, or due to dynamic, compensatory torsional eye movements made by the animals. With these concerns adequately addressed, this would be an important study showing that IT neurons may play a role not only in object recognition but more broadly in physical scene understanding.

eLife assessment

This fundamental work reveals a novel direct projection from the lateral entorhinal cortex to the medial entorhinal cortex. Using multiple techniques, the authors provide compelling evidence that fan cells from the lateral entorhinal cortex project to superficial neurons in the medial entorhinal cortex. This newly identified connection may support the combination of spatial inputs with sensory or high-order signals, providing novel insight into potentially how the 'what' (lateral entorhinal cortex) and 'where' (medial entorhinal cortex) features of memory are incorporated.

eLife assessment

This paper will be of interest to those studying DNA replication in the context of chromatin and development. This important study uncovers a new interaction partner for the chromatin protein SuUR and tries to understand how this complex (SUMM4) functions to control under-replication in polytene chromosomes. While the experiments are of high quality and carefully controlled, the data currently do not fully support all the conclusions, particularly as they relate to conclusions about DNA replication timing.

eLife Assessment

In this manuscript, Sell et al., investigate the role of the long non-coding RNA H19 in regulating cellular senescence. Using several cell models they identify upstream and downstream effectors of H19 including let-7 and EZH2. The advances in this work include the identification of a specific cascade of factors connecting H19, senescence and the actions of rapamycin.

eLife assessment

This study presents a valuable finding that adds to a growing body of evidence reporting heritable cell states that can guide fate choices in single cells, in this case the fate of early IFN-I response. The evidence supporting the claims of the authors is solid, although testing the generalizability of the result to other cell types or contexts and strengthening the link to epigenetic regulation would have strengthened the study. Overall, this work will be of interest to a wide set of scientists, including cell biologists, immunologists, and systems biologists.

eLife assessment

This important study reports cryo-EM structures of human ferroportin (FPN), a protein essential for iron transport in humans. This manuscript will be of interest to researchers studying membrane transport mechanisms as well as to those interested in drug design. The structures detail interactions between FPN and the small-molecule inhibitor vamifeport, which is currently in clinical trials for sickle cell disease, and ta new (occluded) protein conformation that is stabilized by a sybody (a nanobody selected from a synthetic library) is identified. Evidence for the mechanism of inhibition by vamifeport is convincing, but evidence for the physiological relevance of the occluded conformation is still incomplete.

Aral Balkan's personal (single-user) Mastodon instance costs him ~50 EUR per month to run.

eLife assessment

This manuscript is extremely useful for describing an R package that provides a valuable pattern and overlay framework for producing colorblind-friendly scatter plots for the field. The utility of this tool for making plots more accessible was demonstrated compellingly. This work will be of broad interest to many biomedical scientists, especially to viewers with color-vision deficiency.

eLife assessment

The authors investigate the cost and benefits of maintaining seemingly redundant multiple copies of the translation machinery components. The authors demonstrate that while redundant multiple copies are beneficial in a nutrient-rich environment, maintaining these extra copies is costly and deleterious in a nutrient-poor environment. This explains why copy numbers of translation machinery genes are under selection according to the environmental niche an organism occupies. The work is very important and the findings exciting and supported by compelling evidence. In particular, the fitness gain upon deletion of translation genes in poor conditions is an insightful observation.

eLife assessment

Giesberg and colleagues provide evidence both in yeast and human cells that fast elongation speeds of RNA polymerases result in a "downstream-shifted" poly(A) profile while the opposite is true for slower speeds of elongating polymerases. GC content of sequences downstream of poly(A) clusters influences the cluster profiles by affecting elongation and thus allowing more time for the 3'-cleavage complex to find the poly(A) site and form the transcript terminus. Although the findings presented in this manuscript are not surprising, they are new and contribute a missing piece to our knowledge of how the transcription machinery determines which poly(A) site to utilize at the end of genes.

eLife assessment

As shown by the authors, the focal adhesion protein, kindlin-2, plays an essential role in liver development in that its genetic inactivation leads to severe fibrosis and death in young mice. This lethality is attributed to increased liver inflammation and cell death. This work will be of interest to readers studying mechanisms of liver development and pathological fibrosis.

eLife assessment

The authors use a clever experimental design and approach to tackle an important set of questions in the field of decision-making. From this work, the authors have a number of intriguing results. However, questions remain regarding the extent to which a number of alternative models and interpretations, not considered in the paper, could account for the observed effects.

eLife assessment

The authors report that, in the murine liver, intermittent fasting alters the homeostatic regenerative programme. This has fundamental implications for the use of murine models to study liver regeneration and cancer and highlights through a series of solid mechanistic studies the role of FGF/Wnt signalling interactions in modulating fasted associated regeneration. It opens up further questions as to why this occurs, how this is beneficial to adapting to a fasting state, and the potential for translation.

eLife assessment

This study, supported by reasonably solid evidence, will be of interest to breast cancer researchers. The finding that EHD2 promotes tumor growth and impacts store-operated calcium entry (SOCE) adds to our understanding of breast cancer cell physiology. If supported by further research, the study provides a rationale for using SOCE inhibitors in a subset of breast cancers, with high expression of EHD2 serving as a potential predictive biomarker for using SOCE inhibitors.

eLife assessment

The paper will be of interest to cognitive neuroscientists in the field of spatial navigation as well as to systems neuroscientists interested in neural representations. Using simultaneous electrophysiological recordings in the anterior thalamus and the retrosplenial cortex, the study investigates the coordination of neurons coding for the head direction in this thalamocortical network. Environmental manipulations led to a near-synchronous update of the head direction signal encoded by the two populations. Further data analysis is needed to support the main claim of the study.

eLife assessment

This paper, which provides useful information on the assembly of volume-regulated anions channels formed by LRRC8 proteins, will be of interest scientists in the field of ion channels. The authors report the structure of a LRRC8C-LRRC8A chimera with native functional properties as a heptameric complex with a lipid-filled pore. This is very interesting and well-presented work, but the evidence supporting the physiological relevance of the heptameric assembly and the hypothesized role of lipids is still incomplete.

eLife assessment

This is an important study that resolves a controversy about a proposed molecular linkage between the fields of mechanobiology and RNA signaling. While prior research had claimed that a specific mechanosensitive ion channel in the gut responds to a specific fecal RNA, this study provides compelling evidence that the mechanosensitive ion channel does not respond to the RNA.

eLife assessment

This paper will interest neuroscientists working in the field(s) of basal ganglia, amygdala, and fear learning. Overall this is an important study that examines the contribution of an understudied brain region to fear conditioning in male subjects. Some conclusions will benefit from additional verification and evaluation of the specificity of the findings to the amygdala-striatal transition zone relative to adjacent regions.

eLife assessment

The fluorescently tagged SYT-1 mouse line will be useful for the field. Importantly, the authors used a comprehensive set of immunohistochemical and physiological experiments to demonstrate that the fluorescence tagging did not alter the function of SYT-1. These are important control experiments that will make the strain useful for physiological experiments in the future. However, the advance of this manuscript is less clear.

eLife assessment

This paper provides important evidence for the impact of the COVID-19 pandemic on cancer screening for breast, cervix, and colorectal cancer in Italy. The authors compared Invitation and examination coverage, as well as conducted telephone interviews, investigated the population screening test coverage, before and during the pandemic, according to educational attainment, perceived economic difficulties and citizenship. Their findings convincingly show that the lockdown and pandemic restrictions caused delays in screening activities but particularly increased the pre-existing individual and geographical inequalities in access.

eLife assessment

The paper describes an online tool, CausalCell, intended for the analysis of causal links in single-cell datasets. Regarding its significance, this work is timely and important, with potentially broad applications as a generally useful tool. However, there are major concerns about the suitability of the tool for its intended purpose, and the extent of validation in the current manuscript is incomplete.

eLife assessment

This paper provides valuable evidence for a weakening of the association between cognitive ability and height from 1957 to 2018 in the UK. The authors find the strength of the association declined over this time frame. These associations were further attenuated after accounting for proxy measures of social class. This paper is a solid contribution to debates about how genetic, environmental, and social factors have affected the joint distribution of height and cognitive ability over the last 60 years.

eLife assessment:

This study by Li et al describes an interesting attempt to predict the functional status of the p53 tumor suppressor in tumors where no DNA mutations in p53 could be identified. To this end, the authors employed SVM models to train the algorithm for the detection of 'p53 inactivation' features contrasting normal and tumor tissues. The approach could be a valuable tool for attributing tumors with unknown p53 status. The authors provide solid evidence supporting their findings and the concept of the study is solid, but in its current formulation, some of the bioinformatic analyses are incomplete, particularly related to the selection of associated genes and the potential mechanism(s).

eLife assessment

NOX2 is the most well-studied member of the NADPH oxidase family, membrane enzymes that produce reactive oxygen species (ROS), and the proper function of NOX2 is critical for innate immunity against pathogens in mammals. This study reports a high-resolution structure of the NOX2-p22 complex, providing valuable information for a mechanistic understanding of NOX2 activation at the molecular level.

eLife assessment

In this study, Hung et al. address the biology and therapy of chondrosarcoma. The authors provided high-quality data that uncovered a new signaling axis, EZH2/hSULF1/c-Met, that promotes chondrosarcoma growth and progress. The authors also reported evidence showing that c-Met inhibition may be a plausible treatment option for chondrosarcoma. The findings are novel and translational and are of interest to cancer biologists and oncologists.

eLife assessment

Sodium selenate reduced seizures when administered after initiation of epilepsy, complementing earlier work showing efficacy if administered before initiation. The novelty of the results is not much more than the earlier study. Sodium selenate reduced phospho-tau and increased PP2A protein expression, and reversed TLE-associated telomere-shortening. However, whether these effects were critical to the reduced seizures is not clear. Finally, proteome and metabolome data from the animal model of epilepsy is discussed and provide initial insights into the effects of sodium selenate treatment on molecular pathology, however, the data are not well developed so revisions along these lines will be important so conclusions can be made.

eLife Assessment:

Predicting the effect of mutations on protein stability is important both for protein engineering and for helping to decipher the effects of genetic and clinical mutations. The machine learning methodology introduce here is timely in view of the millions of AlphaFold model structures that are now becoming available, which could hypothetically be examined through approaches such as this one. The methodology presented is valuable, but the manuscript would benefit from a substantial amount of comparative data to provide more compelling evidence for the validity of the methods.

eLife assessment

This manuscript addresses the mechanism of ligand specificity of odorant receptors (OR) through mutational analyses and structure prediction. The authors identify a single amino acid substitution that switches ligand specificity between two olfactory receptors. Obtaining structures of OR complexes has been challenging, so such an approach is valuable and will be of interest to scientists within the fields of chemical ecology and sensory neuroscience.

eLife assessment

The manuscript makes an important contribution to understanding the roles of the bee host and microbiome in degrading amygdalin, a dietary secondary metabolite. Several bacterial strains and their enzymes responsible for the deglycosylation of amygdalin are identified. Conclusions are reached convincingly through a comprehensive combination of in vitro and in vivo experiments including gene-expression analysis, proteomics, HPLC-MS, and the use of recombinant E. coli to test enzyme function. As the consequences of microbial-derived amygdalin metabolisation on host health remain uncertain from the experiments conducted, the manuscript could be improved through a clearer discussion of future work needed and in parts more careful wording to not prematurely suggest benefits to the host.

eLife assessment

This paper is of potential interest to neuroscientists expert in cortical circuitry and behavioral role of neuron types. The imaging technique used permitted to detect a specific group of cortical neurons known as vasoactive intestinal peptide (VIP)-expressing interneurons from several cortical regions with high temporal resolution. The main message conveyed by this manuscript is that many VIP-expressing interneurons respond to reward and punishment but also show regional differences. The conclusions drawn are generally supported by the data, but some claims and interpretations require further attention and clarification.

eLife assessment

This large-scale collaborative study is a timely contribution that will be of interest to researchers working in the fields of infectious disease forecasting and epidemic control. This paper provides a comprehensive evaluation of the predictive skills of real-time COVID-19 forecasting models in Europe. The conclusions of the paper are well supported by the data and are consistent with findings from studies in other countries.

eLife assessment

In this valuable contribution, the authors apply an artificial intelligence method to predict the three-dimensional structure of complexes of outer membrane proteins of the Gram-negative bacterium E. coli. Some of the cases presented are compelling, as they explain previously published biochemical data and/or reproduce existing structural data.

eLife assessment

The authors provided strong evidence that the Fusarium oxysporum effector protein FolSpv1 enhances virulence by targeting tomato SlPR1 and preventing the generation of the SlPR1-derived phytocytokine CAPE1, which otherwise positively regulates disease resistance in tomato plants. Strikingly, they show that FolSpv1 translocates SlPR1 from the apoplast back into the nucleus of tomato cell, suggesting a previously unknown mechanism employed by pathogenic microbes.

eLife assessment

The work, which examines how Advanced Glycation End-products (AGEs), commonly found in processed and other cooked foods, affect eating behavior and signaling in the nematode C. elegans, is in a fundamentally important area of research with clear translational potential for humans. Some aspects of the manuscript are compelling, including the well-characterized assays on food intake, while other aspects are still incomplete, such as the mechanistic work on the neural network responsible for the response to AGEs.

eLife assessment

This is an important and timely characterization of a diversity of behaviors male and female rats exhibit during the acquisition of Pavlovian fear conditioning in a conditioned suppression procedure. The data are compelling and provide an exhaustive analysis of behavior in a complex associative learning paradigm that blends aversive Pavlovian and appetitive instrumental elements. The generalizability of these findings to other paradigms could be enhanced, however, with the inclusion of tests of cue responses in a neutral environment. These findings are likely to be of interest to those who study fear conditioning and associative learning more broadly in rodents.

eLife assessment

Primates perceive and detect stimuli differently depending on the stimulus context in which they are embedded, and have a remarkable ability to understand the way in which objects and parts of objects are embedded in natural scenes (scene segmentation). An example of this is figure-ground segmentation, a well documented phenomenon resulting in a "pop-out" of a figure region and corresponding enhanced neural firing rates in visual areas. It is unknown whether mice show similar behavioral and neural signatures as primates. The present study suggests that mice show different segmentation behavior than primates, lacking texture-invariant segmentation of figures and corresponding neural correlates. This reveals a fundamental difference between primates and mice important for researchers working on these species and researchers studying scene segmentation. The findings are further interpreted in terms of neural network architectures (feedforward networks) and are relevant for this field too.

eLife assessment

This study modeled monkeys' behavior in a stimulus-response rule-learning task to show that animals can adopt mixed strategies involving inference for learning latent states and incremental updating for learning action-outcome associations. The task is cleverly designed, the modeling is rigorous, and importantly there are clear distinctions in the behavior generated by different models, which makes the authors' conclusions convincing. The study makes a strong contribution overall, however, there were aspects of the design that were unclear and some alternative accounts that were not considered.

eLife assessment

It's been widely known that the amino acid Glycine can work as a cytoprotectant and inhibit pyroptosis-associated plasma membrane rupture. However, a long-standing question has been: how does Glycine cytoprotection work? The authors observed that Glycine treatment phenocopied deficiency of NINJ1 (a recently reported cell surface molecule critical for plasma membrane rupture), and can inhibit aggregation of NINJ1. Understanding the intrinsic mechanism by which Glycine affects NINJ1 could provide a significant advance in the cell death field.

eLife assessment

The study by Kim et al. combines extracellular recordings from olfactory sensory neurons (OSNs) in locusts with computational modelling approaches to investigate the dynamics of odour responses. The authors demonstrate that OSN responses can be grouped into four distinct response motifs, with OSNs showing different motifs in an odour-dependent manner. Using computational modelling the authors provide some evidence that these diverse response motifs expand the coding space and could facilitate odour discrimination and navigation. This study can be of high relevance to both experimental and theoretical neuroscientists investigating odour coding and odour-driven behaviours such as navigation. In its present form, while the experimental data and analysis are of the highest quality, the modelling part needs to be expanded to fully support the experimental measurements.

eLife assessment

The interesting manuscript shows that breast cancer cells that are poorly migratory in culture can be more metastatic in mice. This is due, at least in part, to the secretion of extracellular vesicles containing the the crosslinking enzyme Transglutaminase-2, which can activate fibroblasts in the tumours. These fibroblasts can then promote metastatic phenotypes. This study demonstrates how cancer cells can manipulate the cells around them in order to disseminate.

eLife assessment

Hearing is mediated by hair cells in the cochlea, which synapse onto the primary dendrites of the auditory nerve. This study shows how deletion of a postsynaptic glutamate receptor subtype strongly influences inner hair cell-spiral ganglion cell synapse formation. Thus pre- and post-synaptic changes are dynamically intertwined, providing insights into how pathological outcomes arise from synaptic perturbations.

eLife assessment

This paper should be of broad interest to developmental biologists who seek to understand spatiotemporal control of myosin-based force generation during tissue morphogenesis during early development. The central conclusions are well-grounded in rigorous quantitative data analysis and modeling. The results challenge current views of how gene expression patterns control myosin II anisotropies and provide new testable hypotheses on the role and importance of tissue geometry.

eLife assessment

The authors identify co-deletion of the mitochondrial AAA+ ATPase ATAD1 with the tumor suppressor PTEN as a factor modifying cancer prognosis, based on a new mechanism of increasing sensitivity to proteotoxic stress induced by proteasome inhibition. The authors also identify the mitochondrial E3 ubiquitin ligase MARCH5 as a gene whose deletion is synthetically lethal with ATAD1. These findings suggest that the use of proteasome-targeting agents may be useful in patients with tumors dually deleted for ATAD1 and PTEN. The study is based on convincing evidence, and makes an innovative contribution to the understanding of the biology of tumors with 10q23 deletions.

eLife Assessment

This report describes evidence that the main driving force for stimulation of glycolysis in dentate granule cell neurons in acute hippocampal slices from mouse by electrical activity comes from influx of Na+ including Na+ exchanging into the cell for Ca2+. The findings are presented very clearly and the authors' interpretations seem reasonable. This is important and impactful because it identifies the major energy demand in excited neurons that stimulates glycolysis to supply more ATP.

eLife assessment

This well-presented and sophisticated study provides significant proof-of-concept for the application of the ForensOMICS approach as a new pathway for forensic taphonomy with great promise to advance future research. The solid foundation of the research combining metabolomics, proteomics, and lipidomics is considered very exciting, strong, and expands the boundaries of forensics research.

eLife assessment

The transcription factor DUX4 is emerging as a key molecule in early mammalian development and in diverse pathologies including muscular dystrophy and solid tumors. While DUX4 has been linked to immune evasion, the mechanisms have not been delineated. In this study, the authors demonstrate that DUX4 functions as a negative regulator of interferon signaling by inhibiting STAT1, thereby suppressing interferon-stimulated gene induction. These studies provide a critical mechanistic link between DUX4 expression and the modulation of immune signaling pathways.

eLife assessment

This manuscript contains fundamental work on hormonal and neurobiological processing of social experience in humans. It sheds compelling new light on potential mechanisms underlying how humans place social experiences in context, demonstrating how oxytocin and cortisol might interact to modulate higher-level processing and contextualizing of familiar vs. stranger encounters.

eLife assessment

In this important manuscript the authors use a powerful cross-specifies approach and cutting-edge experimental methods to examine possible shifts in the excitatory and inhibitory balance in both an animal model of Parkinsonism and in human patients with Parkinson's disease. Their solid findings support such a shift, wherein untreated Parkinson's disease is characterized by excessive activity in the subthalamic nucleus. While a strong paper, there are concerns with some of the methodological choices and their implications.

eLife assessment

In this important study, the authors examine transport and synaptic activity in the corticostriatal circuit in both microfluidic devices and in mice. They convincingly show that the Huntingtin protein regulates the anterograde transport of synaptic vesicle precursors in coordination with the molecular motor KIF1A. Activated Huntingtin recruits KIF1A, accelerates synaptic vesicle precursor's transport, modifies synaptic transmission and motor skill learning in mice. This work sheds new light on the role of axonal transport in synaptic function under physiological and pathological conditions related to Huntington's disease.

eLife assessment

This study presents an atlas of glial cell morphology in Drosophila, from distinct locations at different periods of life. The authors integrate morphological information with the transcriptomic signatures of those cells and find that morphological diversity among glial cells of a given class is not a strong predictor of transcriptional identity. The study is of great value as connecting morphology with scRNA sequencing analysis is rarely done and is a necessary step for understanding the underlying biology of these cells. While the weak morphotype-transcriptomic link in many cases may be due to low sequencing resolution, nonetheless, the data are of very high quality and the study will be a very useful resource for the glial biology field.

eLife assessment

This manuscript proposes that metformin protects against elevated intraocular pressure and oxidative injury by regulating cytoskeleton remodeling through the integrin/ROCK pathway, thus providing a new direction for further exploration toward the treatment of primary open-angle glaucoma as well as investigation of oxidative injury in multiple settings.

eLife assessment

This work is of high relevance to developmental and quantitative biologists with an interest in morphogen-mediated position decoding. A general mathematical model formulation is presented that is nevertheless accessible to a broad audience. Model tests via perturbation experiments in the Drosophila wing disc look promising and inspire a new round of data generation.

eLife assessment

Using a heterologous model system of budding yeast, authors find that nuclear translocation of beta-catenin is mediated by Kap104, the ortholog of Transportin (TNPO)1/2. A TNPO1 binding motif was identified in the C-terminal region of beta-catenin, which serves as a nuclear localization signal, and mutation of the motif inhibits beta-catenin mediated transcription. The manuscript serves as a staring point to study how much this motif contributes to nuclear localization of full-length beta-catenin in mammalian cells and to assess whether inhibiting TNPO1 interaction can reduce hyperactivation of beta-catenin signaling.

eLife assessment

This manuscript puts forward a new idea that topography in neural networks helps to remove noise from inputs. The authors show that there is a critical level of topography that is needed for network to denoise inputs. At present, the analysis is limited to inputs that are constant in time.

eLife assessment

This is an important paper reporting that an adenosine methyltransferase in the model plant Arabidopsis functions to target a key RNA component of the spliceosome, as in fission yeast, and thereby contributes to intron recognition. By contrast, the authors report no major role for the methyltransferase in targeting mRNAs, as reported in previous studies in Arabidopsis. While some of the evidence is convincing, other evidence is incomplete. The conclusions that mRNAs are not a significant target and that specific intronic sequences define sensitivity to the methyltransferase require additional support.

eLife assessment

This study delineates the transcriptomics of lung neuroendocrine cells and provides important new information on the nature of these cells in normal mouse lungs and in a sample of a human lung carcinoid. It will inform future studies investing the roles of PNECs in health and disease.

eLife assessment

Dhurhandar and colleagues developed a computational method that predicts discriminability of odor mixtures based on chemical structures of component molecules. The model first transforms chemical structures into natural language descriptions of odor, and then perform Lasso regressions to obtain a compact transformation into discriminability. The results suggest that the model performs better compared to that without transformation to language descriptions, yet, there are some issues that need to be addressed to make strong conclusions.

eLife assessment

This study applies AlphaFold to the CHESS selection of transcripts with the goal of generating predicted 3D protein structures and a quality measure of folding, the pLDDT score. From these data, the authors build a database for result exploration, documented by several examples, including proteins, where the authors propose the pLDDT score as a measure of presumed superior biological functionality over other isoforms. These results will be highly relevant for anyone working with proteins that occur in different isoforms.

eLife assessment

This important study reveals the role of polygenic scores for four commonly diagnosed cancers with high genetic predisposition (breast, prostate, colorectal, and lung) in East Asian populations, which is developed in participants of European descent. The data is convincing that is derived from a prospective cohort including 21,694 Singaporean participants of East Asian descent. The work will be of interest and provide great help to disease specialists in the field.

eLife assessment

In learning to walk, infants must balance the need to explore their movement repertoire with the need to establish regular movement patterns. Using a longitudinal approach, this paper suggests that while young infants generate high variability from a small number of regular patterns ('primitives'), older infants use a greater number of primitives with less variability. These interesting conclusions are not currently fully supported by the small and somewhat selective sample of data, and some alternative explanations need to be considered more thoroughly.

eLife assessment

This paper will be of interest to those studying retinal angiogenesis and endothelial cell biology. The authors performed rigorous data analysis and presented a logical, well-written report. The key conclusions of the manuscript are supported by the data and uncover a novel factor for retinal endothelial cell growth.

eLife assessment

This study takes a fresh view of the hypothesis that right inferior frontal gyrus is critical in inhibitory control in humans, as assessed by the widely-used stop signal task. It applies recent development in modeling and EEG measures in patients with focal brain damage, yielding causal insights. It will be of interest to neuroscientists and clinical researchers who study the brain basis of response control. Reviewers found this to be a strong, hypothesis-driven study that makes new progress on an important topic.

eLife assessment

This manuscript reports data consistent with a new and unanticipated phenomenon: that Cre or its mRNA may be transmitted between tissues in the mouse and that the male reproductive tract (epididymis) appears to be the most common target of such transported molecules. The data serve as a timely warning to mouse researchers about an unexpected complication of Cre-mediated gene manipulation.

eLife assessment

Type II topoisomerases are essential players in virtually every aspect of genome organization and function of all organisms. The in vitro data presented here clearly demonstrate that eukaryotic type II topoisomerases phase separate under physiological conditions, forming liquid-liquid condensates, and that the outcomes of type topoisomerase II activity on DNA are altered in these condensates. The experiments and methods are sound, clearly described, and fully support the insightful and carefully formulated interpretation of the data. This work has broad implications for dissecting and delineating the myriad fundamental roles of this centrally important molecule.

eLife assessment

This study reports an interesting analysis of evolutionary variation in forelimb/hand bone shapes in relation to functional and developmental variation along the proximo-distal axis. The authors found expected and compelling patterns of evolutionary shape variation along the proximo-distal axis but less expected, yet equally compelling, patterns of shape integration. This paper will be of interest to researchers working on macroevolutionary patterns and sources of morphological diversity.

eLife assessment

This study builds upon previous results of the authors to study the neural computations within the basal ganglia that support behavioral proactive inhibition. Here, the authors identify features of neural activity in the SNr that correlate with proactive inhibition, including changes in firing rate and neural variability, and how both of these variables are influenced by an animal's outcome history. The analyses are rigorous and provide important insights into the neural dynamics in the basal ganglia that support proactive inhibition.

eLife assessment

This paper by Einarsson and colleagues presents a comprehensive analysis on how human genetic variability impacts both gene expression and promoter. Using a new resource of CAGE data in lymphoblastoid cell lines from 108 individuals, they uncover a series of features that distinguish promoters with highly variable expression across individuals from those exhibiting low variability. The authors propose various explanations for the observed results. A few additional analyses and a more pragmatic interpretation of their data may help consolidate or refine the models proposed.

eLife assessment

Seipin is a multifunctional Endoplasmic Reticulum localised protein associated with seemingly unrelated human diseases. Here the authors establish a correlation between the expression of a particular mutant form of Seipin associated in humans with motor neuron disease and altered intracellular calcium dynamics and allied proteotoxic stress. The paper is noted for the clues it provides into how these cellular defects arise and for offering a plausible, but yet unproven hypothesis for the cellular pathology that may account for the human disease phenotype.

eLife assessment

Dingus et al. have developed an innovative approach for improving the intracellular stability of nanobodies. Working with a set of 75 nanobodies, the authors have identified key amino acid changes that can improve the stability of nanobodies expressed within the cell that might be generalized to other nanobodies.

eLife assessment

The replication protein A (RPA) plays a critical role in DNA replication, DNA repair, and recombination by interacting with various proteins. This paper describes the structure of an N-terminus OB-fold of the 70kD subunit of human replication protein A (RPA70N or DNA-binding domain-F) bound to peptides from five different proteins, HELB, ATRIP, BLM, RMI1, and WRN. This paper provides useful knowledge regarding the structural flexibility of RPA70N in the binding to the different interacting peptides. The structural and biochemical analyses of the interaction of RPA70N with the different peptides provide solid evidence for the presented conclusion. The work will be of interest to those studying DNA replication, recombination and repair.

eLife assessment

This study provides new experimental data and detailed modeling of the partitioning of low copy plasmids under the control of the ParABS system in bacteria. The dynamics of the partition complex is tracked over many generations, providing useful data to constrain the models. The authors propose a model which can manifest either regular positioning or oscillations depending on the model parameters. The research will be of interest to biologists and biophysicists interested in cellular dynamics and internal organization in bacteria.

eLife assessment

This high-quality study characterizes a key enzyme in asexual red blood stages of the malaria parasites that is used to salvage lipid precursors needed for membrane biogenesis and parasite growth in red blood cells. A previously identified glycerophosphodiesterase (PfGDPD), is shown to mediate the hydrolysis of host lyso-phosphatidycholine to generate choline, which in turn is required for parasite de novo phosphatidylcholine synthesis. Extensive analysis of the localization, growth phenotype and lipidomic profiles of PfGDPD deficient parasites indicate that this salvage pathway is essential for lipid homeostasis and asexual parasite development.

eLife assessment

Jneid et al find that an entomopathogenic strain of B. thuringiensis and its Cry1A toxins, which are widely used to combat lepidopteran pests, disrupt intestinal epithelial homeostasis in Drosophila-an insect that is generally considered non-suceptible. They demonstrate that the Cry1A toxins act by altering E-cadherin-based adhesion between intestinal stem cells and their new progeny. The findings carry potential implications for unintended, broad effects of B. thuringiensis in agricultural settings.