eLife assessment

This valuable study reports improvements in methods and tools for curating complex pathogen-host interactions. A compelling framework is described, using rigorous approaches and to considerable extent validated by the biocuration community. The developed ontologies and controlled vocabularies could be extended beyond host pathogens, e.g. ecological contexts with multi-species and multilevel interactions.

eLife assessment

This work presents a multimodal approach to ascertain links between risk and resilience to depression and Alzheimer's disease in a large pediatric sample. The authors find two latent imaging variables that may be associated with resilience to adverse life events and disease risk, which show some spatial overlap with disease relevant gene-expression patterns and neurotransmitter expression. Such findings could be important for understanding mechanisms underlying resilience in neurological disorders, however, the analyses are inadequate for fully supporting the interpretation of the variables involved in these models, or for supporting some of the overall conclusions of the work.

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 useful study uses untargeted metabolomics to help us understand how some herbivores are able to be generalists, rather than specializing in the metabolism of specific plant species. This is an important area, since little is known about how generalist insect species metabolize their food. In its current form, the study lacks ecological relevance due to the exclusive use of refined sampling procedures, and the metabolomic analysis is incomplete.

eLife assessment

This important study should be of interest to vision scientists and those seeking to model naturalistic image processing for humans in simulated or real navigational [walking] situations. The experiments aim to provide information about the statistics of "retinal" motion patterns generated by human participants physically walking a straight path in real terrains that differ in "smoothness". State-of-the-art eye, head, and body tracking allowed simultaneous assessment of eye movements, head movements, and gait, with convincing evidence for an asymmetrical gradient of flow speeds during walking, tied predominantly to vertical gaze angle, together with a radial motion direction distribution tied most critically on horizontal gaze angle. While not a major weakness per se, additional details on analytical methods used and estimations of variance across observers would strengthen these results and clarify the basis of the global claims made about visual motion information across the visual field in walking humans.

//Summary* - The central question of the Anthropocene: - why did behaviorally modern humans gain the unprecedented capacity to change an entire planet? - cannot be answered by genetic changes in human behavior. - To explain why human societies scaled up to become a global force capable of changing the Earth and why there are so many different forms of human societies and ecologies shaped by them, - explanations must be sought beyond the theories of - biology, - chemistry or - physics. - Here I introduce a new evolutionary theory, sociocultural niche construction, - aimed at explaining the origins of human capacity to transform the Earth . - As will be seen, this theory also explains why - behaviorally modern human societies came to - transform ecology in so many different ways over the past 50,000 years as they expanded across the Earth. //

eLife assessment

This valuable study provides solid results on the molecular signaling mechanisms of CaM kinase kinase-1 (CKK-1) in the context of the nociceptive behaviors of C. elegans. The authors report previously undescribed elements that control the nuclear/cytoplasmic shuttling of CKK-1, suggesting a complex interplay of multiple nuclear localization and export sequences. Therefore, the work will be of broad interest to scientists studying behavior, neuronal signaling, and signal transduction in general.

eLife assessment

This important study proposes a phenomenologically motivated theoretical framework to explain observed patterns of the temperature dependence of microbial diversity. The methodology is overall convincing, but the explanations of approximations and assumptions, and of their regime of validity, are incomplete. The manuscript should be of interest to microbial ecologists.

eLife assessment

In this study, the authors made important progress in understanding bone metabolic defects of T2D. They have established a valuable model that could mimic some aspects of T2D in mice. Particularly, the study provided important evidence showing bone turnover and metabolism were in defects, and changes in glycolysis would rescue bone defects in T2D. Overall, the authors provide compelling evidence from dynamic histomorphometry, C13 isotype labeling in vivo, scRNA-seq, and metabolic assays to demonstrate that the defective glucose metabolism causes osteopenia associated with T2D.

eLife assessment

The current study provides important, mechanistic insight into the potential contribution of antisense C4G2 expanded RNA to disease in C9orf72-associated ALS/FTD. The authors convincingly demonstrate that expression of this RNA species activates the PKR/eIF2α-dependent integrated stress response. They further provide evidence that this can contribute to disease phenotypes using multiple models and post-mortem patient samples.

eLife assessment

This important study reports a unique N-terminal motif of Staphylococcus aureus GpsB and the co-crystal structure of GpsB with the C-terminus of PBP4. It provides convincing evidence demonstrating the interactions of GpsB with PBP4 and FtsZ, shedding light on the role of GpsB in the pathogen's cell division. However, the functional characterization of GpsB's new motif caused and the structural characterization of GpsB and FtsZ's interaction is incomplete.

eLife assessment

This fundamental work shows the absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity. The evidence supporting the conclusions is compelling, with rigorous PET investigations and state-of-the-art cognitive assessments in a large sample. Given the high interest in the role of dopamine, the work will be of very broad interest to basic neuroscientists, clinical neuroscientists, and clinicians including neurologists and psychiatrists.

eLife assessment

This important manuscript describes a series of cellular phenotypes associated with the depletion of TANGO2, a poorly characterized gene product but relevant to neurological and muscular disorders. The authors present solid data indicating that TANGO2 associates with membrane-bound organelles, mainly mitochondria, impacting lipid metabolism and the accumulation of reactive-oxygen species. A few additional experiments would help to understand the link between the lipid changes reported and the cellular phenotype.

eLife assessment

The paper is of interest to neuroscientists, developmental biologists, and those interested in mechanisms that underlie intellectual disability. The study is well executed and brings new insight into the role of WDR62 and its role in causing microcephaly. The key claims of the manuscript require additional data.

eLife assessment<br /> <br /> This work provides a valuable allele-specific gene editing therapeutic approach to selectively target the human RHO-T17M mutation, one of the most frequent genetic causes of autosomal dominant retinitis pigmentosa. However, the current data are incomplete. Further validation of gene editing efficiency in rods at cellular level in vivo and use of Rho-T17M mice will strengthen the conclusion.

eLife assessment

The present manuscript addresses the controversial issue of the regeneration potential of cerebellar Purkinje cells in zebrafish and their integration into functional circuits. The authors use interesting genetic models to induce Purkinje cell-specific ablation to demonstrate regeneration of Purkinje cells can occur until adulthood and is accomplished by ptf1a+ progenitors. They further show that regenerated neurons reestablish electrophysiological properties and support appropriate behavior. These are important results that may help understand why mammalian neurons do not have similar properties and fail to regenerate. The conclusions on the source of regenerated neurons will however need additional experimental support.

eLife assessment

In this manuscript, Gonzalez et al investigated the dynamics of dopamine signals in the lateral shell of the nucleus accumbens (LNAc) in response to different types of carefully defined visual stimuli. Contrary to reigning theories of dopamine signaling, the authors presented convincing evidence that LNAcc dopamine transients tracked visual sensory transitions rather than any immediately apparent motivational variable. These important findings based on compelling evidence point to a potentially new role for dopamine signaling in the ventral striatum.

eLife assessment

Based on the Cryo-EM structure of human ETB in complex with the vasoconstricting peptide ET-1 and the inhibitory G-protein (Gi), this valuable study presents convincing data on how agonist binding is coupled to Gi-protein binding. The complex structure is solid and will appeal to the GPCR and pharmacology communities.

eLife assessment

Nearly all organisms require a ribonucleotide reductase (RNR) to convert ribonucleotides to their deoxyribonucleotide counterparts. In this important study, the reader learns how the model organism Escherichia coli can adapt to survive without any of its three RNRs. Compelling microbiology experiments to develop this model and analysis of compensatory mutations reveals patterns that are conserved in the few known pathogens that have also eliminated their dependence on an RNR. The manuscript will be of interest to microbiologists, biochemists, and those who work on the evolution of microbial metabolism.

eLife assessment

This work provides a promising first pass at providing an integrative model for how decisions arise from neural circuits. The approach is novel but lacks a more rigorous vetting against alternative model formulations to be able to determine its true significance. More stringent evaluations of the model in the context of existing work, as well as a clearer description of the goals and implementation of the approach, would help to address these concerns.

eLife assessment

The study represents an impressive effort to use atomistic simulations to probe cryptic binding sites in the envelope of six flaviviruses. Moreover, using constant pH simulations, the authors suggest that a cluster of ionizable residues contribute to the pH dependent conformational rearrangements required in the infection process. Therefore, the study provides new mechanistic insights that can be helpful in future efforts to develop drugs that target flaviviruses.

eLife assessment

This is an important study that investigates the impact of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia. Through a combination of pre-clinical in vivo measurements, clinical data, and computational modeling, the authors present solid evidence regarding the heterogeneous effects of TKIs in patients and how the response to treatment may be improved. With the assumptions about differences between normal and leukemic cells addressed, this study would be of interest to those working in the fields of mathematical oncology and cancer biology.

eLife assessment

The authors revisit fundamentals of synaptic transmission using a combination of advanced optical methods capable of visualizing calcium influx and neurotransmitter release at single release sites. By doing so, the authors present evidence for silencing of neurotransmitter release at single release sites as a function of external calcium. The data have relevance to a wide range of phenomena including neural plasticity and inhibitory modulation of synaptic communication.

eLife assessment

This important study presents a machine learning-based classifier that can accurately determine the geographic origin of a Salmonella enterica sample from its whole-genome sequencing data in under five minutes leading to actionable public health insights. Applying the method to 2,313 whole genome sequences collected in the United Kingdom and several external validation datasets, the authors provide convincing evidence that Salmonella genomic data can be used to identify the likely geographic source of a food-borne outbreak and, in most cases, correctly identify the country of origin of an infection acquired overseas. The work presents an excellent case for the potential utility of routine genomics coupled with machine learning for public health microbiology and the methods are likely to be applicable to other pathogens besides Salmonella enterica.

eLife assessment

The findings in this study are important as they establish a rat model of a classic form of early-onset osteoporosis and demonstrate that osteoporosis medications are effective in the model. The evidence supporting the authors' claims is compelling.

eLife assessment

This important landmark paper identifies three distinct stellate ganglion nerve cell subtypes stratifiable in terms of their neuropeptide Y expression correlating these with gene expression and electrophysiological properties. Their innovative use of viral tracing techniques compellingly established their conclusions. This major contribution to cardiac sympathetic excitation is relevant to a wide scientific and clinical audience.

eLife assessment

This important work demonstrates a significant asymmetry between the connectivity statistics of the left and right hemispheres of the Drosophila larva brain. The evidence supporting the conclusions is compelling and represents a first step toward the development of statistical tests for comparing pairs of connectomes more generally. This work will therefore be of interest to the broad neuroscience community.

eLife assessment

This paper will be of interest to scientists involved in understanding the function of long non-coding RNAs. The authors found two genes previously reported as lincRNAs in early studies encode micropeptides in zebrafish. Zebrafish mutants lacking these micro-peptides show altered gene regulatory networks that preferentially affect oligodendrocytes and cerebellar cells in the embryonic brain. The data presented in the study are solid and present convincing additional evidence for the versatile functions of micro-peptides.

eLife assessment

This study is an important contribution to the understanding of Buruli ulcer transmission in Australia. The authors provide compelling evidence that the carriage of Mycobacterium ulcerans by possums, within their small home range, can predict cases of Buruli ulcer disease in individuals who visit those areas. While not directly relevant to the transmission of Buruli ulcer in West and Central Africa, the work will be of great interest to those studying the transmission of opportunistic environmental pathogens.

eLife assessment

This study employs live imaging to investigate the movement of mesodermal cells in early mouse embryos. By examining the dynamics of cell behavior in normal and mutant embryos, the authors propose that apical constriction of cells results from pulsed contraction guided by crumbs2 signals. The paper presents beautiful images and adds to the molecular understanding of cell migration during early development.

eLife assessment

In this Tools and Resources article, Sapiro et al. overcome the technical burden of low Borrelia burgdorferi numbers during infection by physically enriching for spirochetes prior to RNA-sequencing/mass spectrometry. This work is important as it provides technical advances for the study of global transcriptomic changes of B. burgdorferi during tick feeding and builds on the knowledge already collected by the field. The evidence presented is compelling, and the strategy described here could benefit researchers in the field and possibly support broader applications.

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. While the main method used is state of the art and the supporting data are solid, the vigor of the biochemical assays and function validation is inadequate. This work will be of interest to developmental and reproductive biologists working on fertilization.

eLife assessment

This study provides valuable insights into the role of two under-researched sperm-specific proteins (Cylicin 1 and Cylicin 2). The authors provide convincing evidence that they have an essential role in sperm head structure during spermatogenesis, and that their loss leads to subfertility or infertility, with a dose-dependent phenotype. The authors identify infertile males with mutations in both Cylicin1 and Cylicin2: thus the findings from the mouse models might be applicable to understanding human male infertility with similar structural defects.

eLife assessment

Gordon-Fennell et al. present a low-cost, open-source platform for measuring action elicitation and consummatory behavior in head-fixed animals. The findings are important because they allow animals to perform a truly voluntary action whilst their head is held still, and the evidence supporting them is both comprehensive and compelling (in some cases even exceptional). The results have the potential to have a broad impact in the field as many labs start to move towards measuring head-fixed behavior effectively, although this is said with the caveat that such behavior will never be an ideal replication of naturalistic behavior.

eLife assessment

This manuscript describes an approach to creating fat tissue in culture for food applications. Specifically, the efforts of growing cultivated meat focus mostly on growing skeletal muscle. However, the taste component of such artificial meat would be determined by fat content. There is a significant desire and motivation to cultivate fat tissues in vitro for the purpose of the replacement of animal products. This paper provides new technological approaches to expand adipocytes and aggregate them into structures that resemble fat.

eLife assessment

This important manuscript employs a rigorous and multi-pronged comparative genomics approach to unravel how lifestyle modulates the acquisition and domestication of viral genetic elements in the genomes of hymenopteran insects. Using an extensive dataset of over 120 hymenopteran genomes, the authors provide convincing evidence that endoparasitism (where parasite development occurs within hosts) facilitates the uptake and domestication of double-stranded DNA viral elements.

eLife assessment

This valuable paper examines the effect of deiodinase polymorphism on thyroid hormone signaling in the brain by employing a transgenic animal model and then switching to studying T3 axonal transport using microfluid devices. Although methodologically extensive this paper has several claims that are not convincingly supported by the current experiments and furthermore some disjoint is observed between the two halves of the study. The therapeutic implications of understanding T3 signaling in the brain makes it a potentially important manuscript.

eLife assessment

The authors use analytic calculations and numerical simulations to convincingly show that the purported benefits of nonlinear decay in morphogen gradients may be marginal in some cases and completely reversed in others (far from the concentration source). This is a valuable contribution to the field, as it questions common assumptions about the biological function of non-linear morphogen decays during development.

eLife assessment

This important study presents valuable findings on the dissemination of plasmids. In an analysis of five major Enterobacterales genera, the authors convincingly demonstrate that similar plasmids are shared between genera, species, and clones, both within and between ecological niches. Given the size of the dataset and the very detailed level of analysis this study importantly contributes to insights into to the flow of plasmids, including those carrying antimicrobial resistance genes, across niches.

eLife assessment

The authors characterize an H3N2 influenza A virus that jumped from birds into dogs in 2006. Through its evolutionary adaptation to dogs, the virus is now gaining properties that are increasingly consistent with the potential to infect humans. Using experiments with canine H3N2 influenza isolates, the authors found that more recent viruses have acquired receptor specificity for both avian- and human-like receptors, enhanced low-pH stability and in vitro growth, as well as improved replication and transmission in the dog and ferret models.

eLife assessment

This valuable study reveals that patient-derived organoids recapitulate similar genomic signatures as that of the parental tissue, which could be a useful model to evaluate chromosome instability, drug sensitivity, and intratumoral heterogeneity. However, whereas some of the sequencing data are compelling, the theoretical analysis is incomplete and would benefit from a more rigorous definition. With the theoretical part strengthened, the work will be of interest to medical biologists working on ovarian carcinoma.

eLife assessment

Only few species of Leishmania, an important human pathogen, have an RNAi machinery, alternative methods are needed for genetic screens. The authors resent and validate a valuable method, based on the introduction of premature stop codons, that can be used for several different species. The results are very convincing, the data are solid, and the approach will be of interest to researchers studying any eukaryote that lacks the RNAi machinery.

eLife assessment

This convincing work reviews and synthesizes evidence of the impact of the COVID-19 pandemic on a variety of cancer outcomes. The results have potentially useful implications for various fields of cancer research as they review evidence spanning from cancer prevention efforts to changes in diagnoses and cancer treatment modalities.

eLife Assessment:

Mutations in a variety of intermediate filament proteins and their regulators lead to abnormal development, reduced lifetime, and increased stress sensitivity. This manuscript rigorously demonstrates that such defects result from inappropriate assembly of intermediate filament networks, as mutations in a central intermediate filament protein prevent assembly of both the normal network and these inappropriate assemblages and largely rescue most of the defects. This has important implications for our understanding of the assembly of intermediate filament structures and for understanding and potentially treating diseases resulting from mutations in intermediate filament protein genes.

eLife assessment

This important study significantly advances our understanding of the calcium signaling pathway mediated by the kinase CDPK1, in the protozoan parasite Toxoplasma gondii. The evidence supporting the authors' conclusions is in many parts convincing, with rigorous biochemical and microscopy analysis. The work will be of broad interest to researchers in the field of signal transduction and protozoan biology.

eLife assessment

This is an important study that asks why odors smell similar even though their chemical structures appear quite different. The authors use machine-learning to make a compelling case to map the odor-relatedness of compounds to their place in metabolic pathways and propose that this is a general feature of odor perception across the animal kingdom. The conclusions could be strengthened by considering published physiological data.

eLife assessment

Antibodies perform a critical function in host defense against viruses and have emerged as major therapeutic tools in modern medicine, as evidenced by the large scale use antibody-based therapies during the COVID-19 pandemic. This paper describes the characterization of human antibodies to hantaviruses that have the potential to create devastating epidemics. The results teach us about the viral structures that are targets for neutralization and the results are relevant for vaccine development and antibody therapeutic design.

eLife assessment

This study uses behavioral monitoring and cutting-edge calcium imaging approaches to track the activity of cholinergic and noradrenergic axons in cortex of head-fixed mice, and correlate activity with behavioral state. While the evidence that behaviorally related signals are broadly broadcasted to the dorsal cortex is clear from the data, the conclusion that there is also heterogeneity across axons and areas is of less certain significance and might be undermined by methodological artifacts.

eLife assessment

In this work Frantz et al. assess transcriptomic states of melanocyte stem cells that are recruited to differentiate during the process of melanocyte regeneration in zebrafish and they analyze roles for Kit signaling in this process. The analyses are nicely done, and the paper requires only relatively minor modifications and clarifications. The study will provide new insights into melanocyte stem cell biology that should be of interest to those studying pigmentation, regeneration, and melanoma biology using zebrafish and other systems.

eLife assessment

This important study employs auxin-induced degradation to show that the TATA-binding protein (TBP) is not required for ongoing RNA polymerase II transcription nor heat-shock or retinoic acid-induced transcription, but that TBP is essential for RNA polymerase III transcription, with TBP-independent TFIID complexes being assembled and present at the transcription start sites of polymerase II-transcribed promoters. The evidence for the major claims is currently incomplete.

eLife assessment

The authors have developed a useful and user-friendly software to analyse gene expression data from four datasets representing premalignant lung lesions. This software would be of interest to those working in lung cancer and specifically the pre-malignant space. The major strength is the ease of use while the major limitation is the inability for the user to integrate other datasets.

eLife assessment

Determination of the biomechanical forces and downstream pathways that direct heart valve morphogenesis is an important area of research. In the current study, potential functions of localized Yap signaling in cardiac valve morphogenesis were examined. However, the evidence for Yap pathway activation and localization relative to areas of the valve subject to different mechanical stresses is not convincing.

eLife assessment

This is a well-explained and potentially useful study that describes the generation and use of pYtags, recombinant proteins that, if properly used, should allow spatiotemporal monitoring of the activation of different receptor tyrosine kinases in living cells. Although this study has generated new tools to evaluate receptor localization and activation in different cells, the broad concept showing that different receptor dimers generate specific stimuli, and downstream signaling pathways, is quite limited in terms of novelty. Although it is felt that the study is technologically innovative, the analysis of receptor spatial signaling is incomplete and should be improved.

eLife assessment

This fundamental study substantially advances our understanding of the process of ribosome maturation. The authors have purified and determined the structures of several nucleolar ribosome assembly intermediates in yeast using cryo-electron microscopy (cryo-EM). The study combines genetic, biochemical, and structural analysis to provide compelling support for the conclusions the authors wish to draw. The work will be of broad interest to cell biologists, biochemists, and structural biologists.

eLife assessment

This is an intriguing study investigating the molecular mechanisms of neural circuit developmental organization. Using a defined hippocampal circuit, the authors find that ectopic expression of an adhesion G protein-receptor leads to axon mistargeting. This work defines new mechanisms of axon target specificity.

eLife assessment

Russel et al. study and reveal compelling evidence for potential sequence-based factors that may drive VDJ trimming, a mechanism involved in VDJ recombination that shapes adaptive immune repertoire generation. The work is based on a rigorous statistical comparison of logistic regression models to reveal the role and function of cutting enzymes in shaping T- and B-cell receptor diversity. It could provide fundamental new insights into these processes with some claims being currently incomplete.

eLife assessment

This study investigates the spatiotemporal characteristics of human brain activities during object recognition under noisy and ambiguous conditions. By using state-of-the-art data analysis and model-driven fusion of MEG and 7T, this work demonstrates distinct representational profiles in ventral and dorsal pathways, contributing new perspectives to our understanding of the neural implementation of object recognition under uncertainty.

eLife assessment

Siglec-1 (CD169), a plasma membrane-associated sialic acid-binding lectin, has been implicated in the capture of HIV and other viruses by dendritic cells and macrophages. However, the molecular details of how HIV particles are captured by Siglec-1 are poorly understood. In this paper, the authors use advanced imaging methods to analyse the cell surface distribution of Siglec-1 on immature and mature dendritic cells to study the regulation of Siglec-1 distribution by actin and regulators of actin polymerization and to understand how virus-Siglec-1 engagement leads to virus sequestration within so-called virus containing compartments. These types of analyses have only recently become feasible with the implementation of super-resolution imaging and as yet few virus-host cell systems have been examined in detail. Thus, this study has relevance for researchers studying the engagement of HIV and many other viruses with cells, as well as researchers interested in the mechanisms regulating receptor distribution and function on cells.

eLife assessment

Poison frogs sequester alkaloids to make themselves toxic or unpalatable to predators, but how this sequestration occurs is not well understood. This valuable study identifies an alkaloid-binding protein in the plasma of poison frogs, which may help explain how these animals are able to sequester a diversity of alkaloids with different target sites. The supporting evidence is solid and the study adds to our understanding of how toxic animals resist the effects of their own defenses.

eLife assessment

Elbaz-Hayoun et al. investigate the role of macrophages in the gliotic response of retinal Müller glia and photoreceptor cell death. The authors find that macrophages play a role in inducing retinal damage. A role for the muller glia expressed, C-C chemokine receptor axis was identified as a causative factor in promoting retinal degeneration. These important data identify a new link between cells of the immune system and those within the retina which contribute to the progression of retinal degeneration.

eLife assessment:

In this important work, the authors describe a recombinant CRISPR/Cas9 construct, CRISPR-nuPin, that has the reported capacity to rapidly tether DNA to the inner nuclear membrane of cells. They then evaluate the effect of this construct on Herpes Simplex virus type 1 infection, identifying different phases of viral replication susceptible to inner nuclear membrane tethering. This work provides convincing evidence for the effects of intranuclear DNA localization on viral gene expression and replication, using a method applicable to nonviral genes as well.

eLife assessment:

In this fundamental manuscript, the authors provide compelling evidence that a housekeeping ATPase is required for heme utilization in the important pathogen Staphylococcus aureus through its interaction with the canonical heme transporter in this organism. The authors convincingly show that this complex associates with functional membrane microdomains and thus establishes a new paradigm for regional localization of the heme transport system in the staphylococci. The work will be of interest to microbiologists, particularly those studying transport for macromolecules.

eLife assessment

This paper is of potential interest to scientists within the field of drug-induced liver injury. The concept of the study is interesting by generating mitochondrial genotype-specific liver cell lines to evaluate idiosyncratic hepatotoxicity. While the proof-of-concept is clearly presented, the current data do not yet allow to draw broad conclusions about the significance of the study in terms of drug effects.

eLife assessment

The precise cellular and molecular mechanisms and signaling mediators underpinning the development of cardiomyopathy and heart failure in diabetes still remains unclear. In-depth investigations of the cardiac heterogeneity and cell-to-cell interactions could be of use to reveal the pathogenesis of diabetic myocardial fibrosis and thereby identify potential targets for the treatment of cardiac myopathy and heart failure. Utilizing a mouse model as well as in-vitro studies, this manuscript demonstrates cardiac cell mapping that provides novel insights into novel drivers of intercellular communication contributing to pathological extracellular matrix remodeling during diabetic myocardial fibrosis. The work provides compelling and convincing evidence to improve the understanding the cellular and molecular mechanisms of diabetes-induced cardiac pathology.

eLife assessment

Leptin is a fat-derived hormone that curbs appetite, and mutation of leptin causes obesity and diabetes. This manuscript investigates leptin-responsive neural circuits, revealing a key inhibitory connection from leptin-sensitive neurons in the arcuate nucleus of the hypothalamus (AGRP neurons) to neurons in the dorsomedial hypothalamus. Toggling this inhibitory connection impacted leptin effects on feeding and metabolism. The study contains valuable data, including several interesting molecular genetic systems and the demonstration of GABA signaling in the DMH for the control of food intake, however, there is inadequate information about experimental design, including a lack of quantification and controls, and unjustified assumptions.

eLife assessment

This fundamental study by Rose and colleagues addresses key challenges in demographic inference in non-model systems with an innovative approach to model parameter calibration based on known historical events. Using this approach, they convincingly show that human specialization in Ae. aegypti mosquitoes likely evolved due to a past climate event around 5,000 years ago, and that recent rapid urbanization has continued to fuel its spread in West Africa in the past 20-40 years. This work will be of broad interest to population geneticists working on demographic inference, and to mosquito biologists working on the monitoring and control of this important vector species.

eLife assessment

This manuscript presents a series of important findings about the roles of the BAR-domain containing protein SNX32 in endosomal cargo sorting and in neurite outgrowth. The authors provide convincing evidence for their claims, which will be of interest for those working not only in membrane trafficking but also for cell biologists in general with interest in neurobiology.

eLife assessment

The fundamental work represents an important contribution to our understanding of the diversity of photosynthetic mechanisms across the branches of phototrophic life, with the first high-resolution structure (2.9 Å) of a photosynthetic complex from a primitive green alga. This is a valuable resource for understanding function and evolution of light-harvesting antennas. The evidence is convincing in suggesting that the mechanism found here is distinct from the classical antenna state transitions seen in other organisms studied thus far.

eLife assessment

Sanz Perl and colleagues provide important insights regarding the application of computational brain models from neurodegenerative diseases to evaluate brain stimulation protocols in silico. Solid evidence is provided for the disease-specificity of the framework, however, the real-world impact of such stimulation protocols to alleviate psychiatric and neurological symptoms remains to be evaluated.

eLife assessment

This study uses single cell sequencing to characterize transcriptional profiles of cells in a brain region called the PVT that plays many roles in brain function. The authors combine these data with dataset of neuronal connectivity and conclude there are transcriptomically distinguishable populations of neurons in the PVT with different function. These data deepen our understanding of an important brain region.

eLife assessment

This important study of mouse genetic variation in atrial septum formation, a trait correlated with the patent foramen ovale (PFO) cardiac defect, provides convincing evidence for 37 quantitative trait loci (QTL) affecting this trait, combining genetic mapping with transcriptome analysis to zero in on relevant pathways and candidate genes within the QTL, and validating the role of one gene in tissue culture. The paper provides an important resource for hypothesis generation and future studies, which could lead to novel diagnostic or therapeutic approaches that target atrial septal defects in common congenital heart disease.

eLife assessment

In this study, neurons were recorded and combined across the parahippocampal area while rats performed a memory-guided spatial navigation task. Sophisticated analytical tools were used to provide convincing evidence that neuronal populations in these areas show behavior-related changes that might indicate the encoding of errors by the system. The valuable results suggest that rate remapping is a likely mechanism to support changes in representations that support memory-guided behavior in these regions, most interestingly in neurons that code head direction.

eLife assessment

This important paper advances our understanding of the role of lipid peroxidation in loss of muscle mass and force-generating capacity during aging and hind-limb suspension. The evidence is in general solid, drawing from experiments in vivo and cell culture using multiple types of manipulations of the formation of lipid peroxides although some weaknesses were identified. The results should be of interest to those who study the molecular basis for sarcopenia and disuse atrophy of skeletal muscle.

eLife assessment

In this manuscript, the authors investigate the role of histone deacetylases in the spatial epigenetic control of zygotic gene expression in early gastrulation. They discover HDAC1 binding is maternally-controlled and that inhibition of histone acetylation blocks gastrulation and disrupts cell lineage integrity, tied to both positive and negative regulatory effects on gene transcription in space and time. The study contributes to a growing body of evidence that highlights a central role of histone acetylation-deacetylation dynamics in epigenetic regulation of gene expression and cell fating in early tissue patterning of the embryo.

eLife assessment:

This study provides valuable insight into the molecular mechanism of ion selectivity in the broader family of ATP-gated P2X receptors. The experimental data are of high quality, the evidence supporting the conclusions is convincing, and the work will be of broad interest to biophysicists working on ion channel selectivity.

eLife assessment

This important study aimed to identify rhythms linked to primary symptoms of Parkinson's disease such as involuntary shaking of the limbs and slowness. The evidence supporting the conclusions is solid, although validating their behavioural measures and considering the relationship between signatures from different brain regions would have strengthened the study. The work will be of broad interest to movement control, movement disorders, and brain stimulation fields.

eLife assessment

When a neuron is born it correlates with where it targets in the neuropil and this has been best demonstrated in the olfactory lobe of Drosophila. This important study uses sophisticated genetics and advanced live imaging to provide a compelling description of how neuronal dendrites explore the targeting field, eliminate excessive branches, and assort into the correct region during development. In the process, it develops valuable tools. It brings us closer to a comprehensive understanding of how the birth order of a neuron translates to dendrite patterning within the Drosophila antennal lobe circuit

eLife assessment

Black et al., provide evidence that levels of Paternally Expressed Gene 10 (PEG10) protein are regulated by Ubqln2 and that proteolytic fragments from PEG10 cleavage induce changes in gene expression, in particular genes that encode proteins involved in axon biology. Based on these data and the finding of an increase in PEG10 levels and alterations of proteins regulated by PEG10 in the spinal cord of ALS patients, they propose that abnormal induction of PEG10-regulated genes is involved in ALS. However, the evidence for these claims and PEG10 involvement could be strengthened, and the rigor of the work could be enhanced in places.

eLife assessment

This important study provides a provocative potential challenge to explain sensitivity across the visual field by using cortical magnification factors. The evidence supporting this theoretical challenge is solid in general, although the inclusion of subject-specific measurements of cortical magnification factors would have strengthened the study. The work will be of interest to vision researchers of both basic and medical science.

eLife assessment

This valuable study by Pasquereau and Turner examined the activity neurons in the subthalamic nucleus (STN) while monkeys performed a task in which they had to withhold their response during a delay period whose length was defined by a specific cue. The results indicate that the activity of STN neurons was modulated by reward size and delay. The results are potentially important for understanding how STN regulates behavior such as self-control, but the reviewers thought that the study is incomplete as the analyses, at least in the presented forms, have some potential problems and some analyses require clarification.

eLife assessment

This manuscript reports important findings regarding the evolution of snake venom proteins. The conclusions are convincing and are based on appropriate and validated methodology in line with the current state-of-the-art. The findings will be of interest to biologists and biochemists interested in the evolution of venoms as well as those generally interested in the evolution of molecular novelties.

eLife assessment

In this potentially important study, Mahbub and colleagues examine how the small GTPase ARL15 regulates ion transport. Using a complementary array of techniques, the authors gathered solid evidence for the binding of ARL15 to CNNM proteins, resulting in a proposal how this may affect the function of the TRPM7 channel. Additional experiments are required to fully substantiate the claims.

this paragraph shows and explains the key diffrences and requirements of teachers and professors as college students we are adults and have to be treated as such.

eLife assessment

These authors provide compelling evidence that gestational intermittent hypoxia, a component of sleep apnea during pregnancy, increases inflammation in the spinal cords of male mice. Increased inflammation is robustly linked to deficits in respiratory plasticity both biochemically and via functional depletion assays. These data are important given the fact that male infants have worse outcomes in the NICU and are at higher risk of sudden infant death syndrome.

eLife assessment

Brodbeck et al. offer a timely and important contribution to how neural signals in response to continuous temporal modulations (as seen in speech and language processing) can be modelled effectively using temporal response functions. They offer a convincing new approach that includes a novel application of a boosting algorithm in addition to an accessible and didactically useful toolbox for analysis. With further comparison to existing toolboxes, or a more extensive comparison of boosting and ridge regression via simulation, this work will have a compelling impact on methods in speech and language neuroscience, as well as in cognitive neuroscience more broadly.

eLife assessment:

This important study advances our understanding of host-derived lipid droplets' interaction with intracellular pathogens. The use of amoeba species Dictyostelium discoideum as a host for Legionella pneumophila infection is compelling and goes beyond the current state of the art, but the strength of evidence is incomplete, and the main claims are only partially supported by the data. With the experimental part strengthened, this paper would be of interest to cell biologists and microbiologists working on the interaction of microbes with host cells.

eLife assessment

This useful work describes the establishment and characterization of new cell lines derived from specific tissues of the fruit fly Drosophila. The evidence supporting the claims of the authors is solid, although the characterization of the cell lines is incomplete and the genomic findings are not presented in a user-friendly manner. These lines could be a useful resource that complements in vivo Drosophila genetics, improving biochemistry and facilitating high-throughput screening.

eLife assessment

This important study examines the association between SARS-CoV-2 infection and close contact among household members, measured using proximity sensors deployed after the first case was identified in the household. The authors provide solid evidence that transmission of SARS-CoV-2 within households is not dependent upon close contact, but the study suffers from a number of limitations that are fully acknowledged.

eLife assessment

Regulation of gene expression in many biological systems occurs either through a binary mode where gene expression is either on or off (digital regulation), or through an analog mode leading to a graded modulation of gene expression. In this manuscript, the authors report how these two regulatory modes are integrated into a one-way switch pattern to control the expression of the Arabidopsis floral repressor gene FLOWERING LOCUS C (FLC). They suggest that an analog regulation in the autonomous pathway precedes a digital regulation conferred by Polycomb silencing before cold exposure, and this temporal switch correlates with the strength of transcription at the FLC locus in different genetic backgrounds.

eLife assessment

This study combines different approaches to unravel the genetic basis of a pigmentation polymorphism in natural populations of a fascinating study system with well-studied ecology. The paper has the potential to be of general interest to biologists curious about the genetic basis of adaptive variation, which is especially relevant to evolutionary biologists and ecologists. The study reports substantial data and makes a strong case for the contribution of a duplication-derived gene acquiring a morph-specific function. Further information is required to implicate valkea in pigmentation morph formation and for diagnosing the duplicated segment as a supergene (associated with low recombination).

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, though some questions remain about the ease with which it can be put into general use.

eLife assessment

This study presents valuable findings from a study of identical twin pairs discordant and concordant for smoking to assess whether smoking has a direct effect on DNA methylation. The results are a valuable contribution as the study confirms the reported association between smoking and epigenetic profile is indeed due to the direct effects of constituents of tobacco smoke. The study design and methods applied by the authors are solid and provide a starting point for larger studies with rigorous laboratory approaches, as well as for assessing clinical impact. The work will be of broad interest to addiction researchers, genetic epidemiologists, and environmental scientists.

eLife assessment

This is an interesting and potentially significant study that adds important new information to our understanding of the mechanisms of lung epithelial repair after tissue injury. The authors have delineated a novel and non redundant role for the hippo pathway and the down stream regulators Yap/Taz in regulating repair of lung injury. These studies will inform future investigations into the mechanisms of repair of lung injury

eLife assessment

This study presents important results on the predicted impact of cancer screening disruptions in Australia during the COVID-19 pandemic based on consultation with public health stakeholders. The evidence presented is solid, as simulations were based on several previously validated breast, cervical, and bowel cancer screening decision models, though the scenarios were based on hypothetical disruptions that do not always match experienced disruptions. The work will be of interest to local policy-makers, public health specialists, and cancer epidemiologists.

eLife assessment

This work shows that higher socioeconomic status is associated with a higher risk of obesity, which should inform China's obesity public health programs and policies, and also be of interest to other countries and communities. The evidence supporting the conclusions is strong, but the data analysis is incomplete and would benefit from more rigorous approaches.

eLife assessment

This is important work that addresses a long-standing (but rarely acknowledged) question: given that multi-peaked tuning curves optimize Fisher information, why do early sensory areas typically have single-peaked tuning curves? This paper shows clearly, and convincingly, that multi-peaked tuning curves are likely to produce catastrophic errors at short times, so if speed is important, multi-peaked tuning curves should be avoided. This work should encourage neuroscientists to take into account the importance of stimulus encoding time in their formulations of models of neural coding.

eLife assessment

Endothelial cells mediate the growth of the vascular system, but they also need to prevent vascular leakage, which involves interactions with neighboring endothelial cells through junctional protein complexes. This important study provides a full mechanistic insight into how Sun1 is achieving its function, which supports the concept that nuclear anchoring is critical for proper mechanosensing and junctional organization. Although the evidence supporting the claims of the authors is solid and there are several merits and strengths in this study, a weakness is that some important controls are missing. The work will be of broad interest to cell biologists and vascular biologists.

eLife assessment

This manuscript presents a useful meta-analysis of genes with parent-specific expression from mouse published RNA-seq datasets, focusing on genes with weak allelic bias. A combination of systematic bioinformatic analysis and experimental validation convincingly shows that the number of parentally biased genes has been overestimated and the few novel ones lie at the periphery of known imprinted loci. The work will be of interest to genomicists with an interest in imprinting and its mechanisms.

eLife assessment

This study will be of interest to scientists within the field of hematopoiesis and ribosome biology. The paper provides evidence that haploinsufficiency of the mouse ribosomal protein gene Rps12 results in a number of phenotypes including defects in the production of specific blood cells and loss of hematopoietic stem cell quiescence. This work adds to the growing body of evidence that specific cell populations are particularly sensitive to disruption of mRNA translation machinery.

eLife assessment

This important paper advances our ability to understand feeding behavior in fruit flies, and begins to address the challenging question of motivation. With innovative methods based on the detailed monitoring of interactions between foods of different qualities at different hunger states, they present compelling evidence for non-homeostatic feeding not driven by metabolic need.

eLife assessment

This manuscript describes an approach for efficiently integrating diverse libraries into the C. elegans genome. The method is a valuable contribution for researchers carrying out experiments that would benefit from easy generation of such libraries, and the data for the effectiveness of the method is solid. The relative advantages of this approach in terms of ease and effectiveness relative to others with similar aims will emerge as they are put to more general use in addressing biological problems.

eLife assessment

The study has some significance for the field of dementia research and neurodegenerative diseases more broadly. Using the brain-age paradigm, the main findings are that having an older-appearing brain is associated with more advanced stages of amyloid and tau pathology, higher white matter hyperintensities, higher plasma NfL and carrying the APOE 34 allele. Findings were broadly similar in cognitively normal people and people with mild cognitive impairment and the evidence for these findings is convincing. Although sex differences are emphasized, the evidence for this is generally incomplete.

eLife assessment

This study presents important new findings regarding prenatal thalamocortical development. The authors present convincing evidence to overcome substantial methodological challenges in charting prenatal brain development in vivo. This work will be of interest to pediatric and developmental neuroscientists and neuroradiologists.

eLife assessment

The authors present valuable findings regarding the mechanism of high mannose induced cellular toxicity in cancer cells. The evidence supporting genomic instability as the anti-cancer activity of mannose is convincing with multiple orthogonal approaches showing consistent results, but the conclusions related to metabolic remodeling could be further strengthened by additional metabolomics data. While the findings are limited to genetically modified cancer cell lines cultured in vitro, this work will be of interest to cell biologists working on cancer metabolism.

eLife assessment

This potentially important study examines brain age based on resting state functional connectivity (RSFC) following an 18-month lifestyle intervention. The design of the intervention study is generally solid; the randomized controlled trial includes three intervention groups and assessments at two-time points of numerous health markers, however, the methodology for brain age prediction appears somewhat incomplete and would benefit from more rigorous approaches. The lack of control groups also prevents firm conclusions about the extent to which the observed RSFC changes are linked to the intervention. With these parts strengthened, the paper would be of broad interest to neuroscientists and biologists working on obesity, lifestyle interventions, and brain health.

eLife assessment

This paper reports a valuable new method for creating localized damage to candidate brain regions for functional and behavioral studies. The authors present solid support for their ability to create long-term local lesions with mm spatial resolution, although data supporting the extension to primates was incomplete. If the authors can demonstrate that the technique is applicable beyond the specific technical setup they employ, the paper is likely to be of broad interest to brain researchers working to establish causal links between neural circuits and behavior.

eLife assessment

This useful work proposes a framework inspired by chemotaxis for understanding how the brain might implement behaviours related to navigating towards a goal. The evidence supporting the conceptual claim is convincing, but some technical aspects are incomplete. The manuscript proposes a hypothesis that would be of interest to the broad systems neuroscience community, but the reviewers noted the relationship to existing similar hypotheses was not made sufficiently clear.

eLife assessment:

This important paper reports recent improvements and extensions to stdpopsim, a community-driven resource that is built on top of powerful software for performing simulations of population genomic data and provides a catalog of species with curated genomic parameters and demographic models. In addition to describing the new features and species in stdpopsim, the authors provide a set of simple guidelines for implementing realistic simulations. Overall, this convincing manuscript serves as an excellent overview of the utility, challenges, common pitfalls, and best practices of population genomic simulations. It will be of broad interest to population, evolutionary, and ecological geneticists studying humans, model organisms, or non-model organisms.

eLife assessment

This paper presents valuable information on the role of type I PRMTs in programming muscle stem cell identification. The evidence presented is mostly solid, with some weaknesses in the evidence regarding the proposed mechanism. The paper will be of particular interest to those who study skeletal muscle satellite cell biology.

eLife assessment

The authors have used an extensive database to study associations between biphosphanate use and COVID-19. Using careful statistical analyses biphosphonate use appeared strongly associated with a lower risk of COVID-19. If these findings are confirmed in well-designed prospective studies biphosphanate use could be an attractive drug to prevent COVID-19.

eLife assessment

This paper provides a valuable systematic analysis of proteomic profiles associated with a particular murine Ryanodine receptor abnormality. Its analysis technique provides a solid and systematic set of data summarising the differences in different muscle types. The work emerges with insights into pathological mechanism of congenital muscle diseases linked to mutations in a range of other genes related to excitation contraction coupling in workers within the skeletal muscle field.

eLife assessment

This is a rigorous and compelling extension of previous normative modeling work that demonstrates that normative models incorporating lifespan trajectories of structural and functional connectivity provide a strong basis for brain imaging studies across a range of tasks including, univariate group difference assessment, classification, and building regression models. The work is important, rigorous and a valuable contribution to the field.

eLife assessment

This study presents a useful identification of an herbal drug combination for the treatment of plasma cell mastitis (PCM), a breast inflammation with severe and intense clinical symptoms. The data were collected and analyzed using a solid and in clinical trial of 160 patients (NCT05530226) and can be used as a starting point for understanding how herbal drug combinations could be helpful in the management of PCM patients.

eLife assessment

This paper presents an analysis of both contact tracing and whole-genome sequence data to track the elimination of dog-mediated rabies in Pemba Island, Tanzania. The work is a valuable contribution to the literature as it will have practical implications for the elimination of dog-mediated rabies in other regions/contexts. The main claims made are largely supported, but the strength of evidence for the cost-effectiveness is limited.

eLife assessment

This important study presents the idea of "Skeletal Age", defined as the age of one's skeleton as a consequence of fragility fracture, as a potential new tool to raise awareness about the increased risk of mortality following a fracture (particularly hip fractures) and thus improve the medical management of osteoporosis. The evidence is convincing and is derived from a very large database from the Danish National Hospital Discharge Registry. The proposed approach might represent a starting point for making doctor-patient communication about the health risks of an osteoporotic fracture more intuitive and possibly more effective.

eLife assessment

This study presents an important finding on the cause of the widely reported disruption of the excitation to inhibition (E-I) ratio change in Autism Spectrum Disorder (ASD) mouse models. The evidence supporting the main conclusions is solid and well-sampled. These results can be a starting point for studies that assess the functional role of daily oscillations of the E-I ratio in the pathophysiology of ASD, and possibly, reshape our understanding of the nature of the E/I balance alterations that contribute to normal and diseased circuits.