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.

eLife assessment

This work, which will be of interest to scientists in the field of hematology and ubiquitin biology, identifies previously unrecognized functions and regulatory mechanisms of an E3 ubiquitin ligase during erythrocyte progenitor maintenance and differentiation. This work has the potential to reveal that the exchange of scaffold proteins of a modular E3 ligase can have an effect on cell fate and reveal a novel mechanism of E2 enzyme regulation during differentiation. However, additional work is needed to support the major claims.

eLife assessment

This paper describes the anatomy of important fossil remains of the dwarf dinosaur Europasaurus, providing compelling evidence for precociality. Only a handful of papers provide detailed information on sauropod neuroanatomy - as such this paper will be of interest to a relatively wide range of researchers, in particular vertebrate palaeontologists, and comparative anatomists.

eLife assessment

The manuscript is of broad interest in the field of muscle physiology and structure. The authors developed nanobodies against different domains of the giant Drosophila proteins Sallimus and Projectin, which are titin homologs, and used them to define their organization along sarcomeres of distinct fly muscles. This is an important contribution to understand the functional architecture of the muscle; it suggests that in invertebrates two proteins fulfil the role of the vertebrate titin in bridging the A-band and the I-band.

This manuscript was co-submitted with: https://www.biorxiv.org/content/10.1101/2022.04.13.488177v1

eLife assessment

This work provides valuable knowledge to the ongoing research to establish an algorithm to shorten the duration of hepatitis C therapy with direct-acting antivirals. This is an important study that is a nice addition to previous reports evaluating the utility of response-guided therapy for shortening the duration of HCV treatment. Given the disease burden and the high costs of treatment, especially in low-income countries, this is a major goal that was also advocated by the WHO. Although the main objective (shortening therapy to 4 weeks) was not adequately achieved (<90% success rate), the study's results may suggest that re-treatment in case of failure is safe and efficient, although further studies with a larger number of patients are needed for confirmation.

eLife assessment

Igf2 and H19 are the two best-studied imprinted genes in mice. Taking advantage of the varying levels of H19 and Igf2 expression in three existing mouse models, the authors dissect the role of H19 and Igf2 in cardiac and placental development. Their findings suggest that an accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially the development of the heart and placenta. The work is of interest to colleagues studying imprinting as well as mammalian development.

eLife assessment

The authors find a significant and unexpected consequence of hypoxia in lung fibroblasts and smooth muscle cells - decreased lactate production - a finding that is important in the field of pulmonary hypertension. Additional orthogonal assessments of lactate production will strengthen the conclusions put forward.

eLife assessment

The authors present very exciting findings on the cranial bone defect repair using cutting-edge multiphoton imaging to study the role of different vessel subtypes and related oxygen and metabolic microenvironments. The study used microscopy to visualize the oxygen distribution and energy metabolism within the defects at different time points during the process of bone healing. This allows one to understand the pathophysiological progressions of bone diseases and regeneration. It will also provide critical information to optimize the therapeutic bone healing and regeneration approach for different clinical situations.

eLife assessment

Wang, Carlson, and colleagues investigate sensory adaptations in the fruit pest Drosophila suzukii, which prefers ripe over overripe fruit. This study focuses on changes in sensory pathways for sugars and food texture, which may contribute to ecological shifts. Several interesting physiological and molecular adaptations are observed in D. suzukii, but it remains unclear whether these observed changes account for behavioral changes.

eLife assessment

This study addresses a fundamental question about the origin and evolution of selfish genetic elements, focusing on the paradoxical abundance of toxin-antidote elements in selfing Caenorhabditis species. The authors propose for the C. elegans peel-1 zeel-1 locus fitness advantages; if these the findings can be supported with additional data, they will be of considerable interest to the field due to their wider implications for the evolution of such systems.

eLife assessment

The purpose of the study was to evaluate the transcription factor NF-kB, a common transcription factor that is thought to mediate muscle atrophy, in the setting of a rotator cuff injury. The authors used gain of function and loss of function NF-kB inhibitors to show that, surprisingly, NF-kB does not seem to be a major mediator of muscle atrophy in this model (as compared to other atrophy models), but there are sex-related differences. They found that male mice were more likely to have atrophy regulated by autophagy, both of which are interesting, novel findings.

eLife assessment

This manuscript presents a valuable framework and blueprint for the study, in artificial systems, of the principles and mechanisms that underlie proprioception in biological systems. Using artificial neural networks trained on synthetic hand movement data, the authors present solid, albeit incomplete, evidence that action recognition can explain important features of the mechanisms that underlie proprioception in biological systems. Experiments with architectures trained using losses that, in addition to action, take into account velocity and/or other states, could strengthen the authors' findings.

eLife assessment’

This paper is of interest to a broad audience of cell biologists, and researchers who work with cultured endothelial cells. The work uncovers the impact of culture conditions on transcriptional changes of endothelial cells and demonstrates that some of these changes can be recovered by sheer forces or coculture. The authors provide valuable datasets which will be a good resource for the community.

eLife assessment

This manuscript provides a valuable and policy-relevant contribution to our understanding of SARS-CoV-2 viral kinetics in the Omicron era. The authors exploit a rich and unique dataset from the National Basketball Association to describe post-infection viral kinetics and explore evidence for differential kinetics by immune history and demographics. The authors show (as others have) that most people remain with high viral loads 5 days post positive test (though less so in groups who are tested in a more realistic manner), and that older individuals and those who were boosted (but had a poor initial response to the primary vaccine series) were more likely to remain with high viral loads longer after an Omicron infection, while also describing rebound frequencies after Omicron infections.

eLife assessment

In peripheral nerve injury, an immune response occurs to ensure debris clean-up and potential repair, however, there has not yet been a census of cell types and gene expression as these lesions undergo clearance and eventual repair. Zhao et al generate a transcriptional resource by performing scRNAseq on both the naive, injured, and repairing sciatic nerve. They identify the composition of different cell types, gene signatures, and cell-cell communication and contrast these with signatures from the blood, and compare the injured site with distal nerve segments after injury. To dissociate the immune response from injury versus Wallerian degeneration, they use SARM1 KO mice (which exhibits delayed neurodegeneration) and observe that there is still injury-induced immune influx. Overall, this is a convincing study and useful resource for the field of neuronal repair and neural-immune interactions with a clear presentation of the animals and time points, with some follow-up experiments and validation.

eLife assessment

This manuscript uses large-scale neural imaging and network models to show how spontaneous dynamics emerge in such ensembles and how such activity influences behavior. It is a strong addition to the field for explaining many of the observed neural activity patterns and their heterogeneities.

eLife assessment

This paper will be of interest to scientists working on cilia, intraflagellar transport, and structural modeling. Using an integrative modeling approach, the paper provides a fundamental structural model for a part of the molecular machinery that is responsible for cilium assembly. However, additional approaches would improve confidence in the as yet incomplete structure model.

eLife assessment

This paper is an important contribution to the microglia field and will be of interest to a broad readership in the fields of neurobiology, cell biology and immunology. This work describes fundamental mechanisms of efferocytosis by microglia and uses impressive imaging in zebrafish, in combination with molecular manipulations, to provide compelling data of how centrosome movements synchronize with phagocytic cup formation during microglial efferocytosis of neuronal corpses in vivo.

eLife assessment

This paper is of interest for somatosensory neurobiologists studying how polymodality is achieved in peripheral sensory neurons. The work identifies roles in cold nociception and not mechanosensation in chloride transport for a number of ion channels.

eLife assessment

The manuscript makes a fundamental contribution to our understanding of sugar release by symbiotic dinoflagellates, and is of broad interest for the fields of ecology, marine biology, and cell biology. The experiments, which combine algal culture with targeted metabolomics, transcriptomics and the application of inhibitors, provide substantial, though not entirely complete evidence for an acidic environment mimicking conditions reported for the intracellular organelle that hosts the symbiotic algae, leading to upregulation of algal cellulases, which in turn degrade the algal cell wall and thereby releasing glucose and galactose that can be used as a source of food by the coral host. This is a new idea and could significantly contribute to our understanding of photosymbiosis.

eLife assessment

Using a genetically controlled experimental setting, the authors find that the lack of Polycomb-dependent epigenetic programming in the oocyte and early embryo influences the developmental trajectory through gestation in the mouse. By showing a two-phase outcome of early growth restriction followed by enhancement, the authors address previous inconsistencies in the field. However, the link with placenta function and gene misregulation is not yet fully supported.

eLife assessment

This work addresses the mechanisms of action of the transmembrane proteins TMEM87A and TMEM87B, which are thought to play a role in protein transport, but have been implicated in other processes as well, such as signaling and acting as mechanosensitive ion channels. The study represents an important advance of the understanding of this poorly characterized family of proteins. While the structure is of low resolution, it is well interpreted, and authors take good advantage of AlphaFold2 to gain insights into potential function. The work is of interest to colleagues studying transporters and ion channels.

eLife assessment

This paper is of particular interest to researchers who plan to use focused-ion beam scanning electron microscopes (FIB-SEMs) and require fluorescent data to guide the milling process. The authors describe a valuable after-market upgrade that allows fluorescent data acquisition during FIB-milling without stage repositioning. Technical details of the fluorescent module upgrade together with the sample stage redesign are compellingly documented and will enhance the implementation of this important technology.

eLife assessment

This important paper uses advanced imaging approaches to explore how Piezo1 distributes on surface red blood cells. The study provides compelling evidence that this molecule 'reads' the membrane curvature and clear support for the force-through-membrane model of mechanosensation.

eLife assessment

SARS-CoV-2 nonstructural protein (Nsp1) has emerged as an attractive target as it plays an important role in modulating the host and viral gene expression. This study describes multiple druggable sites in Nsp1. A 1.1Å co-crystal structure of Nsp1 with a fragment, together with computational studies, provides a framework for the rational design of potential antiviral candidates. This important study is methodologically convincing and will be of interest to researchers in the fields of structural virology and rational drug design.

eLife assessment

Conditional deletion and reactivation of a gene in situ remain challenging, and this study therefore addresses a gap in the genetic tool box. The authors introduce a reversible conditional gene inactivation and reactivation method using sequential expression of recombinases, with doxycycline treatment terminating gene transcription, while doxycycline and tamoxifen addition restore gene expression.

eLife assessment

This manuscript will be of broad interest to those working in the genetics of complex diseases, with the results strongly supporting the author's primary claims. Overall, this is an important study that demonstrates the power of proteomics-based systems genetics studies in the mouse.

eLife assessment

The authors report results from experiments and modeling that study the motions of molecules in the dense and dilute phases of biomolecular condensates, with the key finding that molecules in the dense phase of condensates formed by folded domains appear to switch between a confined state with low apparent diffusivity and a mobile state with a high apparent diffusivity that is comparable to that of molecules in the dilute phase. The study provides experimental evidence that is suggestive of phase separation coupled with percolation as the operative mechanism that gives rise to biomolecular condensates.

eLife assessment

This manuscript presents valuable and significant data on how lipids may accumulate in the tubulointerstitial compartment of the diseased kidney, but the work is largely descriptive, using methods that are inadequate for quantification (colorimetric assays versus mass spec), thus rendering data interpretation not very convincing. Therefore, while a major strength is the presentation of innovative ideas, additional experiments would be needed to support the main conclusions.

eLife assessment

This important work will be of interest to neuroscientists working on synaptic transmission and modulation of ion channel activity. This work provides solid evidence of how modulation of Nav1.2 channels by SUMOYLation alters the function of layer 5 pyramidal neurons, using convincing methodology that includes the use of a mouse engineered to eliminate the SUMOYLation site on Nav1.2. Some aspects need to be revised to strengthen data analysis and interpretation.

eLife assessment

This paper will be of interest to immunologists and infectious disease experts, as it reports the investigation of a novel treatment of invasive pneumococcal diseases using complement-activating monoclonal antibodies. Using a combination of in vitro and in vivo methods, the authors demonstrate convincingly that the introduction of specific mutations in human monoclonal antibodies that target the surface of pneumococcus bacteria can result in enhanced complement activation after these antibodies bind to the bacterial surface.

eLife assessment

This study shows that cis H3 tail acetylation promotes nucleosome accessibility to H3K4 methyl readers and writers such as MLL1. The findings provide a molecular basis for the long-standing connection between H3 acetylation and H3K4 methylation. Additional evidence is required to fully support the conclusions.

eLife assessment

Authors investigated the role of dopamine (DA) release via GRABDA in the dorsal bed nucleus of the stria terminalis (dBNST) in sign and goal tracking behavior, in response to systemic fentanyl, and to fentanyl self-administration. The behavioral experiments were well-conducted and provide novel information about BNST DA in theories of learning and reinforcement. Identified limitations had to do with acknowledgment and discussion of divergent sources of DA innervation, the low sample size in fentanyl experiments with the exclusion of a large number of animals, and a need for additional analyses of the photometry data and/or control recordings to rule out spontaneous transients in this region.

eLife assessment

The manuscript by Yanis Zekri et al identifies the direct T3 target genes that are important in thyroid hormone signaling in brown adipose tissue (BAT). The findings reported in this manuscript are significant and fundamental to our understanding of thyroid hormone action in response to environmental changes. The strength of the evidence presented with the novel methodological approaches used makes the manuscript exceptional in the area of BAT biology and T3 regulation of adaptive thermogenesis.

eLife assessment

This manuscript examines the inhibition of transmitter release induced by the activation of opioid receptors, both MOR and DOR, using a novel imaging method. The authors specifically examine how the inhibition of transmitter release is changed following prolonged exposure to saturating concentrations of agonists. They showed convincingly that there is a depletion of plasma membrane-associated receptors and suggest that the decline in receptors at the plasma membrane underlies presynaptic tolerance. This work addresses a long-standing question about how tolerance develops at the presynaptic level and indicates that the location of receptors is critically important in the development of tolerance. This work is fundamental and a game changer in the understanding of tolerance at the cellular level.

eLife assessment

This paper will be of interest to neuroscientists who study visual processing or are interested in dendritic integration. The authors used calcium imaging, pharmacology, and electrophysiology to investigate how a large, loom-sensitive neuron in grasshoppers integrates visual input to respond to both light and dark looming objects. These experiments support the finding that the integration is done by two distinct arbors of the neuronal dendritic tree, one of which loses retinotopic information. The authors suggest potential advantages of this dendritic arrangement.

eLife assessment

The complex mechanisms through which diet impact Parkinson's Disease are unclear, limiting the ability to guide patients to an optimal diet. Here, researchers use a mouse model to test the impact of dietary fiber, revealing changes in gut microbes and immune cells in the brain. This study raises intriguing hypotheses about how diet-induced changes in the microbiome could lead to changes in brain function.

eLife assessment

Sanderson developed novel interactive software for visualizing phylogenetic trees representing millions of sequences. This is a fundamental advance over previous software that is typically limited to trees with a few thousand tips. Taxonium has been used intensively by the virus evolution community over the past months and has thus already proven its utility and performance.

eLife assessment

This manuscript examines the functional relationship between neural activities in several cortical areas (such as the primary and secondary motor cortex and the medial prefrontal cortex) and the different sleep states or under anesthesia. The quality of the recordings in infant rats is excellent. Results are important in the field of research into the role of active sleep in the neuronal and circuit mechanisms of early cortical development. Some of the findings presented and hypothesis developed are novel, but the overall demonstration remains incomplete and further in-depth analysis and additional experiments are required to fully support the authors' claims.

eLife assessment

This manuscript will be of interest to researchers within the fields of haematological and bone oncology. It reveals a novel effect of FABP5 inhibition to reduce myeloma growth both in vitro and in vivo, with convincing supporting associations between FABP5 expression and survival in patients with myeloma.

eLife assessment

In their paper, Rao, Li et al. explore the mechanisms by which the microtubule-associated protein, doublecortin (DCX), functions in regulating retrograde transport in neurons. They find that DCX affects the dynein-microtubule interaction to perturb its motion. Impressively, they reconstitute a dynein-dynactin-JIP3 complex, validating JIP3 as a bona fide adaptor, and show that DCX disrupts the transport of this processive complex. This mechanism will be useful in understanding how mutations in DCX cause lissencephaly and this paper will be of interest to those in the cytoskeletal and neurobiology fields.

eLife assessment

The ability of organisms to cope with environmental stressors can be modified by their physiological conditions as well as life experience. Here, taking advantage of the tractability of the nematode C. elegans, the authors find that exposure to elevated temperatures enhances defenses against peroxides, agents whose toxicity is enhanced by temperature. The finding that a key thermosensory neuron is required for this phenomenon is an important advance in understanding the underlying mechanism; further, the authors' proposal that this is an "enhancer sensing" phenomenon is interesting and thought-provoking. The multidisciplinary approach and mechanistic detail revealed by this work will make it of interest to readers in the fields of sensory biology, signal transduction, and physiology.

eLife assessment

This manuscript investigates how the fly visual system can encode specific features in the presence of self-generated motion. Using volumetric imaging, it explores the encoding of visual features in population activity in the Drosophila visual glomeruli - a set of visual "feature detectors". Through an elegant combination of neural imaging, visual stimulus manipulations, and behavioral analysis, it demonstrates that two different mechanisms, one based on motor signals and one based on visual input, serve to suppress local features during movements that would corrupt these features. The results of this study open up future directions to determine how motor and visual signals are integrated into visual processing at the level of neural circuits.

eLife assessment

This work offers fundamental insights into how asymmetric behavioral features in optokinetic eye movements can be predicted from visual responses of direction-selective neurons in the retina. The electrophysiological experiments and model-based analyses are carefully performed and offer convincing conclusions. The presentation could improve in clarity for a stronger focus on the most important results.

eLife assessment

The work by Kim et al., used synthetic constructs in Drosophila to examine the relationship between regulators (activator/repressor) and transcription initiation. By measuring regulator concentrations and the corresponding RNA polymerase initiation rates in different synthetic constructs and using a thermodynamic model, the authors concluded that that higher-order cooperativities between the repressor on adjacent binding sites, and that between the repressor and RNA polymerase are needed to explain the observed response curves in RNA polymerase loading rate. This work targets a challenging question in eukaryotic transcription regulation, where higher-order cooperativity between different molecular components, in addition to simple transcription factor binding and unbinding, is often necessary to account for observed promoter behaviors when multiple elements (repressors, mediators, activators) exist.

eLife assessment

This paper will be of interest to cell biologists, structural biologists, and biophysicists studying programmed cell death, membrane transport, and protein-lipid interactions. The simulation data presented offers atomistic detail of how gasdermin-D N-terminal domains assemble on the plasma membrane and trigger the formation of membrane pores which lead to pyroptosis. The study is well designed and the resulting data are rigorously analyzed; however, some clarifications and additional data are required to fully justify the conclusions.

eLife assessment

This manuscript reports a novel role of Mcm2 licensing factor and helicase subunit of the Mcm2-Mcm7 complex in the differentiation of embryonic stem cells into neuronal lineages. A series of compelling experimental manipulations dissect the abnormalities in the formation of heterochromatin at pluripotent genes and the resolution of bivalent chromatin domains at lineage-specific genes in differentiation in response to mutation of the histone binding domain of Mcm2. These findings provide new insights into the replication-independent roles of Mcm2. This paper will be of interest to scientists working on development and embryonal cell differentiation.

eLife assessment

Understanding the integration and contribution of different combinations of environmental cues to the synchronization of the daily oscillator is important, because it provides insight into how organisms might be able to distinguish (and weight) between irregular (or in the tidal zone highly complex) versus regular individual daily changes of light and temperature. The study, which is thoroughly conducted and provides an impressive amount of experimental and analytical work, dissects the effects of sensory conflict on behavior and gene expression rhythms.

eLife assessment

This manuscript provides an improved version of the little skate genome, which will be of great interest to the field of comparative genomics and evolutionary biology. The authors use the genome to compare gene expression and chromatin accessibility profiles in motor neurons of the little skate and other species (mouse, chicken), aiming to predict conserved and divergent gene regulatory mechanisms underlying motor neuron development. While the manuscript contributes a valuable resource to the field, more rigorous analyses and experimental validation are needed to support the major claims of this study.

eLife assessment

This study provides a valuable analysis of the splicing landscape in colon cancer cells that have properties intermediate between those typically found in primary cancers ("epithelial") and those that are spreading by metastasis ("mesenchymal"). The strength of evidence provided is wide ranging and convincing, and supports current ideas that changes in the way that RNA from particular genes is processed plays a key role in cancer spread.

eLife assessment

Organoids mimic the architecture and function of their cognate organs and have potential as replacements for animal models. Here the authors generated canine organoids from multiple adult tissues, including endometrium, lung, and pancreas, in addition to previously generated organoids from the kidney, bladder, and liver. However more methodological detail and functional characterization are required before this toolbox can be optimally utilized by wider scientific community.

eLife assessment

This manuscript constitutes an important foray into the conformational rearrangements throughout various domains of the notoriously difficult-to-study P2X7 receptor, with a focus on the enigmatic intracellular 'ballast' domain. This is of broad interest to those studying the role of enzymatically active intracellular domains of membrane proteins. The authors provide convincing evidence that the ballast domain is unlikely to undergo major conformational changes upon ATP-induced gating, but additional experimental support is required on the facilitation process and to elucidate the consequences exerted by intracellular factors.

eLife assessment

This study investigates factors that control egg size plasticity in a social insect, the honey bee Apis mellifera. It finds that honey bee queens vary egg size in response to size of their colony, and that the gene Rho1 is involved in egg-size determination. These findings inform our understanding of maternal control over egg size, a key form of maternal investment. The work is relevant to colleagues studying reproduction and social insects.

eLife assessment

This manuscript reports the results of an observational study in 312 cancer patients to assess post-acute sequelae of SARS-CoV-2 infection (PASC). Their descriptive results provide details on the type of persistent symptoms as well as their frequency among cancer patients. This is valuable information to inform clinical policies regarding disease management in cancer patients.

eLife assessment

The premise behind this manuscript is important and timely for muscle biologists and for stem cell biologists. The identification of heterogenous distribution of factors across the myofiber is an important contribution for dissecting how muscle stem cell diversity in a tissue is achieved. However, the mechanism of action proposed by the authors will require additional experimental support.

eLife assessment

This study provides empirical support for how brain function at the system level, particularly network segregation, influences cognitive abilities even in the oldest-old range of human aging. The findings are potentially interesting to understand successful aging.

eLife assessment

This manuscript provides insights into the architecture of the yeast histone acetyltransferase complex NuA4 and is of broad interest to those studying transcription and chromatin modification. The cryo-EM data are of very high quality, and enable the authors to devise a structural model that is in much better agreement with biochemical data than previously reported models. This structure represents an important puzzle piece towards a molecular understanding of chromatin modification.

eLife assessment

This study connects changes in single-cell twitching motility due to substrate stiffness to multicellular phenotypes. It is likely to have a broad impact on those studying microbiology and multicellular communities as it assesses the influence of single-cell behavior on multicellular processes. However, some of the presented data conflict with previously published literature, raising questions about the nature of these differences.

eLife assessment

This paper will be of broad interest to anyone aiming to understand the neural basis of human touch perception. This is an important paper that provides compelling evidence for peripheral tactile encoding of orientation that reflects perceptual capabilities, by using a wide range of stimulus conditions. The results will be valuable to inform both future experiments and computational investigations into the neural representation and processing of small tactile spatial features at the edge of perceptual resolvability and on the emergence of invariant representations in touch more generally.

eLife assessment

This manuscript will be of interest to those working on non-neuronal bioelectricity, particular synthetic biologists and bioengineers. The primary contribution is the ability to leverage engineered gene circuits to control cellular membrane potential. We find issue, however, with the presentation of the data in this work as electrical communication since the synchronous behavior largely arises from external chemical stimuli.

eLife assessment

This manuscript is of interest to researchers investigating genetic mechanisms of aging and transcriptional regulation of developmental processes in mesenchyme-derived tissues. In this study, fibroblast cell lines from patients with and without Hutchinson-Gilford Progeria were compared to pinpoint the molecular mechanisms leading to the phenotypes of persons with this condition. The identification of five major dysregulated functional hubs in fibroblast cell lines derived from Hutchinson-Gilford Progeria Syndrome (HGPS) patients provides a unique opportunity for others working on this disorder to utilize animal models to validate the authors' hypotheses.

eLife assessment

The authors show that the amino terminus of dystroglycan is required for the production of full-length matriglycan, and in its absence, a shorter matriglycan is produced that is still capable of binding laminin. alpha-DGN deficient mice have abnormal neuromuscular synapses and reduced lengthening contraction-induced force. Overall, the well-controlled and convincing data mostly support the main conclusions, which will be of interest to scientists in membrane biology, muscle biology, and glycobiology.

eLife assessment

This work makes an important contribution to the study of the cell cycle and inferring mechanisms by studying correlations in division timing between single cells. By treating the problem in a general way and computing over lineage trees, the authors can infer timescales in the underlying mechanism. This approach is able to detect a general role of circadian rhythms in cell cycle control. The method is validated on data sets from bacterial and mammalian cells and can suggest when additional measurements are needed to distinguish competing models. This paper is of broad interest to scientists in the fields of cell growth, cell division, and cell-cycle control.

eLife assessment

When sensory inputs, such as vision or sound, are chronically disabled, the loss of input activity is counterbalanced by the upregulation of synaptic activity. In this study, the authors provide evidence that instead of synapses that directly represent the sensory information, synapses that show correlated intrinsic network activity are the ones that undergo the change upon sensory deprivation. This fundamental and important paper will be useful to readers in the fields of experience-dependent plasticity, sensory cortical coding, and homeostatic plasticity. While the key claims of the manuscript are well supported by the data, minor changes are suggested for clarification, including the fact that the present study has addressed homeostatic responses in adult animals rather than in juvenile animals with which homeostatic plasticity has been actively studied to date.

eLife assessment

The manuscript by Wardwell-Ozgo and co-authors describes a thorough and interesting study that explores the mechanisms through which a hormone receptor can both repress and activate gene transcription. They have conducted an impressive number of experiments all aimed at showing that by using their new transgenic tool, and Ecdysone Receptor (EcR) ligand binding domain sponge, they can demonstrate that EcR activity is important for eliciting both types of ecdysone responses, repression, and activation, in the Drosophila wing disc and that the EcR binding partner Smarter is essential for the repressive function. The differences in expression levels have however not been quantified, which would lend greater support to their claims.

eLife assessment

This paper will be of interest to scientists studying species-specific immune responses and those studying how transposable elements rewire transcriptional regulatory networks. The work describes a new class of TEs that may act as enhancers of immune genes in mice. A combination of computational and experimental data supports most but not all conclusions in the paper.

eLife assessment

This article is a valuable contribution to the field of neuroimaging. The paper proposes a deep neural network for brain extraction that generalises across domains, including species, scanners, and MRI sequences. Although in some sense brain extraction is not a challenging problem for deep learning, domain generalisation can be. The authors provide solid evidence that their approach works though it may need to be precisely matched to the training data.

eLife assessment

This paper is of interest to cell biologists studying the mechanisms and control of microtubule nucleation. In this work, the authors use a novel protocol for the purification of gamma-TuRCs and for the production of gamma-TuNA that enables them to demonstrate a clear activating effect of gamma-TuNA on microtubule nucleation that depends on the dimerization of gamma-TuNA protein chains.

eLife assessment

This paper will be of interest to the audience in the fields of genome stability and B lymphocyte biology for highlighting the role of R loop metabolism in maintaining genome integrity during antigen gene diversification. Although RNA:DNA hybrids and R loops have been described at the immunoglobulin (Ig) loci long ago, their contribution to Ig heavy chain (Igh) class switch recombination and Igh locus integrity have not been fully elucidated yet. Overall, the experiments and results generally support this conclusion; however, several aspects of the model put forward are highly speculative in the current form.

eLife assessment

In this potentially important study, the authors attempt to explain why hormone replacement therapy with estrogen is not effective in preventing atherosclerosis in post-menopausal women by showing that iron accumulation prevents the hormone replacement therapy benefit through negative regulation of estrogen receptor expression via Mdm2-mediated proteolysis. The strength of evidence is currently incomplete as control groups are missing and there is a lack of clear-cut evidence that this effect is related to the estradiol therapy in addition to the accumulation of iron in the post-menopausal state. The general public as well as specialists might find this work to be of interest.

eLife assessment

This important study reports that a high-fat diet induces biliary epithelial cell proliferation and suggests this may account for the so-called ductular reaction in advanced fatty liver disease. Convincing data support the finding that the transcription factor E2F1 is required for biliary epithelial cell proliferation in mice fed with a high-fat diet, and organoid models indicate that lipid abundance promotes glycolysis in an E2F-dependent manner. These findings are potentially of broad interest to the field of liver biology and disease.

eLife assessment

This paper addresses an important question within adaptive immunity, namely whether the T cell receptor (TCR) repertoire of negatively selected thymocytes shares common features. The authors analyze T cell receptor sequences from mice as they progress through positive selection, CD4/CD8 lineage commitment, and negative selection, to find small but consistent differences between the repertoires at these selection stages. They argue that their findings do not indicate any sequence-specific selection; however, some of the conclusions drawn are currently incompletely supported by the performed analyses.

eLife assessment

This is a very elegant study which clearly demonstrates the existence of CMV specific memory T cells in CMV+ pre-pandemic individuals that are capable of recognising epitopes from SARS-CoV-2. It provides new insights into the development of cross-reactive immune cells that was not anticipated. The study has been elegantly performed and presents important findings. In particular, the discovery of a public TCR which mediates the crossreactivity described is an important finding.

eLife assessment

This paper is of potential interest for skeletal biologist studying osteocytes and skeletal aging. Using a mouse model of partial osteocyte deletion, the authors provide new understanding on the role of osteocytes in regulating other lineage cells in bone, bone marrow, and skeletal muscle. This is an important and logically presented study that offers new insight into the biology of osteocytes. The set of data from the genetic mouse model, bone phenotypic analyses, and scRNA-seq analysis largely support the conclusion.

eLife assessment

Most birds today can lift the upper beak independently of the brain case, enabled by a series of mobile joints and bending zones in the skull. The computed tomography of the skull of a 120-million-year-old toothed bird produced by the authors shows for the first time that the joints were still absent, but also hints at how they may have evolved later. This compelling, important paper is of high interest to evolutionary biologists, vertebrate paleontologists (especially, but by no means only, those working on bird origins) and specialists in biomechanics.

eLife assessment

A commonly held hypothesis about how genetic variants predispose to common diseases and other human traits is that variants have phenotypic effects by altering transcript accumulation. The authors question this view by showing some evidence for shared genetic control of transcript abundance for genes believed to be involved in the traits, and for the traits themselves.

eLife assessment

Functional magnetic resonance imaging (fMRI) yields a notoriously noisy and autocorrelated signal, and the GLMsingle method presented here by Prince and colleagues demonstrably improves the estimation of responses evoked by single trials. This open source toolbox is implemented in a user-friendly manner and will be of interest to researchers using human neuroimaging to study neural responses in condition-rich designs, as is increasingly common in cognitive neuroscience experiments.

eLife assessment

Several mammal species, including dolphins, have evolved to be relatively "hairless". Kowalczyk and colleagues scan the genomes of multiple species to identify genomic regions that appear to have evolved at a faster or slower evolutionary rate along hairless lineages. They identify a number of protein-coding genes as well as noncoding regions that might explain how hairlessness evolved in mammals. This study is of interest to those investigating the development of the skin and its appendages as well as evolutionary biologists, especially those investigating instances of convergent evolution and those developing phylogenomic methods for genome comparisons.

eLife assessment

CRISPR-Cas systems are essential components of an adaptive immune system that protects bacteria and archaea from infection by foreign genetic elements like phages and plasmids. The work presented here demonstrates that some CRISPR systems (i.e., type III-A) rely on host nucleases (i.e., RNase R and PNPase) for faithful processing of CRISPR RNAs. Collectively, this work expands the fundamental understanding of how nucleases involved in RNA metabolism contribute to the adaptive immune response in bacteria.

eLife assessment

This is a valuable study performing elegant experiments making identification of a specific regulator in skeletal muscle regeneration. It will form a foundation for further mechanistic investigation. The work is of importance in the clinical field of muscle injury and regeneration.

eLife assessment

The authors provide a new method to target mouse CSF-cNs via intracerebroventricular injection of adeno-associated virus (AAV) with a neuron-specific promoter, which enabled them to introduce any genes into CSF-cNs. By doing so, they established the structure, connectivity, and function of mouse CSF-cNs in locomotion, recapitulating the findings obtained in zebrafish and lamprey, and extending the recent observations in mice. This study is very conclusive and important for the sensorimotor field.

eLife assessment

This paper on the regulation of microtubule dynamics during C. elegans meiosis will be of interest to scientists in the broad field of microtubule function in both mitosis and meiosis. The experiments are beautifully conducted and presented and generally support the conclusions of the paper. The results are interesting and add to our understanding of the control of microtubule dynamics at the kinetochore and its functional consequences for meiosis.

eLife assessment

Canetta et al. explored the time-dependent effects of inhibition of parvalbumin-positive interneurons in the mouse prefrontal cortex on task learning and cognition. Overall, the study shows that prefrontal cortex PV cell activity during a sensitive period strongly modulates cognitive flexibility and network activity in the adult mouse. This study could progress our understanding of cell behavior in mouse prefrontal cortex.

eLife assessment

This is an important paper that is methodologically solid and highlights structural covariance as the neuroanatomical basis underlying individuality in genetically identical mice. The approach to individuality is very well designed, and the use of brain imaging and anatomical covariance as the underlying mechanism is well thought out. The statistical methods, while overall sound, require further justification and exploration. This paper will be of broad interest to neuroscientists, especially those working in brain plasticity or understanding unique and shared environmental influences on individuality.

eLife assessment

This is an important manuscript that will be of interest to a broad range of researchers studying immunology, obesity and metabolism, as well as the links between maternal health and pathophysiological responses in the offspring. The comprehensive studies using RNA-seq, scRNA-seq, ATAC-seq and scATAC-seq in human umbilical cord monocytes represent an important resource for understanding the transcriptomic and epigenetic shifts in the monocytes of newborns. The experiments involving stimulation of monocytes with pathogens offer convincing evidence for the dysfunction of monocytes in the newborn.

eLife assessment

This paper is a fundamental work in developmental biology that supports its findings with compelling evidence drawn from both theoretical and experiment insights. This work will be of interest to researchers in the fields of developmental and stem cell biology as it provides a potentially general mechanism for the control of a proliferative cell population.

eLife assessment

This important work convincingly shows that taste memory formation requires the same circuit substrates and mechanisms as olfactory memory formation. While the exact mechanisms remain to be elucidated, the compelling data and approach represent a valuable foundation for the study of molecular and circuit mechanisms underpinning taste memory formation and the role of brain energy therein. This study will be of particular interest to the large community of scientists studying the mechanisms and circuits of memory formation in the fly and possibly beyond.

eLife assessment

This paper reports on important observations regarding human CD8 T cells that express shared T cell receptors amongst individuals and exhibit poly-specificity directed mainly to several unrelated viral antigens. Although the majority of the claims are convincingly supported by results from both in silico and experimental approaches, mechanistic molecular details underlying poly-specificity remain incomplete. The results from these studies will enhance the ongoing debate on T cell specificity and potentially, will impact fields related to immunology, for example, immunoparasitology, cell biology, and vaccine development.

eLife assessment

The authors of this manuscript set out to improve on a peptide, ProTxII, which had been previously put forward as a promising blocker of Nav1.7 channels and thus offers a possible non-opiate way to block pain. They develop a useful computational workflow that is based on in silico manipulations of the interaction of ProTxII with a Na channel structure determined previously and evaluation of the predicted mutations with electrophysiology. The authors succeed in producing two peptides with improved selectivity for Nav1.7 over other subtypes and capable of producing ion channel block at low concentrations and the experimental evidence presented is solid, and the general applicability of the method is compelling.

eLife assessment

This paper provides evidence that an unhealthy lifestyle during adolescence accelerates epigenetic age in adulthood, and that these associations are largely explained by the effect of shared genetic influences. The main strengths of this valuable paper are the relatively large sample size, longitudinal assessment of lifestyle factors, and sophisticated statistical analyses. The paper is methodologically compelling and will be of interest for a broad audience, including individuals working on methylation, epidemiology, and/or ageing.

eLife assessment

This is a potentially important paper that takes advantage of an unusually comprehensive evolutionary genetic dataset to tease apart the relationship between genetic variation and phenotypic divergence over the ~medium term (50 generations). The questions addressed have broad relevance across evolution, conservation, and agricultural fields, and this paper will particularly appeal to evolutionary biologists. Nonetheless, the strength of evidence is incomplete for the major results and conclusions reported.

eLife assessment

This paper addresses an important question: the relationship between the cell wall and other, primarily lipid, based components of the cell envelope. Building on previous work, the authors provide data suggesting that the activity of a PonA2, non-essential peptidoglycan synthase, promotes membrane partitioning through its role in cell wall synthesis. While the data are consistent with this model, the reviewers felt additional experiments are necessary to fully support the authors' conclusions.

eLife assessment

This paper is of potential interest to any neuroscientist, given it asks how the brain compensates for its own neural transmission delays. This is a problem that runs across neuroscientific disciplines. The authors use a clever and simple design where they study this question in the context of decoding from EEG signals during visual motion processing. They robustly show evidence that the brain can indeed compensate for these delays, although all compensation appears to be afforded by early processing. The manuscript is well-written but can be strengthened by outlining its significance for the broader community as well as some further analyses.

eLife assessment

This manuscript reports an association between TCR convergence and involvement in an antigen-specific response. TCR convergence is assessed as a potential biomarker of response to immune checkpoint blockade (ICB). From jointly analyzing TCR-seq data, single-cell RNA-seq data, and antigen-specific TCR information, the authors provided evidence that convergence is a potential indicator for ongoing T cell antigen-specific response. Overall, the analyses are sound the manuscript is well-written, and the study provides the first evidence that TCRseq alone could be used to predict clinical outcomes.

eLife assessment

The authors present a rich investigation of the evolution of social-movement rules in animal societies under pathogen pressure. The study should be of interest to a broad readership.

eLife assessment

This research focuses on the role of a long noncoding RNA VPS9D1-AS1(VPS) in colorectal cancer (CRC) immune evasion and provides evidence on how it is responsible for escape from cytotoxic T cells killing via amplifying intra-tumoral TGF-β signaling. The findings are of considerable translational significance since VPS9D1-AS1 was validated targetable in this work, and it is of broad interest to readers in cancer biology and immunotherapy.

eLife assessment

Harkin and colleagues explore functional properties of dorsal raphe serotonin neurons using the approach called a generalized integrate-and-fire [aGIF] model, which incorporates a relatively small number of salient biophysical properties of a specific neuron type, and whose parameters are optimized based on voltage dynamics obtained experimentally. The authors make an interesting finding that after-hyperpolarization and A-type potassium currents, in combination with heterogeneous feedforward inhibition from local GABA neurons, give rise to a derivative-like input-output relationship in serotonin neurons.

eLife assessment

This manuscript is of interest to readers in the field of bone biology. It identifies a novel role for the vacuolar ATPase accessory protein ATP6AP2 within the osteoblast lineage and shows that loss of ATP6AP2 in the mature osteoblast results in disorganized bone formation. A similar, but milder, bone disorganization phenotype is also observed when this gene is knocked out in osteocytes. The authors show that this bone phenotype is partially rescued via restoration of MMP14 action.

eLife assessment

This paper reports on the development of an impressive microfluidic platform for the study of motility, and motility transitions, exhibited by single algal cells in circular confinement. Building on previous work that showed a three-state motility repertoire for certain green algae, the present work uses extremely long time series and a variety of physical perturbations to show how those dynamics can be altered by environmental conditions. The work will be of interest to a wide range of scientists studying motility and nonequilibrium dynamics, but its impact would be improved by a more insightful analysis of the voluminous data, with connections to physical principles.

eLife assessment

This paper asks whether a risk score integrating the impact of common genetic variants across the genome (polygenic risk score) on Type II Diabetes is also to any degree predictive of diabetes in pregnancy (Gestational diabetes or GDM).The study population comprises women of South Asian ancestry, who are particularly susceptible to GDM. Strong evidence is presented in favour of the hypothesis of the hypothesis in two sizeable cohorts, one from Canada and the other from the UK. The paper will be useful to those studying women's health in pregnancy, and in particular GDM, which is associated with a number of adverse pregnancy outcomes.

eLife assessment

We admired the study by Krehenwinkel and colleagues for its novelty, depth, and ecological breadth, but have questions regarding the laboratory, bioinformatic and statistical methodologies that require clarification. It is likely to make a substantial impact in the field of plant-based arthropod metabarcoding, revealing ecological insights that can be derived from existing bio-banked material. The work, which creatively exploits herbarium material to track arthropod communities, will be interesting to a general audience in addition to ecologists, foresters, phytopathologists, and industry.

eLife assessment

This manuscript will be of interest to cardiovascular clinicians, medical geneticists, pharmaceutical companies, and the general cardiovascular disease research community. The study adds evidence for the causal role of triglyceride to several atherosclerotic cardiovascular diseases. Their use of Mendelian Randomization method is appropriate and provides convincing support to their findings, which may provide insights on the mechanism of TG biology and drug repurposing of TG-lowering agents.

eLife assessment

This fundamental study demonstrates that the two isoforms of the ARPC5 subunit (ARPC5 and ARPC5L) of the Arp2/3 complex have specific functions in regulating cytoplasmic and nuclear actin filament assembly in response to DNA replication stress and T cell receptor signaling in T lymphocytes. The data presented in the manuscript are convincing and of good technical quality, and the study provides interesting new insights into specific cellular roles of different Arp2/3 isoforms in T lymphocytes.

eLife assessment

This work examines the evolutionary origins of acid-sensing ion channels (ASICs), a class of pH-sensing receptors expressed throughout the brain and body. By combining analysis of sequences, functional measurements, and measures of tissue distribution, the authors provide solid evidence that ASICs existed far earlier than previously believed. The present data indicate that ASICs emerged after the split between bilaterians (organisms with two-fold symmetry) and Cnidaria (jellyfish, anemones, corals, etc.), approximately 680 million years ago. This evolutionary and functional analysis of ASIC channels across bilaterian lineages provides relevant information about the evolution of nervous and sensory systems.

eLife assessment

This work, which will be of interest to all who study plant-microbe interactions as well as plant cell biology, addresses a fundamental question in symbiosis, placing a classic nodulation defective mutant (rpg) into a plausible protein complex and establishing a hierarchy of "infectosome" assembly. Evidence includes convincing genetics and subcellular localization of components during establishment and maintenance of infection. The study also includes compelling new FLIM-based imaging techniques to distinguish signals from closely associated domains in plant cells.

eLife assessment

This is an important paper that is of interest to researchers interested in the psychological and neurochemical mechanisms of pain and pain relief. It shows that the perception of pain relief is modulated by controllability, surprise and novelty seeking. Moreover, these modulations are influenced by dopaminergic but not by opioidergic manipulations. These findings are supported by solid evidence.

eLife assessment

The parabrachial nuclei are groups of neurons in the brainstem (one on each side) that integrate information about the state of the body to guide appropriate homeostatic responses. The manuscript by Pauli and Chen et al. is a compelling and much-needed study that characterizes the cell types that make up these nuclei and genetic tools to study them. The result is a highly valuable resource to the academic community.