eLife assessment

Understanding specific tau-tau interactions that play key roles in Alzheimer's disease and tauopathies will enable the elucidation of the toxic tau species involved in the pathogenesis of these diseases and therapeutic development in this area. In this paper, the authors developed a series of NanoBiT complementation-based tau biosensors to monitor tau intramolecular and intermolecular interactions. This paper will be of high interest to a broad target audience including researchers in the field of biophysics, biochemistry, cell biology, neuroscience, neuropathology, and drug discovery as well as physicians.

eLife assessment

This important study reveals that slow plasticity in the neocortex is essential to prevent memory interference. The method of artificially increasing plasticity in the prefrontal cortex of rats during learning and its effect on sleep physiology, when memories are believed to be reprocessed, is solid. The work will be of interest to neuroscientists interested in learning and memory.

eLife assessment

Alamia and colleagues investigate the direction of traveling waves in the alpha frequency band during visual spatial attention. The authors' novel perspective adopted here is valuable to understanding the functional relevance of alpha oscillations for spatial attention. The observed pattern of results is consistent with distinct roles for travelling alpha waves in spatially opposite directions and makes a solid case for considering this new perspective on alpha rhythms in human cognitive function.

eLife assessment

Silva and colleagues present useful findings related to the isolation of an anti-S2 antibody that recognizes a previously uncharacterized SARS-CoV2 Spike (S) epitope, adding to the growing repertoire of anti-S antibodies that broadly cross-react against human and zoonotic coronaviruses. The evidence supporting the claims of the authors is solid, although antibody effectiveness as a prophylactic or therapeutic reagent in an animal model would have strengthened the study. The work will be of interest to biologists working to develop pan-coronavirus therapies.

eLife assessment

Germline inactivation of NPHP2, which encodes a protein that localizes to the transition zone at the base of the primary cilium, results in infantile kidney cysts and fibrosis. In this study, the authors provide solid evidence that increased cell proliferation and fibrosis precede cyst formation in Nphp-2 mouse models, that mutant renal epithelial cells are responsible for the phenotype, and that genetic inhibition of ciliogenesis in this model reduces disease severity. They also show that valproic acid, a drug that affects a number of cellular targets and is used to treat other human conditions, slows disease progression. One limitation of the study is that it provides limited insights into the mechanisms responsible for any of its interesting observations.

eLife assessment

This fundamental work substantially advances our understanding of how neighboring genes on a chromosome can be separately controlled in time and space. The evidence supporting the conclusions is compelling, with state-of-the-art genetic perturbations and imaging. The work will be of broad interest to geneticists and cell biologists.

eLife assessment

This study presents a useful tool called Phantasus, a web application to analyze gene expression data generated by microarray or RNA-seq technologies. The web application will help biologists end users, and non-bioinformatics experts to analyze new data or replicate transcriptomic studies. Local use of the Phantasus through its Bioconductor package reveals an incomplete functionality concerning the current best practices in analyzing bulk RNA-seq data.

eLife assessment

In this important work, the authors present a sequence-based approach using transfer learning and Restricted Boltzmann Machines to predict antigen immunogenicity and specificity. The evidence and methodology are compelling. This work should be of interest to immunologists, computational biologists, and biophysicists.

eLife assessment

This important study demonstrates a non-canonical, cancer-cell intrinsic role of the ectonucleotidase CD73 in the regulation of cancer cell metabolism. The evidence supporting the claims is solid, although further experimental details and conditions would strengthen the evidence provided.

eLife assessment

This important study by Bonnet et al addresses the question of how AMPA receptor numbers at the synapse are regulated during basal conditions and during chemically induced Long Term Potentiation. Specifically, the study aims to determine the molecular mechanisms that contribute to the intracellular trafficking of AMPA receptors and determine their insertion into the synaptic plasma membrane. Using compelling methodology, the authors dissect the distinct roles of two proteins that bind to the C-terminal domain of the AMPA receptor subunit GluA1: 4.1N and SAP97. The findings will be of interest to anyone trying to understand molecular events contributing to synaptic plasticity in health and disease, and more broadly, the method could be adapted for tracking intracellular movements of a wide range of proteins.

eLife assessment

This manuscript significantly advances our understanding of the development of drug resistance in the HIV-1 protease. The paper addresses the fundamental relationship between resistance mutations and inhibitor structure and will be useful in the design and development of the next generation of inhibitors.

eLife assessment

This important study evaluates the immunogenicity of 3rd and 4th doses of SARS-CoV2 vaccinations in patients with cancer. Their study is notable in that neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose. With the definitions and patient population better described, this paper would be of interest to those studying the effects of repeated COVID boosters on Omicron immunity.

eLife assessment

This paper proposes a new computational model for replay that is biologically realistic and accounts for a number of important phenomena in hippocampal replay. This is an important study with implications for multiple subfields. Whilst the majority of claims are convincingly supported by the data, simulation analyses for some crucial aspects of replay literature are currently incomplete.

eLife assessment

The authors developed a two-photon fluorescence microscope coupled with adaptive optics (AO-2PFM), allowing in vivo imaging of the mouse retinal structure and function. This new imaging system will be important for exploring normal retinal physiology and pathological alterations in retinal disease models.

eLife assessment

The overarching question of the manuscript is important and the findings inform the patterns and mechanisms of phage-mediated bacterial competition, with implications for microbial evolution and antimicrobial resistance. The evidence in the manuscript is, however, still incomplete and some of the conclusions made are not supported by the data. This manuscript would additionally be strengthened by a clearer narrative, to enable readers to more easily extract the key message this paper wants to convey.

eLife assessment

This is a well-done study to understand how Rab27 and its effectors regulate insulin secretion. The present work examines the relative hierarchy of exophilin-8 and melanophilin using single vs double knockouts and rescue experiments to show that melanophilin functions downstream of and potentially redundantly from Exo8. Imaging and protein co-localization studies were done in a rigorous way. The data are solid, and some additional data will make the work fully compelling. Overall this is an important study that sheds new light on the regulation of insulin granule exocytosis.

eLife assessment

This study presents a valuable finding on the role and function of the Gaq axis on the inflammatory response during decidualization essential for early pregnancy. The evidence supporting the claims of the authors is solid, although some of the methodology and data interpretation require further clarification and justification. The work will be of interest to reproductive biologists and clinicians.

eLife assessment

This important study reports Foxc2+ cells in the testis might be the true spermatogonial stem cells (SSCs). The data supporting this claim are solid and the finding, if proven true, would have a great impact on reproductive biology and stem cell biology as the genes responsible for maintaining the quiescent state of SSCs during spermatogenesis remain elusive.

eLife assessment

This paper reports valuable data on a classic model for cell fate specification in the C. elegans gonad. The data, though extensive, provide so far incomplete support for the major claims of the paper, especially regarding the functional significance of their conclusions. The paper will be of interest to developmental biologists studying transcriptional control of cell fate specification in animals, especially once issues around the functional significance of the condensates are resolved.

eLife assessment:

This manuscript describes development of a new algorithm for integrative analysis of multi-omics data. This work should be of potential interest to scientists performing bioinformatic pathway discovery in multi-omic datasets especially those that relate to signaling.

eLife assessment

This manuscript presents valuable findings that bring together two important topics in cell biology: the function of membrane contact sites and cell migration. The authors describe a role of the ER tether protein VAP-A in focal adhesion dynamics and cell motility. Although the authors present solid evidence to support some of the main claims of the paper, some of the other claims would benefit from stronger experimental support. Nonetheless, this paper will be of interest to those cell biologists and biophysicists working on adhesion, migration, and membrane contact site biology.

eLife assessment

This paper is of interest for skeletal biologists studying bone marrow stem/progenitor cells and bone remodeling. Using Adipoq-Cre-driven conditional deletion of Csf1 that encodes M-CSF and reanalyzing publicly available scRNAseq data, the authors recognize a subpopulation of bone marrow cells (i.e. AdipoQ-lineage progenitors) as an important source of M-CSF. The authors found that M-CSF production from these bone marrow cells influences the development of macrophages and osteoclasts as well as bone mass, including the bone loss associated with estrogen deficiency. This is a clearly written and nicely presented study that has potential to offer important new information regarding the source of M-CSF in the bone marrow.

eLife assessment

This study provides a valuable data resource to study the systemic effects of severe COVID-19. It shows compelling evidence that the transcriptional response to COVID-19 is coordinated across the body, and it highlights cell interactions between macrophages and endothelial cells in COVID-19. This analysis and the associated resource will be valuable to understand the pathogenic mechanism of long-COVID.

eLife assessment

This important study develops a new technical advancement in ex vivo live imaging of hematopoietic tissues to monitor blood cells in their native microenvironment. The new method for live imaging and tracking is compelling, and the strength and breadth of hematopoietic analysis are convincing. This work provides a very useful new system for immunologists and cell biologists, which will supply new perspectives on the system-level mechanisms of cell differentiation and innate immunity.

eLife assessment

This paper is of interest to immunologists conducting single-cell analyses of T-cell recognition. It provides a means of curating datasets to ensure T cell-antigen pairs are identified. The data generated through this method often suffers from a relatively high background, so the authors present a computational approach to enhance the signal-to-noise of this type of analysis. At this stage, it is unclear if the thresholds and filtering steps described by the authors can be generally applied to other datasets of different qualities than the one used here.

eLife assessment

This study presents a valuable mathematical model for the adaptive dynamics of cancer evolution in response to immune recognition. The mathematical analysis is rigorous and convincing, and overall the framework presented could be used in the future as a solid base for analytically tracking tumor evasion strategies. However additional discussion is needed to clarify certain gaps between the theory and cancer evolution in real systems. The work will be of interest to evolutionary cancer biologists and potentially it may also have implications for the design of clinical interventions.

eLife assessment

This study presents a valuable finding on the critical features and patterns of m1A modification and in neurons and OGD/R-treated neurons. Moreover, the authors identified m1A modifications on different RNAs and explored the possible effects of m1A modification on the functions of different RNAs via an integrated approach of omics and bioinformatics. The evidence supporting the claims of the authors is solid, although inclusion of more in-depth studies to analyze the transcription factors for the upstream regulation would have strengthened the study. The work will be of interest to neurobiologist and scientists in the field of RNAs.

eLife assessment

Scott et al use Drosophila as a model to study the sialylation pathway and its role in nervous system function. Surprisingly, they find that the critical substrate for sialylation, CMP-Neu5Ac, is 'outsourced' to glia. This significant study presents a new twist in mechanisms underlying protein glycosylation and uncovers a new layer in the complex interplay of neurons and glia.

eLife assessment

This work is an attempt to establish conditions that accurately and efficiently mimic a drought response in Arabidopsis grown on defined agar-solidified media – an admirable goal as a reliable experimental system is key to conducting successful low water potential experiments and would enable high-throughput genetic screening (and GWAS) to assess the impacts of environmental perturbations on various genetic backgrounds. The authors compare transcriptome patterns of plants subjected to water limitation imposed using different experimental systems. The work is valuable in that it lays out the challenges of such an endeavor and points out shortcomings of previous attempts. However, a lack of water relations measurements, incomplete experimental design, and a lack of critical evaluation of these methods in light of previous results render the proposed new methodology inadequate.

eLife assessment

This study links chromatin remodeling with antifungal drug resistance in Cryptococcus neoformans. The work is important because it reveals a new facet of how drug resistance can emerge and associates. The work presented is well done but the story is incomplete since there are questions about methods and association that need to be addressed. Establishing a link between chromatin remodeling and antifungal resistance is a finding that would be of interest to infectious disease researchers, cell biologists, and drug developers.

eLife assessment

This study uses a combination of compelling biochemical and genetic approaches to identify a highly mutagenic DNA polymerase, which drives a wide spectrum of mutations when overexpressed. The important findings advance the understanding of mutagenesis in mycobacteria. The work will be of interest to bacteriologists interested in mutagenesis and the emergence of drug resistance.

eLife assessment

There are many strengths in this paper that examines patterns of epididymal blood and lymphatic vasculature, supported by quantitative methods, and well-conducted 3D imaging studies (graphics and videos). Minor weaknesses include the lack of higher magnification images and the organization of image panels in some figures. Overall, this is a very important contribution to the epididymis research field.

eLife assessment

This study, of interest to population geneticists and evolutionary biologists alike, aims at investigating temporal variation in patterns of germline mutation during the evolution of human populations. The authors suggest that shifts in mutation spectra occur frequently, over a few thousands of generations, possibly as a consequence of changes in environmental exposure, or of genetic modifiers. There are several important aspects of methodology that need to be clarified, and several additional tests have to be done to confirm that the reported observations are not the result of methodological artifacts. The paper also overstates certain weaknesses of previously published papers on mutation spectrum evolution as well as the generation time hypothesis; correcting these oversimplifications would more accurately capture what the paper's new analyses add to the state of knowledge in these areas.

eLife assessment

This manuscript provides compelling evidence that macrophages transfer mitochondria to cancer cells and that transferred mitochondria stimulate proliferation in recipient cells. The usage an array of clever cell biology-based tools provides compelling evidence for these claims despite the difficulties associated with studying a relatively low probability event. Solid evidence supports the proposed model that transferred mitochondria induce proliferation by stimulating ERK signaling in a ROS dependent manner, although at present some aspects of the proposed model are incomplete. The work has broad significance for both mitochondrial biology and cancer biology as the authors show clear evidence of mitochondrial transfer in mouse models of human tumors.

eLife assessment

Opioid-induced respiratory depression is one of the side effects of opioid drugs. Although opioid overdose deaths are highly prevalent, our knowledge of the neural circuits underlying respiratory depression in the brainstem is far from complete. The present study used a variety of sophisticated experimental techniques to convincingly reveal the identity of brainstem components that are part of the neural circuits involved in the mediation of opioid respiratory effects, together with defining potential synaptic underlying mechanisms. They focused on two regions of the brainstem, namely the Kolliker-Fuse and the preBötzinger Complex, and proposed a combination of three complementary processes at pre- and post-synaptic sites in both KF and preBötC regions to explain respiratory depression linked to opioid exposure. This study provides very important findings on the circuitry involved in opioid-induced respiratory depression, and the present results are of broad interest to the respiratory control research community, as well as medically relevant.

eLife assessment

Candida morphogenesis is important for virulence. This study provides important new information as to how C. albicans regulates the switch from budding to hyphal morphology. Their results identify transcription factors involved in the process of hyphal morphogenesis in the host. The results are convincing and will be interesting to scientists in the fields of medical mycology and cell biology.

eLife assessment

This manuscript analyzes large-scale Neuropixels recordings from visual areas and hippocampus of mice passively viewing repeated clips of a movie and reports that neurons respond with elevated firing activities to specific, continuous sequences of movie frames. The important results support a role of rodent hippocampal neurons in general episode encoding and advance understanding of visual information processing across different brain regions. The strength of evidence for the primary conclusion is solid, but some technical limitations of the study were identified that merit further analyses.

Immu_Constructor - first: element - rest: iList, able to take in EMPTY to end the list

eLife assessment

This study makes valuable observations about the representation of "value" in the mouse brain by using a nice task design and recording from an impressive number of brain regions. The combination of state-of-the-art imaging and electrophysiology data offer solid support for the authors' conclusions. If more thorough statistical analysis of the response of neuronal populations supports the claims, the paper will be of interest to a broad audience of neuroscientists interested in reward processing in the brain.

eLife assessment

This study examines the inflammatory and immune response to live E. coli bacterial infection in neonatal and juvenile mice. Important information is described on the roles of Class II MHC and interferon responsive genes in regulating the host response to infection. This study will inform future efforts to further elucidate the impact of bacterial infections on lung development.

eLife assessment

This is a valuable study showing that fast, but transient, modifications of the synaptic efficacies, alone, can support the integration of information over time. Convincing supportive evidence is provided by showing that feed-forward networks, when equipped with such short-term synaptic modulations, can successfully perform a variety of temporal integration tasks at a performance level comparable with that of recurrent networks. These results will be of interest to both neuroscientists and researchers in machine learning.

eLife assessment:

Bone marrow stromal cells (BMSCs) can differentiate into a variety of cell types such as osteoblasts, chondrocytes, and adipocytes. The authors of this important study provide compelling and strong evidence that ablating O-GlcNAc transferase (OGT) in BMSCs impairs bone formation but promotes marrow adiposity. The results show that the balance of osteogenic and adipogenic differentiation of BMSCs is controlled by reciprocal O-GlcNAc regulation of lineage-specifying transcription factors, and highlights the importance of an intracellular glycosylation process of specific proteins in bone formation and bone marrow adipocytes.

eLife assessment

This theoretical work deals with the problem of homeostasis of protein density within cells, relying on the Pump and Leak model.  The model makes predictions both for growing and senescent cells, which they compare to experimental data on budding yeast. The work extends previous works and makes biologically-relevant predictions, which will be of interest to both theorists and experimentalists interested in cell physiology.

eLife assessment

The analysis of 89,000 independent somatic mtDNA mutations provides compelling evidence that allows the authors to refute the idea that reactive oxygen species (ROS) are a main driver of mtDNA mutagenesis, although ROS effects may still be tissue-dependent. These are fundamental results with convincing evidence, and they should appeal to a broad audience. The discovery of transversion mutations (C>A/G>T and C>G/G>C), which previously were assumed to be almost nonexistent, will nevertheless require additional validation.

eLife assessment

The study presents analyses linking cell-types to monogenic disorders using over-expression of known disease-associated genes in single-cell data to identify 110 disease-affected cell types for 714 Mendelian diseases. Overall this important study combines multiple data analyses to quantify the connection between cell types and human disorders. While some of the analyses are compelling, updates to the method are needed to ensure that statistical inference is appropriately stringent and rigorous.

eLife assessment

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

eLife assessment

This paper presents a valuable advance in the ability to manipulate the integrity of the barrier between endothelial cells. A wide range of data are presented, offering solid support for the effectiveness of the method. This work is likely to attract a diverse audience of both cell biologists and researchers developing tools to manipulate cell and tissue function.

eLife assessment

This important study investigates the dynamic activation mechanism of a key mitotic kinase complex, Aurora B/INCENP. The method of generating specifically phosphorylated forms of the complex is elegant, supporting a compelling biochemical analysis of how these sites synergistically activate Aurora B. However, the limitations of the molecular dynamics approach and how these models compare to previous structural studies are incompletely addressed. This work will be of interest to cell biologists and biochemists studying cell division and kinase regulation.

eLife assessment

This important study advances our understanding of the composition and circuit organization of the preBötzinger complex (preBötC)-the brainstem region that generates the respiratory rhythm and coordinates breathing with different motor and physiological behaviors in mammals. The reviewers agreed that the evidence supporting the conclusion that the preBötC is composed of a segregated subgroup of output neurons that modulates orofacial muscle activity is compelling and based on technically elegant, state-of-the-art combinatorial dual viral transgenic and optogenetic approaches in rats. After the cytoarchitectonic analyses are strengthened, the work will be of interest to neuroscientists and physiologists working on the neural control of breathing and other motor systems.

eLife assessment

This study on snapping shrimp morphological weaponry presents important findings on trade-offs in investment in costly weaponry traits as related to body size and reproduction. Convincing evidence is based on the collection of an exceptional number of fields samples, the inclusion of three shrimp species, and the measurement of numerous morphological and behavioral traits. The evidence shows that there are size-dependent trade-offs, where males and females differ in weapon investment, as weapons are beneficial to males but expensive for females. The findings will be of broad interest to evolutionary biologists and researchers working in the field of animal behavior.

eLife assessment

This valuable study carried out a genetic screening of Drosophila lines expressing wild-type or ALS/FTD mutations of ubiquilin 2, and identified several suppressors and enhancers of ubiquilin 2 phenotypes. The study particularly focused on two genes involved in axon guidance pathways, unc5 and beat-1b. The evidence supporting the conclusions is solid, although some of the presented data are unrelated to the main findings, which detracts from the focus of the work. This work will be of interest to a broad audience studying ALS/FTD and neurodegenerative diseases.

eLife assessment

This fundamental study describes the structure-based design of novel hybrid inhibitors targeting a human sodium channel which is a pain target. Exceptionally strong evidence for key claims was produced with a structural biological pipeline for iterative structural determination of drugs complexed with an engineered sodium channel. This work is expected to be of interest to biophysicists, drug developers, neurobiologist, and pain researchers.

eLife assessment

This valuable study provides a synthesis of sector models for cellular resource partitioning in microbes, and shows how a simple flux balance model can quantitatively explain growth phenomena from numerous published experimental datasets. The study is overall convincing, although there are a few incomplete points regarding parameter values (justification and discussion of robustness). This work should be of interest to the microbial physiology community.

eLife assessment

In this useful and potentially important manuscript, Mazanek and colleagues combine computational analysis and in vitro experiments to develop a comprehensive analysis of the ability of pyrin-only proteins (POPs) to inhibit inflammasome assembly. The results lead the authors to propose that a mixture of favorable and unfavorable interaction surfaces is required for a POP to inhibit a given inflammasome component. The results presented are solid, but additional experimentation is required to fully justify the authors' model.

eLife assessment

Mutations in mitochondrial genes can lead to deafness but the mitochondrial biology of sensory hair cells is not well understood. In this study, high-resolution imaging of mitochondrial development in sensory hair cells of normal and mutant zebrafish lateral line systems was described. The authors provide evidence that the formation of the mitochondrial architecture requires normal hair cell activity. This paper is of potential interest to researchers interested in metabolic homeostasis and sensory hair cell biology.

eLife assessment

This important work presented is of interest to the electron microscopy community, which expanding to more and more cell biologists. The field has long searched for a suitable method to combine the pristine preservation of vitrified samples with a volumetric imaging modality that reveals subcellular architecture at sufficient contrast for ultrastructural analyses, and the authors describe here the use of novel ion beams for imaging cellular samples in three dimensions, concluding that one of the four plasma sources tested produces the highest quality images. This allows them to provide several recommendations for imaging along with software for improving collected images. This approach should be very useful for addressing many biological questions.

eLife assessment

This manuscript reports important and valuable new data about the intriguing role of the lncRNA Charme during cardiac development. Whilst the majority of claims are convincingly supported by the data, the evidence for the cardiac phenotype and the mechanism by which Charme/MATR3 interacts is currently incomplete and requires additional experimental support. This paper is of general interest to cardiac developmental biologists as well as to anyone studying non-coding RNAs.

eLife assessment

This valuable work provides insight into how Plasmodium falciparum optimises the balance between infection of the human host and investment in onward transmission to the mosquito. Based on the appropriate and validated methodology most of the results are convincing, nonetheless, some conclusions are incomplete and require further support.

eLife assessment

A small proportion of the genomes of humans whose ancestors lived outside Africa traces back to an interbreeding event with Neanderthals. While we know that selection has generally acted to remove Neanderthal ancestry, intense interest has focused on understanding the contribution to current human phenotypic variation. This paper uses a new set of approaches to carefully quantify this contribution, taking into account various complicating factors. The work will be of interest to colleagues in human evolution and evolutionary biology more generally.

eLife assessment

This manuscript will be of interest to centrosome and cilia cell biologists. It evaluates the in vivo and in vitro role of PCM1, and by extension, centriole satellites in ciliogenesis. The major strength of this study is the detailed characterisation of Pcm1-/- mutant mice, which reveals a role for PCM1 in biogenesis of specific types of cilia, such as motile cilia on ependymal cells. The claims are generally well supported by the data, but the mechanistic basis for the cell-type specific requirement for PCM1 in ciliogenesis remains to be fully clarified.

eLife assessment

In the present study, the authors discovered the inhibitory neurons that are potentiated during the repetitive visual stimuli and control neurons that transmit looming information to evoke escape responses. Thus, the study elucidated a principle of habituation using a model vertebrate zebrafish.

eLife assessment

The RNA-binding protein Tristetraprolin (TPP) regulates the abundance of mRNAs encoding proinflammatory cytokines. The study by Scinicariello and collaborators examined mechanisms regulating the turnover of TTP in cultured cells and identified the ubiquitin E3 ligase HUWE1 as a regulator of TPP degradation. The conclusions are largely supported by the cellular and biochemical experiments. This paper thus implicates the HUWE1-TPP axis in regulating macrophage inflammatory responses at the post-transcriptional steps.

eLife assessment

This manuscript reports valuable findings regarding the evolution of nitrogenases through ancestral sequence reconstruction and resurrection. The results are solid and support the conclusions of the study, and highlight the historical constraints that have been acting on this enzyme. The findings will be of interest for people interested in enzyme evolution in general and particularly for those interested in the evolution of nitrogenases.

eLife assessment

This is an important paper that combines comparative analysis and experimental assays to investigate the role of protein-coding and regulatory changes at TRNP1 in mammalian brain evolution. The evidence supporting a contribution of TRNP1 is convincing, although the link between protein-coding changes and trait evolution is stronger and more readily interpretable than the data on gene regulation. The work will be of interest to researchers in the areas of mammalian evolution, brain evolution, and evolutionary genetics.

eLife assessment

This important work identifies new proteins and outlines the interactions between molecular players that control diet-induced plasticity in sensory neuron function in the Drosophila taste system. The authors provide solid evidence in support of their working model and open clear avenues to follow up on downstream molecular mechanisms.

eLife assessment

During meiotic prophase I, protein complexes essential for crossover recombination are distributed non-randomly along chromosomes. With mathematical modelling and based on results from super-resolution microscopy, the authors introduce a second type of coarsening of protein ensembles between chromosome axes and nucleoplasm between chromosomes and nucleoplasm to support the random distribution of the complexes in the synapsis-defective mutant. The new model is interesting and may be applied to other chromosomal events accompanied by the formation of large protein ensembles on the chromosomes. The work is of interest to colleagues studying recombination and meiosis.

eLife assessment

This convincing demonstration of intercellular transfer of material and its subsequent function in the acceptor cell lends important evidence for the membrane tubular systems' role in cell communication. Importantly a fusogenic protein, syncytin, is shown to play a role in providing an open connection between the cytoplasms of both the acceptor and donor cells. The work has implications for how cells can influence each other's functions.

eLife assessment

The study presents a useful finding on a potential link between two common public health issues, namely HPV infection and osteoporosis. The evidence supporting the claims of the authors is incomplete as a more robust statistical methodology would have strengthened the study. The work will be of interest to epidemiologists working on associations of infectious diseases with other health issues.

eLife assessment

This is a valuable study that uses an innovative approach to show how the statistics of sound stimulation influence neural coding in an experience-dependent fashion in the developing barn owl brain. The paper will therefore be of interest to the fields of developmental and sensory neuroscience. In its present form, however, the evidence presented to support the main claims of the paper is incomplete and could be strengthened in various ways.

eLife assessment

This fundamental work substantially contributes to our understanding of the mechanisms underlying doxorubicin-induced cardiotoxicity. The evidence supporting the role of EPAC1 inhibition in this context is compelling, using rigorous molecular biology techniques. The work will be of broad interest to scientists and clinicians working in the field of oncology and cardiovascular medicine.

eLife assessment

This extraordinary study mapped the circuit architecture of a brain module for learning and memory in the octopus brain. In particular, one gyrus of the Octopus vulgaris brain vertical lobe was imaged with volume electron microscopy, its neurons reconstructed and their synapses mapped. The acquisition of this pioneering data set was followed by a very convincing analysis of the circuits supporting learning and memory, and therefore behavioral plasticity, in this animal. The data and findings establish an important point of comparison with analogous brain structures in other organisms, such as the vertebrate cerebellum and the arthropod mushroom body, offering a new neural circuit architecture to support the study of behavior and inspire the design of artificial neural networks.

eLife assessment

Overall, this manuscript provides fundamental advances to our understanding of the ancestry of insect gustatory and olfactory receptors, by identifying new members of these two related ion channel families in distant species. The approaches to compare protein structure are exceptional and use cutting-edge techniques, going beyond the commonly used approaches. The authors suggest that the family of odorant and gustatory receptors have a common origin and share structural homology in very distant organisms, although the possibility of convergent evolution still exists. This work will serve as a reference for scientists working on insect olfaction and for those working on molecular evolution.

eLife assessment

In this important article, the authors characterize ancient DNA from maize unearthed in archaeological contexts from Paredones and Huaca Prieta in the Chicama river valley of Peru, recovered by painstakingly controlled excavation. The genetic evidence is compelling, albeit from a small sample size, but the dating evidence, despite the excellent archaeological context, is inadequate. Since the age of the samples is so important for the inferences, the individual radiocarbon determinations should be subject to further scrutiny.

eLife assessment

This study makes a fundamental observation about the role of activity in the mouse thalamus on scalp-recorded voltage fluctuations. The novel approach and sophisticated analysis of neural signals provide compelling support for the authors' observations. This work will likely be of broad interest to neuroscientists.

eLife assessment

This important bibliometric analysis shows that authors of scientific papers whose names suggest they are female or East Asian get quoted less often in news stories about their work. While caveats are inevitable in this type of study, the evidence for the authors' claims is convincing, with a rigorous, and importantly, reproducible analysis of over 20,000 articles from across 15 years. This paper should be of interest to all scientists and science journalists, as well as to those who study science communication.

eLife assessment

The manuscript provides valuable insights into the regulatory role and mechanisms of the spectrin cytoskeleton in mechanotransduction in Drosophila. The data are compelling in establishing the role of spectrins, but questions remain regarding some of the precise mechanisms involved. The work will be of interest to cell and developmental biologists, particularly those who focus on mechanotransduction and the cytoskeleton.

eLife assessment

This is a valuable initial study of cell type and spatially resolved gene expression in and around the locus coeruleus, the primary source of the neuromodulator norepinephrine in the human brain. The data are generated with cutting-edge techniques, and the work lays the foundation for future descriptive and experimental approaches to understand the contribution of the locus coeruleus to healthy brain function and disease. However, due to small sample size and the need for additional confirmatory data, the data only incompletely support the main conclusions presented here. With the strengthening of the analyses, this paper, and the associated web application, will be of great interest to neuroscientists working on arousal-based behaviors and neurological and neuropsychiatric phenotypes.

eLife assessment

The study integrates proteomic and transcriptomic analyses of human stem cell-derived cortical brain organoids, uncovering posttranscriptional regulatory mechanisms for a specific gene module enriched in ribosomal genes. The data analysis is robust and the evidence supporting the conclusions is compelling. The work provides a valuable resource to developmental neurobiologists and highlights a new level of regulation that may be important in cortical development.

eLife assessment

Based on two room-temperature X-ray crystallographic screens of PTP1B phosphatase against two sets of chemical fragments, and by comparing the results from a previous cryo screen, the authors report the important observation that, in addition to overlapping but non-identical sets of hits compared to the cryo screen, the room-temperature screens lead to significant differences in terms of binding sites and poses for some of the hits. The study provides compelling support for the use of room-temperature X-ray crystallography in early-stage drug discovery and highlights that temperature should be used as a parameter in efforts to extract additional insight from such analyses.

eLife assessment

It is well known that Tfr cells have the capacity to preferentially suppress autoimmune antibody responses, but it is not known why such specificity exists. This important work provides new information as to how self-reactive antibody responses are regulated and has significant implications to the fields of autoimmunity and vaccine design. The overall experimental designs and the data quality are largely convincing, but the authors should include more careful controls.

eLife assessment

The authors have combined their two recently developed novel approaches to Mendelian randomization studies (1) Lifecourse mendelian randomization which relates genes to the outcome, eg obesity, at different stages of life, and (2) Tissue partitioned mendelian randomization to determine if there are different genetic effects in different tissues. They have successfully combined these two approaches to investigate the influence of adiposity on circulating leptin in childhood and adulthood to demonstrate the value/proof of concept of combining these two techniques. This is very clearly presented and well-conducted work showing both new methodology and compelling results and will be important to both those who use Mendelian randomization and those who are interested in obesity.

eLife assessment

This study provides important insights on the developmental process and functional heterogeneity of liver ILC1s, especially how IL-7R+ and IL-7R- ILC1s are generated. Authors present compelling evidence on the dependence of ILC1s on IL-7R- precursor and their reliance on IL-15 to develop cytotoxic functions. The work will be of broad interest to immunologists and liver biologists.

eLife assessment

This important study uses elegant in vivo experiments combined with expression data on an imprinted gene, Dlk1, to demonstrate its role in pituitary gland size in mice. The evidence supporting the claims of the authors is solid, although the inclusion of both sexes and a rescue model would have strengthened the study. The work will be of interest to developmental biologists working on the pituitary and hypothalamus.

eLife assessment

This study represents an important step toward unifying two strains of inquiry, one related to the functional role of hippocampal theta oscillations and one related to the behavioral impact of engram reactivation, and thus the findings have implications for our understanding of memory that will impact multiple subfields. In combination with additional context from the literature, the important findings are supported by solid evidence supporting the conclusion that memory recall operations occur preferentially at a specific phase of theta.

eLife assessment

This is an interesting study investigating a mechanism for the elimination of aberrant cells from epithelial tissues dependent on the contractility of the interface between cells with different fates regulated by JNK activity. This work offers insights into robustness and error correction mechanisms that help understand cell-cell competition and the origin of tumors. The study should be relevant for cell, developmental and cancer biologists.

eLife assessment

The paper aims to provide structural and functional information on the hepatitis E virus replication complex. The study will be of interest to a broad number of people studying at virus replication, since the replication complex are targets for therapeutic interventions.

eLife assessment

As digested food moves through the intestines specialized epithelial cells (called Enterochromaffin Cells or EECs) sense and respond to the constituent chemicals. The current work utilizes single-cell transcriptomic analyses and intersectional approaches to define and genetically manipulate subsets of EECs. Key findings are that direct stimulation of EEC subtypes influences key aspects of feeding, specifically gut transit, ingestion, and food preference.

eLife assessment

This study provides evidence that the Stromalin Antigen (SA) proteins known to ubiquitously interact with cohesins, retain their capacity to bind CTCF and chromatin in the absence of RAD21 cohesin component. Authors imply that SA has an independent function in addition to its joint role with RAD21 and CTCF, providing experiments that make them suggest that SA proteins organize around RNA:DNA regions in the absence of cohesin, contributing to R-loop regulation and linking chromatin on structure to cohesin loading. The paper is a nice piece of work of interest to readers in the field of cohesin biology and genome organization. However, additional, experiments would be required to strengthen some of the conclusions.

eLife assessment

Signaling mediated by Semaphorins and their receptors Nrp1 and Nrp2 is crucial for regulating the morphology of dendritic spines and dendritic arborization during development. In this manuscript, the authors found that the post-translational modification of S-palmitoylation dictates the subcellular localization and trafficking of Nrp2, but not Nrp1, and is required for Sema3F-dependent pruning of spines on the apical dendrites of layer V cortical neurons. The study provides important insights into how semaphorin signaling achieves spatial specificity on diverse downstream cellular events.

eLife assessment

This fundamental study from Gold and colleagues substantially advances our understanding of the synaptic targeting of a major postsynaptic protein kinase, CaMKII, which is the basis for the persistence of excitatory synaptic strength in synaptic plasticity. The evidence supporting the claims of the authors is convincing, with cell biological, biochemical, as well as structural biological approaches. This work will be of interest to cell and computational biologists working on learning/memory.

eLife assessment

This study advances the understanding of metabolic regulation underpinning self-renewal of stem cells. The authors report that glutamine-dependent acetylation of the kinase PASK regulates its nuclear localization. Evidence is provided that nuclear PASK binds and disrupts Wdr5 association with the anaphase-promoting complex/cyclosome and is a trigger for the activation of myogenic programs in cultured cells. The study will be of interest to an audience in the areas of stem cells, regeneration and metabolic signalling.

eLife assessment

In this work, Verstegen and colleagues established an in vitro system and describe human B cell differentiation pathways via germinal center B cells towards plasma cells by performing single-cell analysis of in vitro stimulated human B cells. The study provides solid evidence toward establishment of in vitro model for B cell differentiation. This study may be valuable in differentiation of primary naive B cells into ASC ex vivo and will be of interest for immunologists with emphasis in B cell biology.

eLife assessment

The authors state that there is scant experimental evidence of divisive normalization of neural responses in the human brain. They used fMRI BOLD response to high-level stimuli to explore normalization in V1, object-selective (LO and pFs) and category-selective regions (EBA and PPA) as well effects of attention on cortical responses. Specifically, the authors first test the degree to which BOLD responses to body parts and houses exhibit responses predicted by a non-linear normalization model, compared to two linear models (weighted sum and weighted average). They find that responses, when considering responses to one vs two stimuli, are best fit with the normalization model. They then suggest that object-based attention effects can be better accounted for by a normalization model of attention, compared to attention variants of the aforementioned models. The paper could potentially be an important contribution to the fields of perceptual and cognitive neuroscience, but the conclusions are not sufficiently supported by the data at this stage. Several theoretical and methodological concerns limit the conclusions of this study.

eLife assessment

This manuscript describes a mouse model of a human mitofusin 2- related lipodystrophy, generated by knockin of Mfn2 R707W, and reports data suggesting adipocyte-specific effects involving the integrated stress response, mTorc signaling, and epithelial-mesenchymal transition pathways. The data will be important for understanding how mitochondria can be affected in tissue-specific manner to contribute to metabolic disease.

eLife assessment

This study describes an interesting approach using PEGylated isoprenaline to selectively activate beta-adrenergic receptors in the surface sarcolemma of ventricular myocytes. While the concept is compelling, and the core of an interesting and impactful study is presented, the results are preliminary and incomplete at this stage, and would benefit from more rigorous validation of the approach. The work will be of interest to cardiac cell biologists and pharmacologists.

eLife assessment

This study thoroughly characterizes the morphology of an interesting folded membrane structure that links the epidermis to the cuticle in C. elegans. This structure, here named the meiosome, has been noted by several previous researchers. The study would be strengthened by providing additional support to the notion that the VHA-5::GFP transgenic reporter, used by the authors, faithfully labels the meisosome, and by stronger evidence that meiosomes indeed serve as attachment platforms between the cuticle and the epidermis.

eLife assessment

This fundamental and timely study provides insights into the structural dynamics of several relevant mutant forms of SARS-CoV-2 spike protein, including the most recent omicron variant. The hydrogen/deuterium-exchange studies provide compelling evidence for the stabilization of the spike stalk in conjunction with increased dynamics of the N-terminal domain, where binding to the ACE2 receptor occurs. These results have profound implications for the development of small molecule inhibitors of the spike protein-ACE2 receptor interaction.

eLife assessment

This paper reports a bet hedging strategy in bacteria based on chromosomal duplications and rearrangements that confer advantages in certain growth conditions. The work is of fundamental importance for understanding the role of genetic and biological variation in bacteria. The experimental work is exceptionally strong and convincing. The paper will be of interest to a broad audience including bacteriologists, geneticists and evolutionary biologists.

eLife assessment

This study provides potentially important insights into the role of mesenchymal stem cells in CAR-T therapy, and suggest that the STC1 gene could be a key factor in influencing the efficacy of this treatment. This finding has the potential to improve current therapeutic strategies based on cell therapy and may indicate new biology related to how mesenchymal stem cells affect the immune state within the tumor microenvironment. Further research is necessary to clarify the signaling pathways, but the data presented by the authors are generally well-supported and convincing.

eLife assessment

This manuscript makes a valuable contribution to the field. The authors have developed a compelling network model to study mechanisms for the emergence of oscillations in the beta range in the primary motor cortex during movement preparation, and their propagation as traveling waves across the cortical sheet. The model is able to recapitulate several features of motor cortical activity acquired experimentally. Due to the recent results suggesting a functional role for traveling waves, it is of great interest to discover the mechanisms underlying such phenomena, and this work is an interesting step in that direction. However, the evidence for the reported new insights is incomplete at this stage, due to some weaknesses that remain to be addressed.

eLife assessment

This paper will be of fundamental interest to many sub-disciplines of neuroscience, ranging from cognitive neuroscientists to cellular neuroscience. It provides compelling and substantial brain and behavioral evidence of a novel intervention that can boost long-term memory. The key claims of the manuscript are generally well supported by the data, though the correlational nature of the data in different types of experiments raises some issues about interpretation.

eLife assessment

The authors present interesting information regarding the possibility of targeting the oncogenic K-Ras(G13C) mutant with nucleotide competitors. The experiments represent a solid support of the claims and show that this approach can work despite concerns about the high affinity of GTP and its high cellular concentration. These results will be of high interest for all working in the Ras field and in targeting oncogenes with small molecules. A weakness of the manuscript is the lack of direct physiological insights.

eLife assessment

This manuscript will be of interest to a wide range of cell biologists interested in understanding cell-cell communication. The discovery that an engulfing cell can control the extrusion and degradation of large vehicles from its target cell is important and intriguing. The authors present compelling data that show that exophers (large neuronal extrusions proposed to discard toxic cargo) are taken up by adjacent hypodermal cells, split into smaller fragments, and eventually degraded by lysosome fusion. The authors identify a number of small GTPases and accessory components, as well as the phagocytic receptor (CED-1) and the likely eat-me signal (phosphatidylserine).

eLife assessment

The manuscript proposes a mechanism by which different S-adenosylmethionine (SAM) synthase enzymes exhibit specificity towards target sequences, thereby proposing a novel layer of control over H3K4 trimethylation (H3K4me3). Such specificity is demonstrated in the context of responses to heat stress for two Caenorhabditis elegans SAM synthase enzymes, supporting the existence and importance of this novel mechanism of epigenetic control.

eLife assessment

The authors document an in-depth analysis of introduction patterns of 5 variant waves in Mexico. This is an important analysis and dataset since the genomic epidemiology of SARS-CoV-2 in Mexico is generally understudied, and this paper contributes important missing information. The phylogenetic analyses are solid and well-presented, but the lack of detail regarding the collection of samples across Mexican states makes it difficult to evaluate conclusions about the relationship between observed viral lineages and local case counts. Additionally, in its current form, the manuscript is mostly descriptive, without clear hypotheses tested or discussion of implications.

eLife assessment

This important work advances our understanding of the factors that affect the speed of colour evolution in birds and the resulting diversification patterns. It provides compelling evidence that more complex plumage coloration can lead to rapid colour evolution in kingfishers, and could pave the way for more comprehensive analyses that fully embrace the multidimensional nature of colour variation. Hence, the results will be of broad interest to ornithologists and evolutionary biologists in general, once the authors have streamlined the theoretical framework and explained the novel methodological approaches in more detail.

eLife assessment

This valuable manuscript describes a fully automated touchscreen cognitive testing system for rats that reduces the length of training required to learn a task and eliminates the need for daily handling. These features make it possible to assess cognitive behaviors in conjunction with other neurobehavioral paradigms during adolescence, an important advance in the field. The data convincingly show that cognitive flexibility does not promote susceptibility to severe weight loss in the activity-based anorexia (ABA) paradigm. However, support for the claim that cognitive deficits seen in rats that had been exposed ABA adequately capture an important clinical feature of the pathophysiology of anorexia nervosa is incompletely supported.

eLife assessment

This study provides fundamental insights into the relationship between single neuron activity in superficial layers of the cortex and electrical signals recorded at the cortical surface. Based on solid measurements, the results indicate a weak correlation between individual layer 2/3 neuron activity and multiunit activity recorded at the surface, whose interpretation could be reinforced. In particular, a strong contribution of layer 1 axons to surface signals is suggested but relies on incomplete evidence.

eLife assessment

This manuscript provides valuable insight into the molecular mechanism by which destabilized mitochondrial proteins 'clog' import channels and contribute to the pathologic mitochondrial and cellular dysfunction implicated in human disease. The evidence supporting this conclusion is solid, utilizing yeast, mammalian cell culture, and mouse models. However, additional characterization of import clogging in the mammalian model systems would strengthen this study. This work will be of broad interest to researchers in the fields of mitochondrial biology, protein quality control and proteostasis.

eLife assessment

This manuscript tests an important assumption about how sensory information is processed and used to guide motor choices. The widely held assumption is that sensory-motor circuits are capable of integrating evidence, but the validity and generality of this 'principle' have been recently questioned by studies suggesting that other computational operations may lead to similar psychophysical results, mimicking integration without actually performing it. This study makes a compelling case that the integration assumption was likely correct all along and that the model mimicry can be easily disambiguated by using appropriate sensory stimuli and task designs that permit rigorous analyses.

eLife assessment

This important study provides convincing evidence that locus coeruleus is activated during visuomotor mismatches. Gain of function optogenetic experiments complement this evidence and indicate that locus coeruleus could be involved in the learning process that enables visuomotor predictions. This study therefore sets the groundwork for the circuit dissection of predictive signals in the visual cortex. Loss-of-function experiments would strengthen the evidence of the involvement of locus coeruleus in prediction learning. These results will be of interest to systems neuroscientists.

eLife assessment

The paper provides a valuable, in-depth mathematical analysis of the coevolutionary dynamics resulting from a coupling of players' strategies and (collective) risk, as well as illustrative numerical simulations of the system's trajectories for different starting conditions. It is therefore a solid contribution to our understanding of how cooperation can be sustained when there is feedback between individual decisions and the global risk of disaster. This paper will be of interest to scientists working on mathematical biology/ecology, and more generally various aspects of human decision-making, the interplay between human decisions and the environment, and public goods provision.

eLife assessment

This study addressed a long-standing question in biology - the role of fever during infections. Using innovative research strategy, the authors provide compelling evidence for the positive impact of higher body temperature on both pathogen clearance and tissue repair. This study thus provides important advances in our understanding of host defense and its connection with physiology and behavior.

eLife assessment

This manuscript reports novel and important findings on the mechanisms of regulation of CRAC channels. Collectively, the work represents an important conceptual advancement, showing that stromal interaction molecule-1 is not necessary for Ca2+-dependent inactivation of the Orai1 channel and that Orai1 likely contains a Ca2+ sensor for autoregulatio. The experiments are carefully conducted, and the data is of high quality and support the major conclusions of the authors.

eLife assessment

This important paper advances the understanding, in the model plant Arabidopsis thaliana, of the molecular basis of the promotion of flowering in the spring by exposure to winter cold through a process known as vernalization. In Arabidopsis, there are two classes of long non-coding RNAs produced only when plants are in the cold, and this work provides compelling evidence that the cold-induced expression of one of these (COOLAIR) involves C-repeat binding factor proteins that bind to cognate binding elements in the COOLAIR promoter, but also that COOLAIR is not required for the vernalization-mediated promotion of flowering under standard laboratory conditions in which the vernalization response is measured.

eLife assessment

This study provides fundamental insight into the functional impact of CDK4 inhibition on cells in the tumor microenvironment, which is of high importance and interest to the field. The compelling conclusion that proliferative exhausted T cells are associated with response in HPV+ head and neck cancer is supported by the cohort of 14 patients with paired tumor and adjacent normal tissue and rigorous bioinformatic analysis of nearly 50,000 single CD3+ T cell transcriptomes. This work will be of interest to researchers across tumor types and in other immunological fields of study.