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.

eLife assessment

In this work, the authors provide convincing evidence about the existence of two distinct osteoclast populations with specific expression profiles and properties and show that the probiotic yeast S. boulardii may be useful in managing inflammation-mediated bone loss, including estrogen deprivation-mediated osteoporosis. The reported study aims to bring the concept of heterogeneous osteoclasts into a proof-of-principle therapeutic application, which may mean that the use of probiotics might combat osteoporosis towards a better bone quality than current therapies. The molecular mechanism of how the probiotic yeast S. boulardii treatment acts via the receptors remains obscure since it might act via changes in the gut permeability or by components directly released by the fungus.

eLife assessment

This paper will be of considerable interest to researchers studying the psychological and neural basis of variation in prosocial behavior. The authors use a sophisticated combination of computational modeling and EEG to show that variation in generosity produced by changes in context (i.e., disadvantageous vs. advantageous inequality) and variation due to individual differences in concern for others both seem to occur early, during the perceptual or valuation stage of a choice, rather than later on during choice comparison. However, these two sources of variation also appear to operate through distinct mechanisms during this stage of processing, which spurs further questions about the drivers of human prosocial behavior.

eLife assessment

The authors examine the function of Tomosyn, in dense core vesicle fusion in neuronal cultures from mice expressing conditional alleles of tomosyn and tomosyn-2. The authors show here that while loss of tomosyns did not affect dense core vesicle exocytosis, it reduced the expression of several key dense core cargos, including BDNF. However, "rescue" experiments are needed to validate the specificity of the effects.

eLife assessment

This study presents valuable comprehensive data that underpin the enhanced ventricular arrhythmogenesis in elite trained athletes. The study is logistical challenge and the multiscale approaches used is a strength of the study. The data presented are strong and support most of the authors' claims.

eLife assessment

The study provides a recurrent network model of M1 for center-out reaches. The "neurons" in the model show uncorrelated tuning for movement direction during preparation and execution with dynamic transition between the two states. The continuous attractor model provides an interesting example of flexible switching between neural representations.

eLife assessment

This study describes the use of a new and valuable tool, namely phage display of Plasmodium falciparum proteome-wide peptides, for profiling of antibody targets. The study, conducted using plasma from Ugandan children and adults, represents an important aspect of naturally acquired antibodies with seroreactive responses to the intra-and inter-protein repeat regions. The results are, however, so far incomplete, and confirmatory data that antibodies to inter-protein repeat motifs do cross-react are needed.

eLife assessment

This highly important paper uses a Bayesian linear regression approach in a clinical trial to establish that ivermectin does not increase the clearance rate of SARS-CoV-2 relative to no study drug. The strength of evidence is compelling. Particular strengths are that the paper is clearly written, a novel and important adaptive study design, and linear mixed modeling to account for participant heterogeneity. The work will be of interest to clinicians, statisticians, and public health departments.

eLife assessment

In this useful study, the authors utilize state-of-the-art computational methods complemented with some experimental validation to investigate the dynamics of flexible loops of the L1 Metallo-β-lactamase enzyme, resulting in a better understanding of the various conformational states useful for the rational design of superior β-lactamase inhibitors/antibiotics. The evidence supporting the claims is solid, and the work will be of interest to computational, experimental biologists, and drug designers working on antibiotic resistance.

eLife assessment

This manuscript is of potential interest for a broad spectrum of researchers working on the nervous and muscular systems. By combining transcriptome and proteome analyses, the authors reveal the molecular makeup of the different compartments of the muscle spindle. The work is novel, makes important observations, and is well-executed and methodologically convincing to provide the field with new tools for dissecting the development and function of the muscle spindle.

eLife assessment

In this manuscript, the authors devised a new, useful mRNA-imaging approach by combining MS2 and SunTag labeling systems. The authors showed that this new method can be used to image the activation of gene expression and endogenous mRNA dynamics in live C. elegans. While the application in C. elegans has great future potential, this study is incomplete because it lacks essential characterization of the new imaging method to demonstrate that it does not interfere with RNA expression.

eLife assessment

Zhang et al. present convincing data describing a role for Polo-like kinase PLK-2 in restricting the activity of Chk2 kinase and coordinating synapsis of homologous chromosomes with the progression of meiotic prophase in C. elegans. By revealing PLK-2-dependent and -independent mechanisms of CHK-2 activity, this work provides a valuable understanding of the major regulators of meiotic progression.

eLife assessment

Li and colleague report observations that constitute a potentially fundamental advance, pointing to a mechanism by which non-neural cells can influence sleep regulation by neurons, The authors provide evidence in Drosophila showing that ecdysone synthesised outside the brain regulates sleep via ecdysone receptors in cortex glia. It further suggests that steroid signalling in glia can act on sleep through lipid droplet mobilization.

eLife assessment

In this manuscript, the authors provide mechanisms by which HLA-I polymorphism affects the capacity in the endo-lysosomal assembly of HLA-I molecules for constitutive expression and during cross-presentation. The findings may have implications for allotype-dependent variation in T cell responses to antigens localized in different subcellular compartments. However, additional biochemical and quantitative data is essential to bolster the central claims of the paper.

the word disability has been used for such a long time that it has its definition tied to sociopolitical beliefs, therefor when there was an attempt by the community to change its meaning to be more accurate many people still refuse to do so.

ableist and ableis is the way to identify the individuals who see themselves as superior because they are able bodied. theres not enough awareness to make the public asses what is ableist

basically this page talks about how in the previous definition of disability was based on medical terms whose purpose was to sell an idea to the public

eLife assessment

The study is important in that it investigates the effect of reading acquisition on neural responses experimentally, randomly assigning children to one of two training groups. The results provide solid evidence for learning-related changes in the (late) neural response to words, but it is not clear whether this reflects category-specific changes in visual cortex tuning. As such, the study may not yet provide a clear answer to the neuronal recycling debate within which it was framed. This paper is of potential interest to a broad audience of neuroscientists, as it addresses fundamental questions regarding the re-organization of functional cortical responses associated with learning to read.

eLife assessment

This important paper provides detailed cellular and molecular characterization of the olivocochlear efferents that project to the inner ear. These specialized motoneurons are the only source of feedback from the brain to the ear and have been difficult to access. This study convincingly categorizes the efferents, using single nucleus RNA-sequencing and 3D reconstructions of individual fibers and their pre-synaptic contacts onto target neurons in the cochlea.

eLife assessment

This study presents important findings on the regulation of the phosphate export cycle and identify the phosphatase Sit4 as a crucial player in regulation of the inner membrane potential of mitochondria. Whereas some of the data are convincing, the analyses will profit from deeper insights concerning metabolism alterations (carbon sources, amino acids). The major strength however is a new insight on how the cells use alternative ways for maintaining a critical mitochondrial inner membrane potential, and therefore this study is interesting to the broad audience with interests spanning from bioenergetics, metabolism and organellar and cell biology.

eLife assessment

This interesting and important methodologic study presents exciting new data identifying approaches to evaluating the cell biology of lung disease. Namely, the ability to identify and track dynamic and coordinated activities of multiple composite cell types in response to experimental interventions. They have developed an interesting label-free approach that collects biologically-encoded autofluorescence of epithelial cells by 2-photon imaging of mouse tracheal explant culture over 2 days. This study has the potential to inform a variety of experimental conditions in lung injury and repair.

eLife assessment

This study is of interest to epidemiologists and geneticists studying the association between telomere length and lung cancer risk. This work provides useful insight into risk factors for lung cancer. Overall, the results of this study are solid, as the genetic instrument used here is better powered and the battery of MR analysis makes this broad set of results convincing compared to previous work.

eLife assessment

The study is a careful investigation of the physical properties of hagfish slime and the underlying cellular framework that enables this extraordinary evolutionary innovation. It is a careful and detailed measurement with clear images. However, there is a need for a better contextualizing of the findings as a broader biological question, including the evolution of functional novelty, the adaptive processes, and the links between genetic and phenotypic evolution. Furthermore, the conclusions on the evolutionary origins and underlying genetics of hagfish slime based on comparative transcriptomic data need to be better supported.

eLife assessment

The manuscript aims to provide a comprehensive insight into the development of the tuberal hypothalamus of the chick embryo. It thus presents a useful tool for scientists working in this particular subfield. However, the manuscript is incomplete as it is impossible for the reader to follow the conclusions made by the authors because the presentation of the data is not streamlined and the text is difficult to follow, even for experts.

eLife assessment

This study presents important evidence that boosting with the Sinovac Coronavac inactivated vaccine would provide considerable protection from ancestral SARS-CoV-2 in terms of elicited neutralizing antibodies but would offer minimal protection against Omicron subvariants. The evidence supporting the claims of the authors is solid, although using a dilution series instead of one plasma dilution for Omicron neutralization would have strengthened the study. The work will be of very wide interest to the biomedical community and beyond, since it points to the need for a better booster vaccine in China.

eLife assessment

This work presents valuable findings that advance our understanding of the roles of the CA domain in specific binding of HIV-1 Gag to the viral genomic RNA. The compelling evidence obtained using the modified CLIP-seq and chemical crosslinking approaches support the authors' conclusion that the initial Gag lattice formation mediated by CA is essential for Gag recognition of the 5' Ψ sequence. This work will be of interest to virologists working on gRNA packaging of not only HIV-1 but also other RNA viruses.

eLife assessment

Drug-resistant tuberculosis (TB) is a growing threat to global public health. By analysing a large database of clinical Mycobacterium tuberculosis isolates, the authors of this study identify previously unrecognized genetic mutations that might be implicated in improved mycobacterial survival under antibiotic treatment. Using laboratory and experimental infection models, they present evidence that these mutations should be considered potential genetic markers of reduced antibiotic efficacy and accelerated acquisition of TB drug resistance.

eLife assessment

This important study defines new functions for the ER-resident protein HSP47 in the quality control of multi-pass membrane receptor proteins. The evidence supporting the conclusions is solid, with rigorous biochemical assays employed in appropriate models. However, additional consideration regarding the mechanism of HSP47-dependent regulation of membrane protein quality control would have strengthened the study. This work will be of broad interest to cell biologists and biochemists interested in the fields of proteostasis membrane protein quality control, and neuroreceptor signaling.

eLife assessment

This fundamental study is important and carefully executed, providing important insights into the allosteric regulation of GPCRs with exceptional strength of evidence. This work will be of interest to a wide audience in drug discovery and receptor biology. The major strengths are the comprehensive structural and pharmacological characterization with only minor weaknesses, most notably a concern regarding the approach used to quantify efficacy.

eLife assessment

The authors have developed a useful model for how proteins that mediate a connection between invariant components of the T cell antigen receptor and leukaemic cells antigens, called bispecific engagers (BiTEs), mediate immunological synapse formation and impact T cell search for tumour cells in vivo. The model was compared against the in vitro experiments and in vivo data following a solid approach. The developed framework could provide a direction for employing computational mechanistic models for evaluating various strategies for BiTE treatments.

eLife assessment

This important study uses state-of-the-art methods to explore the evolution of dosage compensation between two closely related nematode species. The evidence supporting the rapid evolution of the recognition motifs on the X chromosome, despite a general conservation of the mechanism, is compelling. Provided the discussion on the evolutionary aspect of the findings is improved, this work will be of broad interest to cell biologists and evolutionary biologists.

eLife assessment

This potentially important article identifies an apparent oligogenic architecture for an ecologically relevant trait, the circalunar reproduction of marine midges, which contributes to assortative mating, is likely under divergent selection, and supports reproductive isolation in sympathy. A claim for a causal role of chromosomal inversions in this system is made, but the support for this claim is incomplete.

eLife assessment

This study presents a careful evaluation of the distribution of monocytes and dendritic cells in the the blood and nasopharyngeal aspirates of patients with mild respiratory tract infections. There are some interesting differences between monocytes and dendritic cells and variations with patient age. This is an important contribution to understanding monocyte and DC subset specific functions in dependency on the tissue microenvironment.

eLife assessment

This work provides valuable new insights into the mechanisms by which 25-hydroxycholesterol (which is known to be rapidly produced in macrophages and other cells during acute infections) acts to protect cells and animals from microbial infection. The authors provide compelling evidence that the cholesterol-esterifying enzyme acylCoA:cholesterol acyltransferase (ACAT) that is induced by 25-hydroxycholesterol promotes the depletion of an accessible pool of plasma membrane cholesterol, producing anti-microbial effects.

eLife assessment

This manuscript provides important findings that have practical implications for reproductive medicine and would be of interest to IVF specialists. Based on the compelling strength of evidence, the authors present significant results on improving the predictive value of the live birth model based on blastocyst evaluation and clinical features. However, some methodological information should be added to improve the reproducibility of the study results.

eLife assessment

The authors report the results of three experiments assessing how one or both eyes open under a patch influence resting EEG activity, contrast sensitivity, and binocular balance in normally sighted subjects. Their results suggest that the state of eye opening temporarily, but significantly, influences shifts in ocular dominance with relevance for treatment of binocular visual disorders such as amblyopia that are treated with periodic monocular occlusion. The evidence supporting their conclusions is solid and the findings are important for the field.

eLife assessment

This study highlights a significant concept whereby a retained memory of disease during stem cell reprogramming (likely via epigenetic modifications) affects the chondrogenic differentiation potential of osteoarthritis (OA)-iMSCs. The evidence supporting the conclusions is compelling, with rigorous RNAseq analysis of genes and signaling pathways. The relevance of this research is highlighted by the valuable role of iPSCs as a potential cell source for regenerative medicine. The work will be of broad interest to skeletal stem cell biologists working on osteoarthritis and cartilage regeneration.

eLife assessment

Sorkac et al. present a novel genetically encoded retrograde synaptic tracing method that has the potential for unbiased identification of presynaptically connected neurons. Retro-Tango is based on the previously developed anterograde method trans-Tango, promising high applicability and rendering the significance of this contribution important. The strength of the evidence is convincing.

eLife assessment

This manuscript presents an important mathematical analysis on metabolic "co-substrates" and how their cycling can affect metabolic fluxes. Through mathematical analysis of simple network motifs, it shows the impact on constraining metabolic fluxes and the applied mathematical modeling/simulation approaches and the statistical analysis to compare predictions with data from previous studies offer convincing support for the potential biological relevance of co-substrate cycling. The work will be of interest to researchers who study microbial metabolism and metabolic engineering. However, part of this analysis remains unclear and would benefit from clarification.

eLife assessment

This important analysis helps to shed light on the relationship between blood type and the occurrence of ICD-based phenotypes in a hospital setting. A particularly compelling strength is the analysis' reliance on a population-based patient registry. The results would be further strengthened by an exploration as to whether these phenotypes are driven by patient characteristics (e.g. ethnicity, SES) and not just blood type. Additionally, differences across blood types are driven, in part, by differences in prevalence, somewhat limiting the scope of the analytical findings.

eLife assessment

The study shows that human inflammasome-forming sensor CARD8 contains a specific motif that allows cleavage by the proteases of HIV-1 and its direct precursor infecting chimpanzees. In comparison, CARD8 proteins from non-human primates contain changes in this motif and seem largely resistant to proteolytic activation. The results are important, and the data on the cleavage of CARD8 in HEK293T cells are convincing, while effects on inflammasome stimulation and cell death in primary viral target cells are insufficiently supported.

eLife assessment

This work provides important new insights into the mutational pathways of SARS-CoV-2 to achieve antibody escape, as well as how these pathways are shaped by epistasis. The evidence supporting the conclusions is compelling based on rigorous analyses of data from a high-throughput binding assay. The study is important for evolutionary medicine and biology and relevant for human health.

eLife assessment

The current study employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with NSC-derived exosomes extracted from NSCs to treat cerebral ischemia, and they made an important observation. Remarkably, NSC-derived exosomes could promote NSCs differentiation, reduce the oxidative stress and inflammation, and alleviate the formation of glial scars after ischemia and reperfusion, and as a result, could enhance the therapeutic effects of NSC transplantation, which is compelling. The solid experimental evidence strongly supports their major claims.