eLife assessment

This important study presents evidence to support the efficacy of oral administration of DNL343, an integrated stress response (ISR) suppressor, in two mouse models in which neurodegeneration is induced. This suggests a therapeutic potential for ISR-related neurodegenerative diseases based on DNL343. The results from the in vivo animal models are convincing. However, adequate analyses are needed to fully support the conclusion, as there is no evidence that DNL343 acts in vitro.

eLife assessment

This fundamental study has major implications that can be paradigm-shifting for our understanding of how the phage lambda DNA motor works and what the precise roles of the TerS and TerL proteins in the motor complex are. The experiments are exceptionally well done, providing compelling evidence for the conclusion of the authors.

eLife assessment

This fundamental work by Cao et al. advances our understanding of the role of senescent osteoclasts (SnOCs) in the pathogenesis of spine instability. The authors provide compelling evidence for the SnOCs to induce sensory nerve innervation. Subsequently, reduction of SnOCs by the senolytic drug Navitoclax markedly reduces spinal pain sensitivity. This work will be of broad interest to regenerative biologists working on spinal pain.

eLife assessment

The findings of this article provide valuable information on the changes of cell clusters induced by chronic periodontitis. The observation of a new fibroblast subpopulation, named AG fibroblasts, is interesting, and the strength of evidence presented is solid.

eLife assessment

This is a valuable comparative study of adaptation across multiple species. The results provide a solid example of the application of genotype-environment associations to demonstrate that local adaptation is repeatable.

eLife assessment

Multimodal experiences that for example contain both visual and tactile components are encoded as associative memories. This manuscript is a valuable contribution supporting structural and functional brain plasticity following associative training protocols that pair together different types of sensory stimuli. The results provide solid support for this plasticity being a basis for cross-modal associative memories.

eLife Assessment

This valuable paper presents a new protocol for quantifying tRNA aminoacylation levels by deep sequencing. The improved methods for discrimination of aminoacyl-tRNAs from non-acylated tRNAs, more efficient splint-assisted ligation to modify the tRNAs' ends for the following RT-PCR reaction, and the use of an error-tolerating mapping algorithm to map the tRNA sequencing reads provide new tools for anyone interested in tRNA concentrations and functional states in different cells and organisms. The results and conclusions are solid with well-designed tests to optimize the protocol under different conditions.

eLife assessment

This valuable study reports on the potential of neural networks to emulate simulations of human ventricular cardiomyocyte action potentials for various ion channel parameters with the advantage of saving simulation time in certain conditions. The evidence supporting the claims of the authors is solid, although the inclusion of open analysis of drop-off accuracy and validation of the neural network emulators against experimental data would have strengthened the study. The work will be of interest to scientists working in cardiac simulation and quantitative pharmacology.

eLife assessment

This is an important study highlighting a distinct role of WASP dependent actin foci in B cell antigen receptor signalling. The evidence supporting the conclusions is compelling. The proposal of higher molecular density in B cell receptor clustering leading to kinase exclusion and attenuated signalling is provocative as it contrasts with models for other antigen receptors.

eLife assessment

O'Brien and co-authors addressed how statins reduce levels of aldosterone in humans and provide important data demonstrating that tissue-resident macrophages can exert physiological functions and influence endocrine systems. However, the strength of evidence, as of now, is incomplete, as the sole description of the phenotype of MARCO-deficient mice is insufficient to claim that MARCO in alveolar macrophages can negatively regulate ACE expression and aldosterone production at steady-state. The work will be of broad interest to cell biologists and immunologists.

eLife assessment

This study presents a useful inventory of the joint effects of genetic and environmental factors on psychotic-like experiences and identifies cognitive ability as a potential underlying mediating pathway. The data were analyzed using a solid and validated methodology based on a large, multi-center dataset. The claim that these findings are of relevance to psychosis risk and have implications for policy changes is partially supported by the results.

eLife assessment

This study presents a valuable finding on relationship between high protein diet and resistance exercise on fat accumulation and glucose homeostasis. The evidence supporting the claims of the authors is solid, although inclusion of mechanistic insight would have strengthened the study. The work will be of interest to dietician and exercise biologists working to understand the synergy between diet and physical activity.

eLife assessment

This study reports a new approach to determine the architecture of peptidoglycan (PG), the primary component of the bacterial cell wall, validating the pipeline through an architectural analysis of several members of the human gut microbiota. The technique is potentially valuable for this sub-field as it would enable researchers interested in peptidoglycan in a range of organisms to easily assess muropeptide composition in an easy, automated manner. However, there is some uncertainty about whether the pipeline was fully automated and it was noted that the pipeline requires prior knowledge of the peptidoglycan composition of an organism. Additionally, the use of the technique to investigate whether PG cross-bridge length is a determinant of cell wall stiffness produced evidence that would need more direct support and is therefore so far incomplete.

eLife assessment

This manuscript reports important findings, demonstrating a critical role for a cysteine-containing dimerization interface in the secretion of FGF2 through an unconventional pathway. The authors provide compelling evidence, combining in vitro biochemical assays with structural simulation. The work will be of interest to researchers working on protein trafficking and secretion.

eLife assessment

This important study describes the coordinated regulation of cellular size and protein translation in response to chronic stress as an adaptive mechanism, termed the 'rewiring stress response' regulated by the heat shock response. The evidence supporting this conclusion is solid, utilizing diverse methods to monitor and manipulate cell size and evaluate stress resistance. The study could be strengthened by the inclusion of more experiments focused on defining the mechanistic basis of this coordination and broadening the scope of the specific role of the 'rewiring stress response' across different chronic cellular stresses. This work will be of broad interest to researchers interested in diverse fields including cellular proteostasis, stress-responsive signaling, and aging and senescence.

eLife assessment

This is an important contribution to the origins and translational consequences of the relatively low rate of translation elongation in the first ∼30-50 codons of genes in most organisms. The authors provide convincing evidence that the prevalence of rare codons in the first ~40 codons in yeast is due to the relatively recent evolution of these coding sequences, or of lower purifying selection operating on them, and that a preponderance of codons encoded by rare tRNAs near the N-terminus is not associated with higher translational efficiency in the manner proposed by the "translational ramp" hypothesis. The work is incomplete in that the results of reporter assays may have been confounded by alterations of mRNA sequence or structure that could have influenced their translation or mRNA stability; that the work cannot fully account for a greater enrichment of slowly translated codons in N-terminal vs. C-terminal regions; and that the work does not resolve whether translation elongation through N-terminal coding is truly slow.

eLife assessment

This manuscript provides important insights into the degradation of a host tRNA modification enzyme TRMT1 by SARS-CoV-2 protease nsp5. The data convincingly support the main conclusions of the paper. These results will be of interest to virologists interested in studying the alterations in tRNA modifications, host methyltransferases, and viral infections.

eLife assessment

This study reports biochemical and structural analysis of two PLP decarboxylase enzymes from plants. The findings are useful due to the utility of these enzymes in industrial theanine production. While certain aspects of the study are solid, other components elucidating the role of a Zn(II)-binding motif are incomplete. In addition, some of the finding could be presented more clearly, including the connections between the structural findings and the reaction mechanism. The work will be of interest to enzymologists studying PLP enzymes and those interested in enzyme engineering in plants.

eLife assessment

This manuscript provides important structural insights into the recognition and degradation of the host tRNA methyltransferase by SARS-CoV-2 protease nsp5 (Mpro). The data convincingly support the main conclusions of the paper. These results will be of interest to researchers studying structures and substrate recognition and specificity of viral proteases.

eLife assessment

This comprehensive study provides valuable information on the cooperation of Ikaros with Foxp3 to establish and regulate a major portion of the epigenome and transcriptome of T-regulatory cells. However, the characterization is incomplete in that incontrovertible evidence that these are intrinsic features regulating biological function and not outcomes of the inflammatory micro-environment of the genetically manipulated mice is missing.

eLife assessment

This valuable study advances our understanding of the relationship between different mammalian ligands and receptors of the Notch signaling pathway. The authors systematically evaluate the effects of different combinations of ligands and receptors on levels of pathway activation. The convincing though not always complete data uncover interesting and unexpected differences, which provide a foundation for interpreting Notch signaling events in normal and disease contexts where this pathway operates.

eLife assessment

In this valuable study the authors propose a new regulatory role for one the most abundant circRNAs, circHIPK3, mediated by the RNA binding protein IGF2BP2. While the study presents interesting and largely solid evidence, part of the work is incomplete, requiring additional controls to more robustly support the major claims. The work would also benefit from further discussion addressing the apparently contradictory effects of circHIPK3 and STAT3 depletion in cancer progression.

eLife assessment

This is an important study describing the function of Laminin γ1-dependent basement membranes in the development of the olfactory placode, including morphogenesis of the placode, boundary formation, and olfactory axonal pathfinding. The study uses elegant live imaging approaches, and detailed mutant analyses to provide a convincing description of the role of Laminin in olfactory placode development, although the mechanisms by which Laminin γ1 regulates these processes are not conclusive. In addition to the contributions this study makes to understanding olfactory placode development, it will also be of broader interest to individuals interested in extracellular matrix regulation of tissue morphogenesis, and neural development including neuronal pathfinding.

eLife assessment

In a valuable study that will be of interest to the mechanistic membrane transport community, the authors capture the first cryo-EM structure of the inward facing melbiose transporter MelB, a well-studied model transporter from the major facilitator (MFS) superfamily. Cryo-EM experiments and supporting biophysical experiments provide solid evidence for transporter conformational changes. The supporting evidence is incomplete in that the maps were not provided for review.

eLife assessment

This important study convincingly shows that the less common D-serine stereoisomer is transported in the kidney by the neutral amino acid transporter ASCT2 and that it is a non-canonical substrate for sodium-coupled monocarboxylate transporter SMCTs. With a multi-hierarchical approach, this important study further shows that Ischemia-Reperfusion Injury in the kidney causes a specific increment in renal reabsorption carried out, in part, by ASCT2.

eLife assessment

This is a useful study that investigates neural circuits mediating behavioral responses to cold in Drosophila larvae. Using a combination of behavioral analysis, neuronal manipulation, EM connectomics, and reporters of calcium activity, the authors convincingly show that cold-induced body contraction is mediated by specific central neurons. However, the strength of evidence is incomplete due to the concern that larval contraction is a result of chilling the nervous system and muscles, which causes spreading depolarization and mechanical contraction of the body, rather than an active sensorimotor response to cold. With these concerns addressed, this paper would be of interest to neuroscientists interested in temperature sensing.

eLife assessment

Antibodies are some of the most critical tools in biomedical research. However, their quality and specificity vary significantly. This fundamental study provides guidelines for how the quality of an antibody should be assessed and recorded and provides compelling data on the selected antibodies. This paper will be of interest to researchers working in experimental cell biology.

eLife assessment

This is an important study on how behavioral context affects decision making in the nematode C. elegans. Behavioral analyses at multiple time scales combined with genetic and neuronal manipulations revealed how arousal states affect decision making. The results and interpretations are convincing. This work will be of interest to both neuroscientists and ecologists.

eLife assessment

In this valuable study, the authors characterize the role of splicing factor SRSF1 during spermatogenesis with a conditional knockout for Srsf1 in male mouse germ cells. The requirement of SRSF1 for maturation of postnatal gonocytes into spermatogonia, and the molecular role of SRSF1 in regulating alternative splicing in juvenile testes are convincingly supported. The paper also provides strong evidence that the mRNA encoding Tial, a factor relevant for spermatogonial maintenance and male fertility, is alternatively spliced in testis and that this splicing is regulated by SRSF1. The work will be of interest to reproductive biologists and stem cell biologists.

eLife assessment

This valuable study provides extensive high-quality imaging data and new insights into the process of the endothelial-to-hematopoietic transition (EHT), which generates nascent hematopoietic stem cells from the ventral wall of the dorsal aorta. This study provides strong evidence that, based on apicobasal cell polarity, different morphologies exist for emergent hematopoietic stem cells. The study is incomplete at present in that it does not yet support the additional claim that there are functional consequences, as altered cell fate related to these different morphologies has not been definitively shown.

eLife assessment

Studies of synaptic development and plasticity in the nematode C. elegans have been limited by the difficulty of rapid, accurate assessments of synaptic structure. In this valuable work, the authors convincingly introduce and validate a computational pipeline, "WormPsyQi," that allows rapid, reproducible quantitation of fluorescent synaptic puncta while minimizing human error and bias. The authors also describe a new set of strains carrying synaptic markers. Together, these tools should provide many groups studying this model system with the ability to quantitatively characterize chemical and electrical synapses, even in densely packed regions in 3D space such as the nerve ring.

eLife assessment

Using the continuum theory of elastic solids, the authors suggest that periodic muscle contraction leads to elongation of C. elegans embryos by storing elastic energy that is subsequently released by extending the embryo's long axis. This important finding could apply to other developmental processes and be exploited in soft robotics. While the presented evidence is in principle convincing, features of the the theory are not explained in sufficient detail.

eLife assessment

This is an important demonstration of how the false-positive rate of high-resolution 2D template matching to find particles of a given target structure in 2D cryo-EM images (2DTM) relates to overfitting the data towards the template. The authors present new methods to measure the amount of model bias that gets introduced in high-resolution features of such maps, with compelling evidence that high-resolution features that are not present in the template can still be reconstructed in 3D from images obtained by 2DTM.

eLife assessment

This study presents a useful new approach for efficient computation of statistics on correlations between genetic variants (linkage disequilibrium, or LD), which the authors apply to quantify the extent of LD across chromosomes. The method and its derivation are solid. The authors document that cross-chromosome LD can be substantial, which has implications for geneticists who are interested in population structure and its impact on genetic association studies.

eLife assessment

This important proof-of-concept study strongly supports the utility of functional ultrasound imaging for evaluating cerebral hemodynamics in rat models of brain injury. Functional ultrasound affords a distinct coverage/spatial/temporal resolution tradeoff when compared to other modalities for studying brain hemodynamics. The solid data presented indicate high fidelity of the recordings, a particular feat given that the rats were awake. On the other hand, single slice imaging and complexity of registration of subsequent imaging sessions limit the usefulness of the approach, particularly for quantitative imaging, and the small sample size will need to be followed up with and verified by future studies. This work will be of interest to researchers working in functional neuroimaging and more precisely with preclinical models of stroke in rodents.

eLife assessment

This important study shows that pharmacologically enhanced catecholamine levels and increased voluntary spatial attention have overlapping as well as dissociable effects on performance on a visuospatial attention task and corresponding EEG markers. The findings provide solid evidence regarding how neuromodulatory arousal and selective spatial attention jointly shape perceptional decision-making.

eLife assessment

This study presents valuable findings about synaptic connectivity among subsets of unipolar brush cells (UBCs), a specialized interneuron primarily located in the vestibular lobules of the cerebellar cortex. The evidence supporting the claims are interesting although incomplete in some areas. The work will be of interest to cerebellar neuroscientists as well as those focussed on synaptic properties and mechanisms. Although several compelling pieces of data were presented, substantial work remains to be conducted in order for the hypothesis and predictions of the manuscript to confirm how these factors play out in the actual brain circuit and how it would impact the processing of feedback or feedforward activity that would be required to promote behavior.

eLife assessment

This manuscript provides valuable insights to the underlying mechanism for Spinocerebellar ataxia 6 (SCA6) due to defective endolysosomal trafficking of BDNF and its receptor TrkB. The findings are compelling and significant in understanding the underlying pathology of SCA6. The authors have acknowledged the experimental weaknesses and recognize there may be multiple mechanisms to explain the findings.

eLife assessment

This valuable study illuminates molecular movements of acid-sensing ion channels by combining advanced chemical biology and biophysical techniques. The evidence for the main claim, lack of interaction of molecular termini, is compelling and challenges prior models. This work is expected to pique interest in the ion channel signaling field, providing a fresh perspective.

eLife assessment

Miyano et al. study the impact of RIM-BP2 deletion at mossy fiber synapses, using direct electrophysiological recordings from mossy terminals and STED super-resolution microscopy. The paper addresses an important question in the field of synaptic transmission and provides compelling evidence demonstrating reduced calcium channel abundance in mossy terminals upon RIM-BP2 removal.

eLife assessment

This manuscript provides a useful demonstration that distractor effects in multi-attribute decision-making correlate with the form of attribute integration (additive vs. multiplicative). The evidence supporting the conclusions is generally solid, but there are concerns regarding the robustness of the statistical analyses. In addition, the lack of a clear theoretical motivation complicates the interpretation. The manuscript will be interesting to decision-making researchers in neuroscience, psychology, and related fields.

eLife assessment

The study by Ghafari et al. addresses a question that is highly relevant for the field of attention as it connects structural differences in subcortical regions with oscillatory modulations during attention allocation. Using a combination of magnetoencephalography (MEG) and magnetic resonance imaging (MRI) data in human subjects, inter-individual differences in the lateralization of alpha oscillations are explained by asymmetry of subcortical brain regions. The results are important, and the strength of the evidence is convincing. Yet, clarifying the rationale, reporting the data in full, a more comprehensive analysis, and a more detailed discussion of the implications will strengthen the manuscript further.

eLife assessment

Richevaux and colleagues conducted a valuable study that investigated the integration of thalamic and retrosplenial inputs in the dorsal presubiculum, an essential hippocampal region involved in spatial navigation and memory. Through ex vivo optogenetic electrophysiological experiments, they discovered that many presubicular pyramidal cells receive convergent inputs from both the anterior thalamus and the retrosplenial cortex. These solid findings provide a potential cellular mechanism for anchoring the brain's internal compass to external landmarks, shedding light on how the brain integrates spatial information with an animal's sense of its position in space.

eLife assessment

The authors present a software package called osl-dynamics that uses generative models (Hidden Markov Model and Dynamic Network Modes) that can be adapted to the data, and the latent states and transition across states obtained through the model can be used to describe spectro-temporal characteristics of the brain signals, as well as for oscillatory burst detection. This approach is important and adds to the repertoire of techniques that can be used to study high-dimensional data and having access to this software (with tutorials and examples) will help other researchers test the usefulness of their approach. The evidence is convincing, but could further benefit from an objective way by which the output of their model can be compared/judged or through results from synthetic data with known properties.

eLife assessment

This paper by Aitchison and colleagues describes nanobody neutralizing and binding activity against various SARS-CoV-2 variants of concern. The findings are important in that the described nanobodies may have broad therapeutic relevance against current and future variants of concern and may be able to avoid significant resistance. The claims are incomplete: while the study is well-executed and uses a nice balance of biochemical and cellular assays, the efficacy of the proposed nanobody library against VOCs is not completely supported as IC50 values appear to increase against newer variants and are higher than previously used therapeutic bNAbs, animal data showing in vivo efficacy is lacking, and protection against future possible variants is not proven.

eLife assessment

This study presents a useful differentiation method that produces syndetome-like cells from human induced pluripotent stem cells as determined through single-cell RNA sequencing analysis. Nevertheless, it is essential to note that the authors' assertion that the efficiency of syndetome differentiation can be enhanced by inhibiting BMP and Wnt requires further substantiation, as the evidence provided remains incomplete. The major weaknesses of the manuscript center on issues related to data representation in figures and their subsequent interpretation. The work holds relevance for scholars in the field of musculoskeletal research who are dedicated to advancing translational medicine for the benefit of patients.

eLife assessment

This study presents valuable structural data for the bacterial adhesin PrgB, an atypical microbial cell surface-anchored polypeptide that binds DNA. There is convincing support for the claims regarding the overall function and importance of individual domains, which integrate a wide range of new and previously published experimental data. The structure-based model of PrgB molecular activity will be impactful in the field of bacterial adhesins, conjugation, and biofilm formation, especially because it focuses on a clinically relevant Gram-positive pathogen, whereas most work in the field has been focused on Gram-negative model systems.

eLife assessment

This paper describes innovative force measurements of the bending modulus of gliding cyanobacteria, along with measurements of the critical buckling length of the cells, which combined lead to valuable insight into how these cells produce the force necessary to move. The major findings are well supported by the data; however, the evidence that the results favor an adhesion-based mechanism is currently incomplete.

eLife assessment

This fundamental study identifies the homeodomain transcription factor and suspected autism-candidate gene Meis2 as transcriptional regulators of maturation and end-organ innervation of low-threshold mechanoreceptors (LTMRs) in the dorsal root ganglia (DRG) of mice. For a few years, the view on autism spectrum disorders (ASD) has shifted from a disorder that exclusively affects the brain to a condition that also includes the peripheral somatosensory system, even though our knowledge about the genes involved is not complete. The study by Desiderio and colleagues is therefore not only scientifically interesting but may also have clinical relevance. The work is convincing, with appropriate and validated methodology in line with current state-of-the-art and the findings contribute both to understanding and potential application.

eLife assessment

This paper presents a new method called MINT that is simple yet effective at BCI-style decoding tasks in stereotyped settings. While the reviewers raise caveats, overall they believe the work is a valuable study for the field of motor control, and the evidence to support their claims is solid.

eLife assessment

What makes one member of the species behave differently from another is a core problem in behavioral neuroscience. The authors studied the specific case of odor preference behavior in fruit flies, and searched for links to activity in the first and second stages of the olfactory system. This is a valuable study, but the results are overstated and the evidence incomplete. It is difficult to discern robust links between neural structure/function and behavior in the data set as presented here.

eLife assessment

In zebrafish, primary motor neurons (PMNs) control escape movements, and a more heterogeneous population of secondary motor neurons (SMNs) regulate the speed of rhythmic swimming. Using single cell RNA sequencing (scRNAseq), the authors have obtained compelling evidence that PMNs, and two types of interneurons innervating them, express a set of three genes encoding voltage-gated ion channels enabling rapid firing. The PMNs also express high transcript levels of proteins involved in exocytosis, which would be expected to support rapid neurotransmitter release. These results will be important for those working on spinal cord function and zebrafish genomics/transcriptomics.

eLife assessment

This study presents a valuable set of experiments to test whether Bombus terrestris bumblebees can detect lethal-level doses of a series of pesticides in nectar-mimicking sugary solutions. Behavioural essays were coupled with electrophysiological measurements to show that B. terrestris mouthparts cannot detect high levels of the tested pesticides. If confirmed using pesticide formulas, and other bumblebee species, the study will be of general interest in environmental science research. Most experimental data are compelling, and the conclusions are sound, but the write-up would benefit from a broader ecological context.

eLife assessment

Müller glial cells of the zebrafish retina can differentiate into all neural cell classes following injury, providing full regenerative capabilities of the zebrafish retina. This valuable study presents a description of transcriptional changes of Müller glia cells in the adult and regenerating retina using single-cell RNA sequencing. The overall evidence supporting the main claims of the authors is solid.

eLife assessment

This important study identifies the gustatory receptors for sugar sensing in the larval and adult forms of the cotton bollworm, which is responsible for the destruction of many food crops world-wide. The authors find that the larval and adult forms utilise different receptors to sense sugars. The data are convincing and will be of interest neuroscientists working in sensory coding of sugars and to the pest management field.

eLife assessment

This manuscript will provide a valuable method to evaluate the safety of MR in patients with orthopaedic implants, which is required in clinics. A strength of the work is that the in-silicon testbed is solid, based on the widely available human project, and validated. In addition, the toolbox will be open for clinical practice.

eLife assessment

This important work by Hann et al. advances our understanding of the role of the survival motor neuron (SMN) protein in coordinating pathogenesis of the spinal muscular atrophy (SMA). The authors provide convincing but, nevertheless, incomplete evidence in terms of skeletal analyses not being able to satisfactorily elucidate SMN regulation of bone development. The paper appears to be descriptive and will benefit from additional experiments to justify the hypothesis. With amendments, this work will be of broad interest to biologists especially those working on the SMA.

eLife assessment

This study presents valuable data on how HSCs are expanded under PVA cultures. The functional evidence supporting the claims of the authors is solid, although an extended multi-omic data analysis could have strengthened the study. The work will be of interest to individuals within this HSC field.

eLife assessment

This study presents valuable new insights into HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, and delineates the kidney cell types that express HIV genes and are injured in these HIV-transgenic mice. A series of compelling experiments demonstrated that PKR inhibition can ameliorate HIVAN with reversal of mitochondrial dysfunction (mainly confined to endothelial cells), a prominent feature shared in other kidney diseases. Although there are concerns regarding the specificity of C16 to PKR inhibition, as well as with the in situ hybridization studies, the data suggests that inhibition of PKR and mitochondrial dysfunction has potential clinical significance for HIVAN.

eLife assessment

This valuable study examines the effects of NFKB2 mutations on pituitary gland development through hypothalamic-pituitary organoids. The evidence supporting the main conclusions is solid, although analysis of additional clones to exclude inter-clone variability would strengthen the conclusions. Insight into the mechanism of action of NFKB2 during pituitary development is incomplete. This work will be of interest to endocrinologists and biologists working on pituitary gland development and disease.

eLife assessment

This useful article reports the possible roles of the natural product TRPV1 activator Eugenol on muscle performance and remodeling. It provides as yet incomplete evidence for eugenol, through TRPV1, but nevertheless merits future investigation.

eLife assessment

This study presents a valuable report on the first warm autopsy case of a metastatic prostate cancer patient and the follow-up genomic and epigenomic analysis. The evidence supporting the claims of the authors is solid, although inclusion of more discussion of the study limitation and elaboration of mechanistic link for TP53, CDK12, and CDKN1B mutations would have strengthened the study. The work will be of interest to medical biologists working on prostate cancer.

eLife assessment

This compelling and novel mathematical method assesses drug pro-arrhythmic cardiotoxicity by examining the electrophysiology of untreated cardiac cells. It will be valuable for future drug safety design.

eLife assessment

This study presents valuable findings on diabetogenic risk from colorectal cancer (CRC) treatment. The authors claim that postoperative screening for type 2 diabetes should be prioritized in CRC survivors with overweight/obesity, irrespective of the oncological treatment received. The evidence supporting the claims is solid but requires confirmation in different populations. These results have theoretical or practical implications and will be of interest to endocrinologists, oncologists, general practitioners, gastrointestinal surgeons, and policymakers working on CRC and diabetes.

eLife assessment

Trypanosoma brucei evades mammalian humoral immunity through the expression of different variant surface glycoprotein genes. In this fundamental paper, the authors extend previous observations that TbRAP1 both interacts with PIP5Pase and binds PI(3,4,5)P3, indicating a role for PI(3,4,5)P3 binding. They therefore suggest that antigen switching might have a signal-dependent component. The evidence is mostly compelling, but with some caveats because tagged proteins were used.

eLife assessment

This important study demonstrates widespread introgression between species of cyanobacteria in hot springs in Yellowstone National Park. Using single cell sequencing of hundreds of genomes, the authors provide one of the most convincing demonstrations to date of the importance of selection and hybridization in shaping polymorphism within a natural community. The strong enthusiasm for the paper is only dampened slightly by the methods not being described in the clearest possible manner.

eLife assessment

This work provides valuable insights into mucosal antibody responses against SARS-CoV-2 following intranasal immunization by characterizing a large number of monoclonal antibodies at both mucosal and non-mucosal sites. The evidence supporting the claims is overall solid, although the flow cytometric assessment of antibody-expressing cells would benefit from more rigorous controls. The demonstrated in vitro antiviral activity of antibodies characterized provides a rationale for developing mucosal vaccines, especially if confirmed in vivo and benchmarked against antibodies generated following intramuscular vaccination.

eLife assessment

While decades of research findings have supported the idea that action attenuates predicted touch, recent work has countered this, proposing that action actually enhances predicted touch and the previously observed attenuation is due to tactile contact. This present study resolves these contradictory claims regarding the role of prediction in perception of self-action. This important work provides compelling evidence that self-generated touch is attenuated compared to the same touch externally-generated, and a clear explanation for recent high-profile results that appeared to support the opposite view.

eLife assessment

This work presents useful and potentially valuable findings on how food signals may influence reproduction in the nematode C. elegans. In the current manuscript, the evidence in support of the authors' model is incomplete, and additional experimental data is needed to buttress the authors' conclusions.

eLife assessment

The authors studied the mechanisms by which dead cells are removed from the wounded skin in a process called efferocytosis. By analyzing different cell populations in the skin, the authors find that proteins involved in mediating the cell death and marking the cells as undergoing this process are elevated during distinct times in the wound healing program. Interestingly, these same proteins are elevated even higher in diabetic wounds. Finally the authors demonstrate that blocking the process of efferocytosis alters the wound healing program, thus illustrating its importance in effective wound repair.

eLife assessment

This work is fundamental in providing compelling evidence of mitochondria-encoded RNAs playing a role in controlling nuclear gene expression. How mitochondria and the nucleus communicates is an important but yet not well-appreciated area of biology. Using the iMARI (in situ mapping of RNA-Genome Interactions) technology developed by this team, the authors found that mitochondria-encoded RNAs play an unexpected role in regulating nuclear gene expressions in endothelial cells and intriguingly, depletion or overexpression of a specific mt-caRNA altered stress-induced transcription of nuclear genes encoding for innate inflammation and endothelial activation. Overall, these findings are interesting and supported by experimental confirmation, bulk-RNA-seq, and snRNA and scRNA-seq data and will be of interest to the field studying RNA regulation, gene expression and cell biology.

eLife assessment

Brodsky and colleagues report here an unexpected cis-activation mechanism of caspase-11. The authors use cellular imaging methods and cleavage site mutants to show that the LPS-induced speck formation by caspase-11 depends on the autoprocessing between two subdomains. This new finding opens multiple doors for further investigating how this non-canonical inflammasome is regulated and activated at the molecular level.

eLife assessment

This study presents a useful mathematical analysis of different signaling networks in an attempt to provide general rules that give rise to biphasic responses, a widely observed behavior in biology in which the outputs of the network depend non-monotonically on the inputs. Determining general conditions that underlie this behavior would be useful in engineering synthetic biological systems and for mechanistically understanding biphasic responses in biological systems. However, whereas the mathematical approach and methods are solid, as they stand, the analyses are inadequate to assess how these findings are applicable in nature and which are general.

eLife assessment

This paper presents valuable findings from whole-brain modeling of persistent activity states (underlying working memory) in the mouse brain. The most novel finding is that a spatial gradient of the density of inhibitory neurons supports a corresponding spatial gradient of propensity to support persistent activity. However, the evidence for this finding appears to be incomplete.

eLife assessment

This important work reveals that increased flux towards one carbon metabolism improves neuronal regeneration after injury in C. elegans. The presented data are solid and provide compelling support for this conclusion. The manuscript can still be improved in order to strengthen some of the specific conclusions made and to increase the clarity of the presentation.

eLife assessment

The paper introduces a new, important framework for neural modelling that promises to offer efficient simulation and analysis tools for a wide range of biologically-realistic neural networks. The paper's examples provide solid support for the ease of use and flexibility of the framework, but the comparison to existing solutions (in particular in terms of accuracy and performance) is incomplete. With a more careful evaluation of the tool's strengths and limitations, the work would be of interest to a wide range of computational neuroscientists and researchers working on biologically inspired machine learning applications.

eLife assessment

This valuable study presents a tool for hyperaligning functional brain topography between individuals, which is based on fMRI connectivity data gathered when participants watched different movies. The tool is validated through strong correlations between functional topographic maps generated from a participant's own localizer data and those derived from other participants' data based on this hyperalignment, even when the training and target participants were drawn from different datasets. The study will potentially be of interest to researchers working with a wide range of fMRI datasets.

eLife assessment

The authors establish a Drosophila model to assess the severity of disease-linked alleles of Uba5. Using both in vivo and in vitro experiments, this valuable study demonstrates the alleles fall into mild, intermediate, and severe classes, with convincing evidence to support their conclusion. This well-executed study establishes a model for further characterization of Uba5-related phenotypes in a powerful model system.

eLife assessment

This fundamental study reports differential expression of key genes in full-term placenta between Tibetans and Han Chinese at high elevations, which are more pronounced in the placentae of male than in female fetuses. If validated as functionally relevant, these results will help us understand how human populations adapt to high elevation by mitigating the negative effects of low oxygen on fetal growth. At this time, while the differential gene expression analyses are solid, the downstream analyses offer incomplete support for the connection to hypoxia-specific responses and adaptive genetic variation.

eLife assessment

This important study presents a new apparatus and experimental paradigm to examine deficits in finger control in stroke patients, with the goal of understanding their potential (biomechanical and neural) underpinnings. The paper presents solid experimental design and quantitative analyses to characterise these deficits and infer their origin, but a few technical aspects related to data analysis and statistics could be improved, and alternative interpretations of the results considered. In addition to the scientific results, this novel methodology can be used as a starting point for further research on hand function impairments in stroke, which is of significance for theoretical studies in neuroscience and applied research in rehabilitation.

eLife assessment

In this important paper, the authors report a link between brumation (or "hibernation") and tissue size in frogs, summarizing convincing evidence that extended brumation is associated with smaller brain size and increased investment in reproduction-related tissues. The research is of broad interest to ecologists, evolutionary biologists, and those interested in global change biology, as the dataset involves significant field work and advanced statistical analyses for insights into how expensive tissues in these ectothermic animals respond to environmental seasonality.

eLife assessment

This manuscript describes valuable information on how the extraocular muscles (EOM) are preserved in a mouse model of familial Amyotrophic lateral sclerosis (ALS) that carries a G93A mutation in the Sod1 gene. The authors provide convincing evidence of how the integrity of neuromuscular junction is preserved in EOM but not in limb and diaphragm muscles of G93A mice. Overall, this interesting work provides new evidence regarding the etiopathogenesis of ALS and insights for the development of therapeutic targets to slow the loss of neuromuscular function in ALS.

eLife assessment

This useful study reports on how Notch activity regulates the termination of neurogenesis in central brain during larval-pupal stages in Drosophila. The evidence supporting the claims is solid. The work will be of interest to developmental neurobiologists.

eLife assessment

This study presents the valuable finding that sustained calcium signaling in induced-Treg (iTreg) cells can lead to the loss of Foxp3 expression and iTreg identity by altering the chromatin landscape. The evidence supporting the claims of the authors is convincing. The work will be of interest to immunologists working on Treg cell therapy.

eLife assessment

This valuable study is focused on the requirement of the photoreceptor-specific tetraspanins, ROM1 and PRPH2, for the formation of light-sensitive membrane discs. The evidence supporting the claim that deficiency in one of the proteins can be compensated by the other is convincing, with both established and advanced techniques yielding results that will be of interest to those studying photoreceptor development and membrane curvature.

eLife assessment

This useful study aims to advance our understanding of the structure of the native form of a viral toxin secreted from infected cells. Some of the findings confirm previous reports, but the new claims in this study are only inadequately supported by the methods and analyses used. More rigorous approaches are needed to justify the main conclusion that the structure of the viral toxin derived from infected cells in this study is distinct from previously reported structures of recombinantly expressed versions of the toxin.

eLife assessment

This important study shows, based on analyses of single cell RNA-seq data sets of thymus cells, that transposable elements (TEs) are broadly expressed in thymic stromal cells, especially in medullary thymic epithelial cells and plasamacytoid dendritic cells. The authors also show that at least some TE-derived peptides are presented by MHC-I molecules in the thymus. The results suggest a possible role of TEs in thymic T-cell selection and immune self-tolerance, but the current analyses are incomplete and not yet fully support the claims.

eLife assessment

This work presents fundamental new insights into the conductivity of freshwater cable bacteria. The evidence supporting the conclusions, which was collected using appropriate techniques, is compelling. The work will be of interest to environmental microbiologists and the microbial electrochemistry community.

eLife assessment

This valuable study reports on several variants of the COVID-2 spike protein that are studied using well-established computational approaches, followed by attempts to validate the findings using experimental approaches. The evidence supporting the claims of the authors is solid, although there are known limitations of the computational approaches. The manuscript would benefit from a deeper discussion of the limitations and better contextualization of the work. The study will be of interest to biophysicists working in the general areas of allostery and protein evolution.

eLife assessment

This useful manuscript explores conditions for epigenetic inheritance by studying the stability of simple network models to permanent and transient perturbations. A novel aspect of the study is that it unifies non-genetic inheritance phenomena across cell divisions of unicellular organisms and in the germline of multicellular organisms. However, the models studied are more a collection of vignettes of numerical studies than a systematic study, therefore the evidence presented remains incomplete. This work will be of interest in the field of epigenetic inheritance as a first step towards building a more systematic theoretical framework.

eLife assessment

This valuable study reports that auxin exposure perturbs feeding behavior, survival rates, lipid metabolism, and gene expression patterns in adult flies. The solid results are based on proper methods and data analyses, which broadly support the conclusions with only minor weaknesses. This work should be interesting to fly geneticists who are interested in using the auxin-inducible gene expression system for inducing target protein degradation acutely.

eLife assessment

This manuscript presents valuable findings that inform our understanding of the genetic underpinnings of the model plant Arabidopsis' resistance to turnip mosaic virus (TuMV). The strength of the evidence in the manuscript is convincing, with very large sample sizes, careful controls, multiple follow-up experiments, and broadening to the evolutionary context. There is very good support for each of the manuscript's conclusions and the work could pave the way for functional studies.

eLife assessment

This study presents important findings that homo- and heterosynaptic plasticity outside of the window at which a weak associative fear memory is formed can transform this memory into a stronger one, and can produce fear memory even when stimuli were not paired. This work therefore expands our views on the role of time- and input-specificity of plasticity in learning processes. The evidence, based on state-of-the-art in vivo manipulations and activity recordings in behaving mice, supporting the conclusions is solid, although further validation of the methods used is required in order to reaffirm the authors' conclusion. Once resolved, the work will be of broad interest to neuroscientists interested in activity-dependent synaptic plasticity and associative memory.

eLife assessment

This study enhances our understanding of the relationship between cortico-hippocampal interactions and behavioral performance. Using an inter-areal coherence metric to gate trial initiation in real time, the authors provide solid evidence that links high hippocampal-prefrontal theta coherence to correct performance on spatial working memory and cue-guided decision-making tasks. Although reviewers agreed that the results do not demonstrate causality between hippocampal-prefrontal synchrony and behavioral performance, the findings are viewed as important given their potential implications for brain-machine interface applications in humans.

eLife assessment

Host cell death is an effective strategy to protect against infection, and is believed to function primarily by the elimination of the intracellular niche for pathogen replication. Abele and colleagues address an important question: does the mode of cell death affect its effectiveness in pathogen clearance? Consistent with prior observations, the authors provide compelling new evidence that the answer can depend on the cell type and/or tissue involved.

eLife assessment

This study describes CLEVER, an improved method for fast and efficient rescue and mutagenesis of SARS-CoV2. While the principle of this method is not new, this work significantly improves upon existing protocols, providing an important advancement in the field of viral infectious clones. Convincing proof-of-concept experiments were performed that demonstrate the utility and efficiency of the method.

eLife assessment

This manuscript provides fundamental findings on the association between sleep regularity and mortality in the UK Biobank, which is a popular topic in recent sleep and circadian research in population-based studies. The study is based on a large accelerometer study with validated follow-up of incident diseases and deaths, and the data quality and large sample size are convincing and strengthen the credibility of the conclusion. This will be of wide interest to researchers in the sleep study field, epidemiologists, practicing clinicians and the general public.

eLife assessment

This small-sized clinical trial comparing nebulized dornase-alfa to the best available care in patients hospitalized with COVID-19 pneumonia is valuable, but in its present form the paper is incomplete.

eLife assessment

This important study unravels the interaction between effort cost, pupil-indexed brain state, and movement (saccadic) vigor during foraging decisions in marmoset monkeys. Based on a normative computational model, the authors derive the prediction that anticipated effort should affect both decisions and movement vigor during foraging; and then provide solid behavioural and pupillometric evidence for this prediction in a foraging task. This paper will be of interest to decision and motor neuroscience as well as to all researchers studying animal behavior.

eLife assessment

This study presents valuable observations indicating that the electrophysiological excitability of cultured sympathetic motor neurons progressively increase during aging, and are inversely correlated with the magnitude of KCNQ currents. The alterations in membrane excitability are broadly relevant for those interested in understanding how the nervous system changes during aging. While the data as a whole are solid in showing that the excitability of sympathetic neurons increases in neurons cultured from older mice, the mechanism of the underlying changes and in vivo relevance is incomplete.

eLife assessment

In Drosophila melanogaster, the Store-operated Ca2+ entry (SOCE) channel, Orai, is required for the development of flight-promoting dopaminergic neurons. Here, Mitra et al. determine that expression of a loss-of-function Orai1 mutant during the 72-96 hour window of pupal development impairs gene expression in dopaminergic flight neurons in part through the expression of Set2, a histone methyltransferase. The authors identify a large number of genes that are controlled by Set2, and show that Set2 is controlled by the Trl/GAF transcription factor. Although the findings reported here are important, the evidence supporting some of the claims is incomplete.

eLife assessment

This study provides useful insights into the mechanisms of electron transport in STEAP proteins, consistent with current models. The work strengthens and supports previously published biochemical and structural data, and the experimental results are of solid technical quality. The manuscript will be of interest to colleagues who work on STEAP proteins and related electron transfer systems.

eLife assessment

This study presents useful insights into core genome mutations that could have contributed to the emergence of the Staphylococcus aureus lineage USA300, a frequent cause of community-acquired infections. The solid approach used is innovative in combining genome-wide association studies and RNA-expression analyses, both applied to extensive publicly available datasets. This strategy reduces the rate of false positives attributed to high genome-wide linkage disequilibrium. It is noted that this method cannot be used for most phenotype-genotype studies, especially those requiring essential population structure correction, and it can therefore not be readily replicated in different datasets.

eLife assessment

Understanding how genomic regulatory elements interact to control spatiotemporal gene expression is essential to explaining cell type diversification, function, and delineating genetic variation and disease. In this important study, the authors provide solid evidence showing that, in general, enhancers influence gene expression in an additive way. The findings contribute to ongoing discussions about the selectivity and combination of regulatory elements. Improved clarity regarding the statistical analysis, computational methods, and definitions used would strengthen the conclusions.

eLife assessment

This manuscript describes an important NMR investigation of allosteric interactions within Abl kinase. The authors identify helix I as a major element that couples the Abl active site with the myristate-binding pocket. The convincing findings have implications for understanding Abl kinase activation and how to target Abl kinase in diseases.

eLife assessment

This study provides a valuable resource that documents the protein-protein interactions (PPI) network for alpha-arrestins in both human and Drosophila based on affinity purification/mass spectrometry and the SAINTexpress method followed by a series of bioinformatic and functional assessments. Through these, the authors confirmed the roles of known and novel interactions, including proteins involved in RNA splicing and helicase, GTPase-activating proteins, and ATP synthase. This study represents a convincing example of how to adopt comparative molecular interactions and how to interpret the functional implications.

eLife assessment

In this study, the authors (1) build a detailed model of the process whereby visual information is stored in neuronal activity from the moment that a stimulus is presented until some time later when such information needs to be recalled, and (2) test numerous mechanistic assumptions by fitting the model to rich psychophysical experiments performed by human participants. The evidence supporting the claims is convincing, utilizing detailed model comparison to evaluate potential mechanisms. Overall, the results represent a valuable advance in our understanding of how sensory representations are encoded in and then recalled from, working memory.

eLife assessment

This is a fundamental work that significantly advances our understanding of the role of mossy cells in the dentate gyrus in Fragile X Syndrome. Carefully designed experiments provide evidence that changes in their excitability occur due to up-regulation of Kv7 currents. While the evidence supporting the authors' conclusions is solid, some of their claims did not consider other potential factors and explanations. The work will be of interest to neuroscientists working on unveiling the mechanisms of Fragile X pathology.

eLife assessment

This study presents useful findings from a large sample of participants from the UK Biobank on the relationship between menopause (including status, type, and age of onset), cognition, neuroanatomical measures derived from magnetic resonance imaging, and Alzheimer's disease. The strength of evidence is incomplete, and the study would benefit from clearer methodological descriptions, more careful consideration of potential confounds, and better theoretical integration with prior work in the field. This paper will be of interest to people working in the fields of cognitive neuroscience, endocrinology, and dementia.

eLife assessment

This manuscript describes valuable findings on the expression pattern of orexin receptors in the midbrain and how manipulating this system influences several behaviors, such as context-induced locomotor activity and exploration. The overall strength of evidence - which includes anatomical, viral manipulation studies, and brain imaging - is solid and broadly supports claims in the paper, however, there are several areas in which the conclusions are only partially supported by the data provided. These results have implications for understanding the neural underpinnings of reward and will be of interest to neuroscientists and cognitive scientists with an interest in the neurobiology of reward.

eLife assessment

In this important study, the authors integrated genetic and genomic datasets from humans and mice to unveil shared networks and pathways associated with coronary artery disease. Their compelling analysis led to the identification of new regulatory genes and pathways in vascular tissues and in the liver, allowing for a more in-depth understanding of the pathogenesis of coronary artery disease.

eLife assessment

This study and associated data is compelling, novel, important, and well-carried out. The study demonstrates a novel finding that different chemotherapeutic agents can induce nucleolar stress, which manifests with varying cellular and molecular characteristics. The study also proposes a mechanism for how a novel type of nucleolar stress driven by CDK inhibitors may be regulated. The study sheds light on the importance of nucleolar stress in defining the on-target and off-target effects of chemotherapy in normal and cancer cells.

eLife assessment

This study reports that neural activity in the auditory cortex (field L) of singing male songbirds can be modulated by social context. These potentially important findings indicate that the presence of a female conspecific alters the response of auditory cortical neurons to the male bird's own song and to perturbations of auditory feedback that the bird has been trained to expect. While they extend recent work showing that the activity of dopaminergic neurons in songbirds is also affected by an audience, the evidence presented is incomplete since it is unclear how much of the apparent modulation of cortical neurons may be due to other factors, such as changes in the recorded neurons or their properties over time, which will require additional analyses to work out.

eLife assessment

This important study discovered DBT as a novel gene implicated in the resistance to MG132-mediated cytotoxicity and potentially also in the pathogenesis of ALS and FTD, two fatal neurodegenerative diseases. The authors provided solid evidence to support a mechanism by which loss of DBT suppresses MG132-mediated toxicity. While activation of autophagy is shown to be associated with DBT knockdown, it remains unclear if this is the underlying mechanism driving improved survival.

eLife assessment

This fundamental study provides an unprecedented understanding of the roles of different combinations of NaV channel isoforms in nociceptors' excitability, with relevance for the design of better strategies targeting NaV channels to treat pain. Although the experimental combination of electrophysiological, modeling, imaging, molecular biology, and behavioral data is convincing and supports the major claims of the work, some conclusions need to be strengthened by further evidence or discussion. The work may be of broad interest to scientists working on pain, drug development, neuronal excitability, and ion channels.

eLife assessment

This useful study summarises the effect of optical stimulation of the A13 region on locomotion in healthy mice and experimental Parkinsonism and could potentially be of interest to basic and clinical neuroscientists. Behavioural analyses and evidence for pro-locomotor effects of stimulation are solid. However, anatomical analyses are incomplete and do not yield mechanistic insights due to various issues with specificity, sample size, statistical analysis, and data presentation in the present form of the study.