eLife assessment

The authors provide a new powerful tool as well as a large database that should be useful to the neuroscience community, but not only. The authors developed and applied a methodology to automatically estimate the volume, cell number, and density of mice brains from multiple regions, by detecting the native fluorescence of the cell nuclei. Using this platform, they analyzed an existing dataset containing multiple mouse brains, available in the Allen Mouse Connectivity project. The data provides a comprehensive neuroanatomical comparison of brain nuclei between males and females, between hemispheres, and between 2 strains of lab mice.

eLife assessment

In its current form, the reviewers felt that the work describing the use of a CycleGAN for alignment of neural activity from a neural interface across sessions was useful, with solid evidence showing that it improved performance over similar-concept previous approaches.

eLife assessment

This is an interesting and valuable study describing the importance of a focal adhesion protein vinculin in osteocytes in controlling bone formation by regulating the expression of sclerostin, which inhibits bone formation. The data are generally convincing and support the conclusions. Some additional investigation and discussions are required to further strengthen the conclusion and interpretation.

eLife assessment

Small subthreshold dendritic-somatic depolarizations can propagate to presynaptic nerve endings and may modulate transmitter release, but the mechanisms of this modulation remain poorly understood because the technical challenge of recording from small bouton synapse. Here the authors directly record from small cerebellar bouton terminals In paired somatic and presynaptic recordings, they demonstrate that small synaptic potentials can travel within 2 to 3 ms to the bouton and arrive there with an amplitude attenuated by 20 to 70% with respect to the somatically recorded potential. As expected, this amplitude attenuation depends on axon length. In recordings of MLI-Purkinje cell pairs the authors further demonstrate that small somatic subthreshold depolarizations of about 20 mV size can enhance AP-triggered IPSCs recorded in the Purkinje cells and change synaptic plasticity during AP trains. In order to address mechanisms of such presynaptic modulation, the authors measure presynaptic AP waveforms via cell attached recordings and found these very stable. On the other hand, presynaptic ICa(V) directly recorded in voltage-clamped MLI boutons facilitated in response to small pre-depolarizations and such facilitated ICa(V) produced larger IPSCs in paired recordings of MLI boutons and coupled Purkinje cells. The authors propose that an accumulation of partially gated channels during small presynaptic depolarizations is able to produce more rapid gating of VGCCs during the AP waveform on arrival of an invading presynaptic AP.

eLife assessment

The phenomenon of summit disease, where complex animal behaviours are controlled by single-celled parasites, captivates biologists and non-scientists alike. In this valuable study, the authors use a laboratory model (Drosophila melanogaster infected with Entomophthora muscae) for this disease to provide compelling evidence for the neuroanatomical and physiological underpinnings of summit disease. This is an excellent example of how seemingly intractable questions in behavioural ecology can be effectively addressed in laboratory settings using decades of work in creating 'models' for biology.

eLife assessment

This is an important report on the discovery of a strong sensitizing effect of cannabidiol on the activation of TRPV2 channels by 2-APB. The conclusions are convincingly supported by solid electrophysiological recordings and cryo-EM structures, but identification of a clear molecular mechanism will require additional structural work. The paper will be of interest to the ion channel research community.

eLife assessment

This valuable paper uses a cohort of SARS-CoV-2 infected people to link immune signatures 3 months post-infection with persistent, long COVID-19 symptoms. The strength of the evidence presented is solid based on a wide array of immunologic assays and a strategically designed cohort, with some claims that are incomplete based on a lack of specifically designed endpoints, lack of analysis of regulatory signals, and incomplete use of control samples. A couple of findings are novel and will be of interest to clinicians and immunologists, particularly that degree of inflammation at 3 months does not impair the generation of SARS-CoV-2 humoral and cellular memory responses and that cellular immune signatures are only somewhat correlated with long COVID-19 symptoms.

eLife assessment

Protein abundance is the result of many layers of regulation, including at the levels of transcription, mRNA stability, translation and protein degradation. Many transcripts contain short upstream ORFs (uORFS), but their effects on the translation of the main ORFs are difficult to predict as they are sometimes negative, positive and of different magnitudes. Here, the authors identify features of uORFs using massively parallel reporter assays, and these features help predict uORF effects on translation of main ORFs. The results will be an important resource for the community of researchers using this model organism and for the molecular and cell biology community in general as they allow to better understand how genes are regulated. There are also areas in which the authors' claims or conclusions are not fully justified and require either additional statistical analysis or new experimentation.

eLife assessment

This important study was designed to examine the bypass of Ras/Erk signaling defects that enable limited regeneration in a mouse model of hepatic regeneration. This hepatocyte proliferation is associated with the expression by groups of cells of mRNA-loaded CD133+ intracellular vesicles that mediate an intercellular signaling pathway that supports proliferation. These are new observations, supported by convincing data, that have broad significance to the fields of regeneration and cancer.

eLife assessment

This valuable study presents a novel and theoretically interesting model to account for viral diversity within hosts in evolutionary and genomic analyses of pathogens. The simulation results presented are solid, although there are some aspects of the methodology that require further investigation in order to establish their validity. The application to SARS-CoV-2 shows promise, but would benefit from further evaluation.

eLife assessment

This study presents the important finding that gene editing could be used to activate delta-globin expression to treat disorders of red blood cell synthesis. The evidence supporting the claims of the authors is solid, particularly in the immortalized cell lines, although inclusion of a larger number of donor patient samples may have strengthened the conclusions that were able to be drawn from the primary cell experiments. The data show this approach to have promise and identify avenues of effort that could be pursued to advance it to a clinical strategy for hemoglobinopathy treatment.

eLife assessment

Early life stress can have profound effects on animal behavior, including potential influences on individuality. In this valuable work, the authors use a rich new dataset to solidly demonstrate that the behavioral consequences of early life stress in C. elegans can be buffered by neuromodulators previously implicated in patterns of individuality. While much remains to be learned about the mechanisms by which stress might influence individuality, these studies provide an important entry point that will be of interest to neurobiologists studying interactions between behavior, neuromodulation, stress, and individuality.

eLife Assessment:

In addition to identifying several components regulated by checkpoint kinases, the authors identify a novel non-canonical activation mode for the central checkpoint kinase Rad53, a phosphorylation event that does not depend on Mec1 and instead depends on proteins involved in retrograde signaling through Rtg3. The study thus reveals unanticipated complexities in the DNA replication stress response. Overall, the work is well done and the data support the main conclusions.

eLife assessment

Reao et al. investigate a question that has long puzzled neuroscientists: what features of ongoing brain activity predict trial-to-trial variability in responding to the same sensory stimuli? The data demonstrate that the outcome of the previous trial, specifically a miss, allows these associations to be seen - while a correct response appears less likely to do so. and this is a valuable advance in our understanding of the relationship between brain state, behavioral state, and performance. Technically, the study is solid, ie, the methods, data and analyses broadly support the claims, with some weaknesses remaining.

This entire comment is gold

eLife assessment

The important study by Barreat and Katzourakis examines the evolutionary history of eukaryotic viruses (and related mobile elements) in the Bamfordvirae kingdom, and evaluates potential alternative scenarios regarding the origin of different lineages in this highly diverse kingdom. Through convincing phylogenetic analyses, the authors propose a new evolutionary model for the origin of this kingdom where their last common ancestor is inferred to have been an exogenous, non-virophage DNA virus with a small genome. This work advances our understanding of the deep evolutionary history of viruses, the interaction between viruses and the first eukaryotes, and the diversification of viral lineages.

eLife assessment

ZMYM2 is a transcriptional corepressor but little was known about how it is recruited to chromatin. This study reveals that ZMYM2 homes to distinct classes of retrotransposons bound by the TRIM28 and ChAHP complexes in human cells, an important finding in the field of transcriptional regulation. The evidence supporting the claims of the authors is solid, although inclusion of more functional data would have strengthened the original model proposed.

eLife assessment

This study represents a valuable mechanistic contribution towards understanding how ribosomal RNA is processed during ribosome biogenesis. The biochemical evidence supporting the major conclusions is solid, but the structural biology data is incomplete and would benefit from more rigorous analysis. After further strengthening, this work would be of interest to cell biologists and biochemists working on ribosome biogenesis.

eLife assessment

Caveney et al. overexpressed an engineered construct of the human membrane receptor guanyl cyclase GC-C in Hamster cells, co-purified it with endogenous HSP90 and CDC37 proteins and determined the cryo-EM structure of this complex. This important work shows that the pseudo-kinase domain of GC-C associates with CDC37 and HSP90 similarly to how the bona fide protein kinases CDK4, CRAF and BRAF have been shown to interact. The methodology used is state of the art and the evidence presented is convincing.

eLife assessment

This valuable study links natural variation in a steroidal glycoalkaloid to disease and insect resistance in potato species. The study design is straightforward and thorough, and the evidence supporting the main conclusions is solid; however, other relevant studies are not discussed with enough context. The work will be of interest to plant biologists and breeders.

eLife assessment

In this important study, the authors provide compelling evidence that the interplay between alternative polyadenylation (APA) of mRNA encoding Aurora Kinase A (AURKA) and hsa-let-7a miRNA governs AURKA protein levels. The authors show that short 3'UTR isoform of mRNA encoding AURKA is efficiently translated throughout the cell cycle, while the long 3'UTR isoform is suppressed by hsa-let-7a miRNA in a cell cycle-dependent manner. These findings delineate post-transcriptional mechanisms regulating AURKA expression that may be implicated in increase in AURKA protein that is frequently observed across a variety of cancers.

eLife assessment

This valuable paper sheds new light on the growth trajectory of bonobos (Pan paniscus), with explicit contributions to discussions of the exclusivity of certain aspects of growth in modern humans, most specifically with respect to components of the adolescent growth spurt, which may be less human-specific among primates than presumed to this point. The results are solid, based on the largest sample ever considered in the study of bonobo growth and include both morphometric and endocrinological data. This work will be of interest to human evolutionary biologists, primatologists, and researchers studying the ontogeny and evolution of growth and development in general.

eLife assessment

This study reports useful information on the limits of the organotypic culture of neonatal mouse testes, which has been regarded as an experimental strategy that can be extended to humans in the clinical setting for the conservation and subsequent re-use of testicular tissue. The evidence that the culture of testicular fragments of 6.5-day-old mouse testes does not allow optimal differentiation of steroidogenic cells is compelling and would be useful to the scientific community in the field for further optimizations.

eLife assessment

This important study functionally characterizes hemoglobin from Steller's sea cow, a cold-water adapted sirenian that went extinct ~250 years ago. Using ancestral sequence reconstruction, site-directed mutagenesis and biochemical assays to compare Steller's hemoglobin to those from (sub)tropical extant sea cows (all of which are proficient divers despite lacking massive muscle oxygen storage), the authors build a solid case for the molecular basis of cold adaptation, centered around an increased solubility and higher oxygen carrying capacity. Remarkably, a single amino acid replacement would explain most of the distinctive functional features of this hemoglobin, which include a hitherto unknown resistance to DPG. Overall, this work will be of interest to evolutionary biologists, physiologists, and biochemists, as well as an enjoyable and informative read for the general public.

eLife assessment

This important study identifies more than 1500 genes that are differentially transcribed over the cell cycle of the single-celled eukaryotic pathogen, Trypanosoma brucei. Analysis of the two major developmental stages of these pathogens suggests that a core set of genes are similarly regulated in both stages, while many cell cycle-related changes in gene expression were unique to one stage. Intriguingly, the levels of far fewer proteins are differentially regulated over the trypanosome cell cycle, indicating that protein levels are primarily regulated by post-transcriptional processes. The study represents a significant technical advance in analyzing gene expression at the single-cell level in unfractionated trypanosome cultures.

eLife assessment

This is a fundamental study of the activation process of Nurr1, an orphan nuclear receptor that may be a significant target for the treatment of neurodegenerative disorders. Nurr1 functions as a monomer, but may also heterodimerize with RXR which represses Nurr1 transcriptional activation. The authors provide compelling evidence for Nurr1 activation through ligand-induced dissociation of an inactive Nurr1-RXRa heterodimer. These data will be important for biochemists and cell biologists working on regulatory / activation mechanisms of nuclear hormone receptors.

eLife assessment

This manuscript is of big interest to physicians and geneticists who may struggle with interpreting the clinical significance of novel or rare missense variants in the TNFAIP3 gene in patients with systemic inflammatory diseases. There is also much debate about the potential mechanisms by which these missense mutations might be pathogenic. El Khour et al. addressed these questions by using a combination of in silico analysis and in vitro functional assays. However, their conclusions require additional experimental support and should be expanded to include other reported likely pathogenic missense variants.

eLife assessment

This interesting and important work shows that diacety, a volatile organic compound released by yeast in fermenting fruit, can act as a histone deacetylase (HDAC) inhibitor and trigger wide changes in gene expression, together with suppression neurotoxicity in a Drosophila model of Huntington's disease. While the effects on gene expression changes and degenerative phenotypes are convincingly shown, additional data are required to connect olfactory sensory neurons and odorant receptors with the demonstrated physiological effects of diacetyl.

eLife assessment

Genome-wide association studies on asthma have been challenging due to innate heterogeneity and the syndromic nature of asthma, variable accuracy in phenotyping, and potential gene-environment interactions. Here, the authors identified genetic loci associated with subtypes of childhood wheezing in combined data of multiple birth cohorts, by coupling latent class analysis of clinical phenotypic data with GWAS discovery. A mechanistically plausible genetic locus close to annexin 1 (ANXA1) was associated exclusively with early-onset persistent wheeze and provides new translatable molecular insight into asthma pathogenesis.

eLife assessment

The findings in this manuscript have important theoretical and practical implications within the fields of bacterial morphogenesis, peptidoglycan, and cytoskeletal function. The evidence presented is convincing and uses validated methodology in line with current state-of-the-art. This manuscript will be of interest to cell biologists studying the cytoskeleton and bacterial morphogenesis.

eLife assessment

This valuable study reports on the role of transposable elements in gene expression variation in rice and how TE-associated expression changes could have been selected during domestication. The combination of evidence from linkage studies and selection scans for a subset of insertions is convincing, although it is currently unclear how large the contribution of TEs to gene expression variability compared to other variants is, which should be reflected in the title. The work will be of interest to colleagues working on the role of transposable elements in adaptation and to biologists working on domestication.

eLife assessment

Necarsulmer et al describe an interesting new mouse model of TDP-43 proteinopathy in which gene editing was used to introduce a K145Q acetylation-mimic mutation previously shown to impair RNA-binding capacity and induce downstream misregulation of target genes. Mice homozygous for this mutation are convincingly shown to display cognitive/behavioral impairment, TDP-43 phosphorylation and insolubility, and changes in gene expression and splicing. This novel mouse model replicates some important hallmarks of human frontotemporal lobar degeneration and will be an important contribution to the field after several points are adequately addressed.

eLife assessment

This fundamental work reports the unique finding that specific ligands and receptors in the natriuretic peptide signaling pathway act during early embryogenesis to discriminate between neural crest and cranial placode fates using two distinct mechanisms. This work will be of broad interest to both developmental and cell biologists.

eLife assessment

Rapan et al. report a new multi-modal parcellation of the macaque frontal cortex based on cytoarchitectural division complemented with functional connectivity and neurochemical data. This builds on prior highly influential maps that subdivide the cortex based on anatomical fingerprints, both confirming these prior reports and defining new subdivisions. As such, this is a fundamental contribution with compelling results that can guide future neuroscientific research into the function of the frontal lobes.

eLife assessment

This is a valuable study, carried out in a solid and comprehensive manner. The results advance the understanding of one of the steps of the HIV life cycle, via a better description of the mechanisms underlying Gag-Pol dimerization.

eLife assessment

This study by Mohebi, Collins, and Berke presents valuable findings on the control of the neurotransmitter dopamine by cholinergic interneurons, a sparse but important subclass of neurons with the ventral striatum, a key brain region involved in motivational behaviors. The evidence supporting the claims of the authors is solid, although the inclusion of a key experiment presenting causality between cholinergic neuron activity and dopamine release during behavior is needed. The work will be of broad interest to neuroscientists in the fields of motivation and decision-making.

eLife assessment

This important paper compares the neural basis for different calling songs in five species of clawed Xenopus frogs using neural activity recordings combined with lesions of pathways and stimulation of specific parts of the circuit. The evidence supporting the claims is mostly solid but in part incomplete. The work will be of broad interest to neurophysiologists beyond the vocalization topic.

eLife assessment

In the DNA damage response (DDR) pathway, single-stranded DNAs (ssDNAs) activate a downstream kinase cascade with ATR/Chk1. Replication protein A (RPA) is believed to be essential for DDR activation by recruiting an ATR-partner protein, ATRIP, to RPA-coated ssDNAs through direct protein-protein interaction. This important paper provides convincing results, showing that an AP endonuclease, APE1 (APEX1), plays a role not only in RPA-dependent but also in RPA-independent recruitment of ATRIP on ssDNAs for DDR activation.

eLife assessment

This study provides a clearly presented and thoughtfully analyzed single cell-resolution dataset of gene expression in wildtype and mutant zebrafish skin. These data are used by the authors to develop and test hypotheses about cell lineage relationships and signaling interactions between cell types in the skin, allowing them to identify roles for several signaling pathways and the hypodermis in scale and pigment cell development. The reviewers have suggestions for clarifications and acknowledging caveats to some experiments, but overall assess the significance of the manuscript to be fundamental and the quality of the data compelling.

eLife assessment

This study presents valuable findings on the changes of immune cell populations and stromal cells occurring at the CNS borders in a neonatal bacterial meningitis model, focusing on fibroblasts, macrophages and endothelial cells. The study provides solid snRNA-seq dataset and high quality immune fluorescence images of dissected brain border regions, that will be useful for the community. These observations and datasets will be of interest to the neuro-immunology community.

eLife assessment

This study represents a valuable body of work in which the authors assemble a molecular description of colorectal cancer and classification into subtypes. Overall, the evidence supporting the findings is solid and could be improved with more detail. Consensus over a diverse range of data from publicly available sources is convincing. When added to existing knowledge this work may contribute to future biomarker discoveries for colorectal cancer.

eLife assessment

This important study advances our understanding of the metabolic and hemodynamic underpinnings of different brain networks. The evidence is convincing, drawn from multiple datasets and including simultaneous fMRI and PET, although the authors should make clear which claims are supported by their evidence and which are speculation based on the literature. The study will be of interest to neuroscientists and researchers who use functional neuroimaging tools to study brain activity.

eLife assessment

This study presents useful information on the environmental and epigenomic associations of obesity in children and adolescents. The data were collected and analyzed using a solid and validated methodology and can be referenced at the clinics and health authorities to make a guideline and a policy strategy.

eLife assessment

This manuscript presents an exciting set of experiments on the mechanisms through which PSD proteins induce actin bundle formation. The work included deep mechanistic analyses which determine the necessity of upper vs. lower levels of PSD proteins for actin bundle formation, identify the domains and interactions of these proteins that are necessary and sufficient to induce actin bundles, and provide a first assessment in neurons of potential roles of the newly discovered mechanisms.

eLife assessment

This paper presents a valuable cross-validation study of mesoscopic measurements of axonal orientations from three different modalities: x-ray tomography, scattered light imaging, and diffusion MRI. The authors show convincing similarities and differences in fibre orientations from all three methods over partial ex vivo brain samples, though as only a single diffusion method is investigated, there is inadequate evidence to support conclusions about diffusion MRI reconstruction methods in general. As a first example of work comparing these three modalities, it is of interest to researchers who want to apply x-ray tomography or scattered light imaging to image the white matter ex vivo or use these methods for future validation of diffusion MRI methods.

eLife assessment

This study has important implications for the impact of sexual conflict on population viability under different temperatures. The authors propose that male harm to females in sexual conflict can be reduced as a function of temperature within the optimal reproductive range of a species. The evidence for this proposal is currently incomplete because there is methodological detail that needs to be further clarified. The results could have implications for the likelihood of the evolutionary rescue of species facing the climate crisis.

eLife assessment

The authors use computational modeling of the mammalian visual system to address an important and understudied problem: how precise temporal properties of synaptic transmission might impact the kinds of neuronal correlations that instruct development. The present description of the simulations provides mixed evidence for the authors' conclusions. That slow NMDA currents help to minimize rapid timescale correlations is compelling, but other aspects of the simulations, such as neuronal heterogeneity may also contribute.

eLife assessment

In this important study, the authors generate and analyse single-cell datasets for the human parasitic nematode Brugia malayi. The new resource has the potential to uncover new details of the biology of secretory systems in this filarial nematode but the main claims are only partially supported and strengthening them would require additional experimental support and new analyses. With the methodological part strengthened, the new resource would be of broad interest to parasitologists and nematode biologists and would have the potential to accelerate research in the search of new anthelmintics and vaccines.

eLife assessment

We believe this study has the potential to be fundamental for the field of microbial communication and compelling evidence with the chance of changing the current state-of-the-art in this area has been presented. This is will be of natural interest to the field of parasitology, but scientists in the general area of cell-to-cell communication will certainly benefit from this contribution too. A major strength of this manuscript is the clear demonstration of the role of cytoneme-like structures and extracellular vesicles in parasite communication using the Trichomonas vaginalis model. Given the potential of these findings, the authors could deepen their discussion and perspectives for other areas.

eLife assessment

This study reports a cutting-edge set of experiments examining evolutionary models of paralog function differentiation for the mammalian ribosomal proteins eS27 and eS27L. No differentiated roles were identified for either paralog, but the paralogs are differentially expressed, and they preferentially associate with different transcript classes. Reciprocal switching of their coding sequences yielded no detectable phenotypes, but loss of either paralog resulted in lethality at different developmental stages, suggesting that subfunctionalized expression patterns underlie the retention of these paralogs. The work will be of interest to colleagues studying the evolution and diversification of ribosomes.

eLife assessment

The authors show that tunneling nanotubes or TNTs are used by cells to transfer full-length mRNAs. The data show that as much as 1% of the endogenous mRNA are passed between cells by this procedure. The transferred mRNA affect the transcriptome of the acceptor cells thus highlighting the significance of this nanotube mediated trafficking of mRNA between cells. We appreciate the difficulty of this exercise. The strength of the presented evidence could be questioned based on technical limitations.

eLife assessment

After mating, animals show a repertoire of behavioural changes. In flies, this includes an increase in egg-laying, salt, and food (particularly protein) consumption, and a concomitant decrease in sexual receptivity. This valuable study compellingly shows that flies also have an increased sugar appetite and they identify the central brain circuitry that controls this increase in the mated condition.

eLife assessment

The large genetic association studies conducted in East Africa have shown that the Dantu blood group provides substantial protection against severe malaria since it increases the surface tension of red blood cells making it harder for malaria parasites to invade. In this important work, the authors show that parasite growth is indeed restricted in vivo by testing this hypothesis in adult Kenyan volunteers infected with P. falciparium under careful monitoring. They were able to show convincingly that indeed, parasite growth was reduced amongst Dantu adults.

eLife assessment

Seelbinder et al. describe a new method for perturbing chromatin in living cells by local heating. Employing this approach, the authors uncover interesting behaviors that underscore the variability in the mechanical response of subnuclear domains and structures. The study is timely, and if some conceptual and technical aspects are improved, it should be of broad interest to both the cell biophysics and cell biology communities, in particular since the method can also be applied to study mechanical relationships of subcellular compartments in other cellular and multicellular systems.

eLife assessment

This study presents a useful inventory of chromatin modifications and genes that are up- and down-regulated during cerebellar development in vivo and in primary culture. The main claims were incomplete and would benefit from further analysis and/or additional experiments. The work will be of interest to biologists working on brain development.

eLife assessment

This study presents important findings regarding the quantification of dynamics in fish communities in changing ecosystems by combining a large-scale environmental DNA metabarcoding time series with novel statistical approaches. The methods are convincing, with controlled experiments, thorough statistical analyses, and a substantial dataset covering two years of detailed observation, which can provide sufficient power to detect fine-scale ecological interactions. This work is relevant for informing future research on assessing community stability under climate change.

eLife assessment

The authors use a combination of structural and MD simulation approaches to characterize phospholipid interactions with the pentameric ligand-gated ion channel, GLIC. The general agreement between structures and simulations increases confidence in the description of the lipid interaction poses, and provides a solid basis for the prediction of a state dependent interaction site where lipids could dynamically modulate channel gating. The results will be very useful to understand the nature of phospholipid interactions with pentameric ligand-gated ion channels, although the functional or structural significance of these lipid interactions remains unclear.

eLife assessment

This interesting study builds on previous work by the PI implicating Greatwall/MASTLKinase in recovery from DNA damage in cultured human cells. This study identifies a ubiquitin ligase that may regulate the stability of Greatwall/MASTL protein stability, and the authors propose that this constitutes a molecular "timer" that controls recovery from DNA damage. Should this be validated it would be an important advance for the field, but the data presented are currently incomplete and do not yet fully support this claim.

eLife assessment

The authors have uncovered a new target that may be exploited to selectively kill BRCA2 mutant cancer cells. Strengths of the study include the novel pathway uncovered (ROCK kinases) and the strong data in support of the findings. Weaknesses include limited detail regarding the mechanism of BRCA2-specific cell death by ROCK kinase inhibitors, limited information on why some ROCK kinase inhibitors are not effective, as well as whether the cell killing in BRCA2 wild-type cells by ROCK kinase inhibitors is the same mechanism but just attenuated. The work will be of interest to cancer biologists and colleagues studying kinases.

eLife assessment

This manuscript is of interest to readers in the field of neural development. The study is important as it examines two mutations within a homeodomain transcription factor called Cone-Rod Homeobox (CRX) that cause retinopathy in humans. The data are solid, and the work contributes to our understanding of the underlying pathogenetic mechanisms.

eLife assessment

This study combines experiments in developing embryos and embryo extracts to investigate a fundamental relationship in biology - how the size of mitotic chromosomes scales with changes in cell size during development. By combining the unique tools available in the Xenopus system with modern genomic approaches, the authors convincingly demonstrate that mitotic chromosome scaling is mediated by differential loading of maternal chromatin remodeling factors during interphase. Although it remains unclear exactly how these factors impact chromosome size, the findings reported here will be of broad interest to the cell biology community and are likely to spawn new avenues of experimental inquiry aimed at understanding intracellular scaling relationships.

eLife assessment

This study provides important estimates from international cancer screening data repository about the impact of the COVID-pandemic related disruptions on cancer screening programs in selected low- and middle-income countries. The evidence supporting the study is solid and relies on national-level screening program attendee volumes and assessments of screen positives during 2019 (pre-pandemic) and 2020 (during the pandemic). The study provides real-world data estimates of proportions/volumes of missed screenings due to pandemic control measures (lockdowns and closures) and may contribute to future modelling efforts for measuring the impact on late/advanced stage detection and excess case burden and mortality.

eLife assessment

This paper addresses an important clinical concern which is how the antidepressant ketamine exerts its effects acts rapidly. The authors suggest the reason is that ketamine increases glutamatergic transmission in the hippocampus. The strengths are the data are mostly very good, and the limitations are a lack of compelling evidence that the hippocampus is the location where effects occur, as well as several other issues.

eLife assessment

This important study will be of interest to those working on mycobacterial signal transduction. A combination of experiments provides convincing evidence to show how universal stress proteins bind to cAMP and function by direct sequestration of the second messenger. Although the methods, data and analyses broadly support the conclusions, the main claims are only partially supported and can be strengthened through further analytic approaches.

eLife assessment

Villalobos-Cantor et. al. describe a new technique for cell-type specific in vivo labeling of nascent peptides, which they call POPPi. POPPi is based on sequence-independent incorporation of the puromycin analog OPP into an elongating peptide, which also simultaneously terminates the growing peptide. To achieve cell-type-specific labeling, the authors used an OPP derivative, PhAc-OPP, as the labeling substrate. The method is potentially interesting but needs further characterization to be able to assess its use.

eLife assessment

This important study combines a screen of known N6-methyladenine (m6A)-dependent RNA modifying factors to identify ALKBH5 as critical in crush injury response. They demonstrate through gain and loss of function an effect on ALKBH5 m6A-dependent Lpin2 mRNA stability during injury-induced axon regeneration in both dorsal root ganglia nerve and optic nerve regeneration. The results provide new insight into the role of RNA modification on neural injury. However, the limitations of the experimental design on the conclusions drawn require additional consideration. With additional control experiments and further consideration of the limitations, the paper will provide a link between N6-methyladenine and neurotrauma.

eLife assessment

This study describes important results and convincing evidence linking myofibroblast senescence in the aged heart with a pro-arrhythmogenic phenotype. This is in turn related to higher mortality after myocardial infarction in the aged rabbit heart. These constitute important empiric as opposed to detailed findings. They nevertheless will be of interest to clinician scientists studying cardiac function and disease.

eLife assessment

Non-communicable diseases (NCDs) are rising rapidly in urbanizing populations in many parts of the developing world, including in sub-Saharan Africa. Temba and colleagues show important evidence that healthy Tanzanians display a pro-inflammatory phenotype with enrichment of specific immune-metabolic pathways. Dood-derived metabolites were identified as an important driver of inflammation-related molecules. These findings provide solid evidence that the dietary transition that occurs in urbanizing areas in sub-Saharan Africa may contribute significantly to the increased incidence of non communicable diseases in this part of the world.

eLife assessment

This important interdisciplinary study substantially advances our understanding of the prolactin receptor interactions with the membrane lipids and the effect of these interactions on cell signaling. The authors use a combination of state-of-the-art NMR structural analysis, simulations, and cellular assays to provide compelling experimental evidence for protein complexes being regulated by IDR-membrane interactions. The work will be of broad interest to structural biologists and biochemists, and the results presented herein are likely relevant for other non-tyrosine kinase receptors.

eLife assessment

This important study demonstrates that the transcription factor Chinmo is a master regulator that maintains larval growth and development as part of the metamorphic gene network in Drosophila. Chinmo does so in part by regulating Broad expression in imaginal tissues (exemplified in the wing disc) and in a Broad-independent manner in other larval tissues such as the salivary gland. Finally, they demonstrate that the role of Chinmo in promoting larval development is conserved between holometabolous insects and hemimetabolous insects, which lack a pupal stage. The data were collected and analyzed using solid and validated methodology and will be of interest to a broad audience including those interested in development and evolution.

eLife assessment

Using surface micropatterning, optical activation, and theoretical analysis, the authors provide compelling evidence that adjacent cells actively propagate mechanical stress in epithelial tissues. The response of the receiver cell is active and enhanced when the principal stress direction is perpendicular to the orientation of actin fibers. This work is important and a must-read for everybody wanting to understand tissue mechanics.

eLife assessment<br /> <br /> This is an important study that uses the song system in a bird model to understand the transcriptional mechanisms underlying neuronal adaptations to sensory deprivation. The manuscript offers compelling data in support of their hypothesis that these transcriptional changes are related to song plasticity. The work will be of interest to biologists who study neuronal plasticity mechanisms.

eLife assessment

Inferior olivary neurons drive complex spiking activity in Purkinje neurons of the cerebellar cortex, ultimately playing critical roles in controlling motor coordination and plasticity. Using transgenic mice or optogenetic techniques to independently control a major excitatory and inhibitory pathway to the inferior olive, the authors show that the probability and phase of olivary neuron output depend critically on the relative timing of excitation and inhibitory inputs. Network models predict that appropriately timed excitatory and inhibitory input patterns efficiently synchronize larger clusters of inferior olivary neurons, raising the possibility that input timing can gate the output of the motor commands. These valuable findings have the potential to impact the field's understanding of sensorimotor processing, but the strength of evidence is currently incomplete.

eLife assessment

The study provides evidence that the hormone PTH increases bone mass by, at least in part, regulating the factor Zfp467. In turn, Zfp67 controls expression of the receptor for PTH, thus creating a feedback loop that overall augments bone mass. The findings are novel and of potential great interest. Overall, the study is of interest to a broad audience and significant as it unveils a novel feedback loop involving PTH, a critical endocrine regulator of calcium, phosphate, and bone mass.

eLife assessment

This paper describes a new method to investigate Staphylococcus aureus intracellular virulence that has produced important insights into the mechanisms of staphylococcal pathogenesis. The results are convincing and the methodology is state-of-the-art. This paper will be of interest to scientists studying microbial intracellular pathogenesis and cell biology.

eLife assessment

This paper demonstrates the genetic architecture of heart mitochondrial proteome that influences cardiac hypertrophy, using a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). The HDM panel is a very powerful tool to study the genetic basis of various physiological and pathological processes in mice. The authors have used this panel extensively before, and in this paper, they extend their proteomic studies to demonstrate the genetic basis of cardiac hypertrophy. The studies will allow us to better understand the genetics of hypertrophic cardiomyopathy.

eLife assessment

This important study greatly expands our knowledge of the fossil record of Mermithid nematodes, modern members of which are ecologically important parasitoids of arthropods, annelids and mollusks today. The most important finding, convincingly presented, is that mermithids parasitized a number of insect clades in the Cretaceous that they are not known to infect today or in Cenozoic amber. The evidence for a shift in exploited hosts from heterometabolous insects in the Cretaceous to holometabolous ones in the Miocene is solid but could be made exceptional by adding a small quantitative analysis with confidence intervals and bar plots from the data already compiled in the supplementary material; potential collection bias should be addressed as well.

eLife assessment

This fundamental work uses deep neural networks to simulate activity evoked by a wide range of stimuli and demonstrates systematic differences in latent population representations between hearing-impaired and normal-hearing animals that are consistent with impaired representations of speech in noise. While the evidence supporting the conclusions is compelling, additional analyses would facilitate the generalizability of the neural-network approach. The research will be of interest to auditory neuroscientists and computational scientists.

eLife assessment

This manuscript provides valuable data gathered using a new video fluoroscopy method by which movements of artificial joints can be visualized in real time. These solid data add to the understanding of the links between symptoms of unstable joints after total knee replacement and actual joint instability. The paper should be of interest to those who study biomechanics after total joint replacement.

eLife assessment

In this study, Li and al describe valuable insights into the mechanisms underlying sex-differences diet-induced obesity in mice, with a role of macrophage-derived RELMa secretion in female-specific protection. They provide solid evidence for the impact of RELMa signaling in eosinophil recruitment for diet-induced obesity protection in female mice. Single-cell RNA-seq analysis of the stromal vascular fraction of control and RELMa deficient animals methods were used to investigate molecular mechanisms underlying the protection as a powerful method, although the analysis of this data is difficult to evaluate with incomplete methodological information.

eLife assessment

In vertebrates, ciliary motility is powered by axonemal dyneins, known as OADs, tethered to doublet microtubules by a pentameric docking complex including the Armc4 and Calaxin subunits. This valuable study combines zebrafish genetics with cryo-electron tomography to convincingly show that Armc4 plays a critical role in the docking of OAD and that Calaxin stabilizes the molecular interaction. The work will be of interest to those studying the structure and function of the axoneme, and motile cilia in general.

eLife assessment

This important study combines behavior, computational modelling and magnetic resonance spectroscopy to address the question whether age-related declines in learning are driven by declines in working memory or deficiencies of the RL system. The general approach is solid, but the presented evidence to support the papers' main claims could be stronger. With additional analyses and adaptation of the main claims, the paper could be of high interest for researchers in the field of cognitive aging and decision making.

eLife assessment

The authors present a manuscript aiming to understand the mechanism(s) underlying myeloid bias in HSCs, specifically focused on the role of Pcgf1, and therefore PRC1.1, in the regulation of hematopoiesis. This important work is of interest to the community of researchers interested in myeloid differentiation, lineage fate decisions in hematopoietic stem cells, and the molecular mechanisms that contribute to the initiation of myeloid malignancies. The methods are rigorous and the results convincingly support the authors' conclusions.

eLife assessment

This is a valuable paper describing an attempt to reconstruct the evolution of Dicer. Using ancestral reconstruction approaches, the authors carefully examine the biochemical characteristics of reconstructed proteins at various junction points in the animal lineage. They provide solid evidence that the deepest ancestrally reconstructed protein has double-stranded RNA stimulated ATPase activity and that this characteristic was lost along the vertebrate lineage. This paper will be of interest to scientists in the RNA-protein interaction and protein evolution fields.

eLife assessment

The authors have established new formulas to predict maximum oxygen uptake for cyclists and runners based on submaximal exercise testing and anthropometric characteristics. This is an important study with a large and comprehensive dataset, which may be helpful for many exercise labs. The work is convincing, using appropriate and validated methodology in line with the current state-of-the-art, as shown by references to common exercise books.

eLife assessment

In the current manuscript, the authors study the effects of hypoxia or genetic and pharmacologic modulation of the hypoxic pathways on T cells. The findings about T cells sense hypoxia and how hypoxia affects T cell (and CAR T cell) differentiation and function are significant and interesting for the field. The data supporting these findings are mostly robust, yet some questions remain open and some statements seem unsupported by evidence.

eLife assessment

This fundamental work substantially advances our understanding of polymer physics underpinnings of genome folding, organization, and regulation. The conclusions are supported by both convincing computer simulations and analytical theory. The work will be of significant interest to the genome folding community.

eLife assessment

This manuscript will be of interest to scientists in the field of tissue injury and repair. It provides novel molecular mechanisms of a transcription factor, Prrx1, in fibroblast activation following lung injury. Overall, the work suggests that PRRX1 plays a functional role downstream of TGFb1 to elicit some aspects of the fibrotic response and that PRRX1 could represent an important therapeutic target to treat fibrosis. The strengths of this work are the multiple approaches applying human and mouse lung tissue used by the authors to test the role of PRRX1 in lung fibrosis, however, in its current form, major limitations need to be addressed.

eLife Assessment

The study has advanced our mechanistic understanding of lung regeneration. While the importance of regeneration of alveolar capillaries for long response to injury has been long recognized, the regulation of this process has not been well understood. Your study provides novel, comprehensive, and compelling evidence that the expression of the transcription factor Atf3 in alveolar capillary endothelial cells plays a critical role in the regeneration of alveolar capillaries following lung injury.

eLife assessment

This study concerns an important area, that of monoallelic expression, but the study does not provide sufficient information about the candidate regulatory RNA to provide a significant advance over previous work, which should also be discussed in more detail.

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 study examines the principles according to which neurons connect to each other in the brain. The authors find that data could be best explained by the homophillic wiring principle where neurons preferentially connect to neurons within overlapping groups. The work will provide a valuable resource to the neuroscience community once analyses are standardized across various datasets included.

eLife assessment

This valuable work advances our understanding of the acoustic features driving the attraction of female mice to male vocalizations. The evidence supporting the conclusions is solid, with well-designed place preference assays and manipulations of male song structure. The work will be of broad interest to neurobiologists and ethologists working on mouse social interactions, auditory processing and communication.

eLife assessment

This manuscript combines cryo-EM and a suite of compelling whole cell and proteoliposome transport assays to establish the mechanism and structure of the full-length human SLC26A6 chloride/bicarbonate exchangers, including the first partial view of the previously unresolved IVS region of an SLC26 STAS domain. In combination with prior studies on additional SLC26 paralogs, including the SLC26A9 paralog initially reported by the same group, the current study provides important insight into the mechanistic diversity of the SLC26 transporters. This study is of interest to the biophysics community and the field of membrane transport.

eLife assessment

This study evaluated how naturalistic behaviors are encoded in the striatum by analyzing neural ensembles engaged during grooming behavior. The study shows that neural responses are highly heterogeneous during grooming, but ensembles were detected in which units were more correlated during grooming than during the entire session. This study presents an important contribution to the field by shedding light on how ensembles of neurons encode innate behavior. The results are convincing.

eLife assessment

This important study uses an innovative genome-wide approach and targeted testing to identify S. aureus genes that affect susceptibility to serum, serum-derived antimicrobial products, and commonly used antibiotics. The findings are significant in that they highlight evidence of evolution of virulence determinants in the setting of exposure to host stressors expected to be present during bacteremia and antibiotic therapy. The evidence is solid, but the presentation could be improved by providing details that clarify the methods and highlighting the limited current understanding of the major target, tcaA.

eLife assessment

This contribution provides important insights into the thermodynamic landscape of cation transporters of the Cation Diffusion Facilitator (CDF) superfamily, together with a detailed structural investigation of the role of the three zinc(II) binding sites of YiiP. Despite the relatively low resolution of the cryo-EM structures presented in this work, the combination of structural, functional and modeling techniques yields solid evidence for the proposed model. This work will be of interest to biologists and biophysicists that work with membrane transporters; it is an excellent example of how different techniques can be combined to obtain relevant information on the complex mechanism of action of a transporter.

eLife assessment

This important study combines behavioral and imaging experiments to understand how levels of important brain chemicals shape the processing of information in the brain in children and young adults. The sample size and data quality are outstanding and some of the data are quite convincing. However, the calculation and interpretation of the brain chemical concentration measurements as well as the interpretation of the model-based behavioral parameters are not fully justified and support for the overall conclusions is incomplete. This work will be of interest to neuroscientists, psychologists, and neuroimaging researchers investigating the developing brain in health and disease.

eLife assessment

This is a valuable addition to the literature as it helps us understand the role of tRNA modifying enzymes in Mycobacterium tuberculosis. By knocking out one of the enzymes, the authors convincingly demonstrate the importance of tRNA-modifying enzymes for intra-host growth of tubercle bacteria. Some of the claims regarding modification as well as the role in virulence could be strengthened through further bioinformatics and phylogenetic analyses as well as experimental approaches. The work will be of interest to microbiologists.

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 study presents a valuable 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, but some aspects of the analysis are incomplete and would benefit from additional experimental evidence to support the existence of different types of Müller glia and their distribution in the retina.

eLife assessment

This valuable study provides insights into mechanisms of placental aging and its relationship to labor initiation. The authors provide solid evidence and have thoroughly investigated the molecular characteristics of normal placental aging using in vivo and in vitro model systems and human placental tissue analysis to corroborate their findings. This work contributes to existing work in placental aging and preterm birth and will be of interest to reproductive scientists.

eLife assessment:

This valuable study presents convincing evidence that metabolite levels in Escherichia coli bacteria from a long-term evolution experiment have changed in consistent ways, which in turn can be explained by recurrent mutations in regulatory genes that affect enzyme expression levels. The use of high-resolution mass spectrometry measuring bulk metabolite levels, in combination with existing gene expression and DNA sequencing datasets provides valuable information linking changes in an organism's genome, transcriptome, and metabolome. The current version of the paper lacks clarity in parts, most critically in the introduction, and would benefit from some rewriting to improve its structure, precision, and readability.

eLife assessment

This study reports important findings regarding the systemic function of hemocytes controlling whole-body responses to oxidative stress. The evidence in support of the requirement for hemocytes in oxidative stress responses as well as the hemocyte single-nuclei analyses in the presence or absence of oxidative stress are convincing. In contrast, the genetic and physiological analyses that link the non-canonical DDR pathway to upd3/JNK expression and high susceptibility, and the inferences regarding the function of hemocytes in systemic metabolic control are incomplete and would benefit from more rigorous approaches. The work will be of interest to cell and developmental biologists working on animal metabolism, immunity, or stress responses.

eLife assessment

Muroňová et al. provide valuable information about CDCC146 as a centriole and microtubule associated protein essential for sperm flagellar formation and male fertility. Mutations were identified in human patients suffering from MMAF syndrome, but the evidence that these human mutations were causative of the abnormal phenotype is incomplete. To further explore the causality, mouse models are generated and the findings from the mouse study, support that the key roles of CCDC146 for microtubule-based structures throughout sperm development in general but requires statical analysis.

eLife assessment

This important study reports investigation of the dynamics of PKA at the single-cell level in in vitro and in epithelia in vivo. Using different fluorescent biosensors and optogenetic actuators, the authors dissect the signaling pathway responsible for PKA waves, finding that PKA activation is a consequence of PGE2 release, which in turn is triggered by calcium pulses, requiring high ERK activity. The evidence supporting the claims is solid. At this stage the work is still partly descriptive in nature, and additional measurements would increase the strength of mechanistic insights and physiological relevance.

eLife assessment

This manuscript reports important findings regarding the potential for self-policing and a division of labor among biofilm-inhabiting Bacillus cells. Overall, this work is robust in its use of various techniques and provides solid insights into the intersections of well-understood regulatory controls and the suppression of cheaters. Despite some concerns about the data, all reviewers were excited by the potential impact of this work. Colleagues interested in microbial social interactions should find this study's narrative about the internal mediation of cell differentiation particularly valuable.

eLife assessment

This study presents important findings on the mechanism as to how Mycobacterium-containing vacuoles are recognized by host cell factors and subjected to membrane repair or autophagic degradation using Dictyostelium discoideum as a useful model. The evidence for the role of TrafE in damaged-membrane repair and xenophagy induction is convincing, but that in autophagosome closure is rather incomplete.

eLife Assessment:

Zemel and colleagues provide a report on the fundamental electrophysiological properties of motor neurons driving song in the zebrafish and provide complementary information about cell morphology, pharmacological sensitivity, and ion channel expression and heterogeneity. They provide mainly convincing data supporting the claim of a particular ion channel class, Kv3, that plays an important role in fast electrical spiking (action potentials) in song-related neurons.

eLife assessment<br /> <br /> Within this paper, the authors describe a rapid and easy-to-implement CRISPR/Cas9-mediated knock-in approach to precisely insert large transgenes in the African turquoise killifish. The established method will be instrumental for many researchers working with unusual model species, and, in particular, will expand the killifish community toolbox. It will revolutionize the field and bring the killifish, an emerging animal model in aging biology and disease modeling in vertebrates, into the spotlight even more.

eLife assessment

This valuable study addresses the anticipated but poorly understood interconnections between ER proteostasis and lipid metabolism. The authors discovered key metabolic enzymes required for integration of ER stress and lipid synthesis and followed up with several direct experiments that provide solid evidence for a broad conservation of the described interactions.

eLife assessment

Motivated by previous demonstrations that cognitive modulation of heart beat evoked responses (HER) might distinguish minimally consciousness state and unresponsive wakefulness syndrome patients, the present work sought to determine whether contextual processing of auditory regularities (local-global paradigm) differentially affects HER in these patient groups. The results provide preliminary evidence for the usefulness of EEG and oddball paradigms in informing diagnosis of the state of consciousness. This paper will be of interest to those researchers studying signs of consciousness in post-comatose patients and more broadly to those studying brain-body interactions. However, some aspects of the study design and data analysis need to be clarified, particularly as these affect the conclusions that can be drawn.

eLife assessment

Hernandez-Perez et al. perform a detailed analysis of Kazrin, a widely expressed protein that appears to be involved in many diverse cellular processes, but whose exact function is unknown. The authors employ mouse embryonic fibroblasts and biochemistry to investigate the function of Kazrin and determine that Kazrin promotes the dynein/dynactin-dependent transport of early endosomes. These findings are valuable to those in the field of intracellular transport, but the story will benefit from additional experiments to prove the main claims, or from textual modifications.

eLife assessment

In the current study, Mondoloni and colleagues reveal how a selective nicotine receptor in the interpeduncular nucleus is involved in nicotine consumption, which is an important contribution to the understanding of individual differences in drug addiction. However, the preferred hypothesis would benefit from testing in additional experimental models, metabolic assessment, and cell-type specificity.

eLife assessment

The cerebellum plays a critical role in motor learning, but exactly which forms of synaptic plasticity contribute to learning, as well as the underlying molecular mechanisms, remain poorly understood. In this study, Wang and colleagues show that presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapse is required for one form of motor learning, and involves a previously-unknown signaling cascade, where EPAC activation leads to PKCε-dependent threonine phosphorylation of RIM1α. This study provides new insights into the underlying mechanisms and functional consequences of presynaptic LTP.

eLife assessment

This paper expands on prior work by using whole-brain calcium imaging in Drosophila to examine how spontaneous and forced walking and turning affect neural activity in the brain. The measurements presented will serve as a valuable resource for the fly systems neuroscience community and suggest many testable hypotheses that may serve as the basis for future studies. Analyses of the data are solid, but conclusions drawn should be presented with more caveats. This article will be of interest to neuroscientists engaged with the central problem of how behavior modulates neural activity.