eLife assessment

The authors describe the dynamics underlying allostery of the adenosine A1 receptor, providing valuable insights into the receptor's activation pathway. The enhanced sampling molecular dynamics simulations of available structural data, followed by network analysis, reveal transient conformational states and communication between functional regions. The authors carefully state the limitations of their work, including the restricted convergence of the free energy landscape and missing water-mediated hydrogen bond coordination. Collectively, they provide a convincing framework for advancing rational design strategies of specific modulators with desired modes of action.

[Editors' note: this was originally reviewed and assessed by Biophysics Colab]

eLife assessment

Yamamoto and Matano provide solid evidence that a G63E/R CD8+ T-cell escape mutation in the accessory viral protein Nef may facilitate the induction of neutralizing antibody (nAb) responses in rhesus macaques infected with SIVmac239. Functional analyses support that this mutation specifically impairs Nef`s ability to stimulate PI3K/Akt/mTORC2 signalling. This important study suggests that the accessory viral Nef protein impairs B cell function and effective humoral immune responses and is of interest for researchers and physicians interested in HIV/AIDS and vaccine development.

eLife assessment

This manuscript describes useful data on the mechanisms underlying the activation of the receptor tyrosine kinase FGFR1 and stimulation of intracellular signaling pathways in response to FGF4, FGF8, or FGF9 binding to the extracellular domain of FGFR1. Solid quantitative binding experiments are presented to demonstrate that FGF4, FGF8, and FGF9 exhibit distinct binding affinities towards FGFRs.

eLife assessment

This study of extrachromosomal DNA (ecDNA) aims to identify genes that distinguish ecDNA+ and ecDNA- tumors. This timely study is important in addressing the genes responding to the amplification of the ecDNA. The data presented are for the most part solid, there were concerns regarding the clarity in the description of the analysis methods and whether the evidence for specific genes required to maintain the ecDNA+ state was entirely conclusive.

eLife assessment:

This study introduces a valuable paradigm in the field of adipose tissue biology: blocking triglyceride storage in adipose tissue does not lead to lipodystrophy and impaired glucose homeostasis but instead improves metabolic health. The evidence supporting these claims is convincing, based on a comprehensive metabolic analysis, although mechanistic studies would strengthen the study and its impact. This study will be of high interest to those in the adipose tissue biology and metabolism fields.

eLife assessment

This study provides an important, original framework to study locomotion on the ground with physics-based simulations. Through numerical simulations, the authors propose that intermediate numbers of body modules and high body symmetry enhance speed. The evidence that evolution may favour bilateral symmetry and modularity for efficient directed locomotion is still incomplete, however.

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

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

eLife assessment

The manuscript describes a valuable theoretical calculation focusing on the structural changes in the photosynthetic reaction center postulated by others based on time-resolved crystallography using X-ray free-electron laser (XFEL) (Dods et al., Nature, 2021). The authors provide solid arguments that calculated changes in redox potential Em and deformations using the XEFL structures may reflect experimental errors rather than real structural changes.

eLife assessment

This study presents valuable findings on Legionella pneumophila effector proteins that target host vesicle trafficking GTPases during infection and more specifically modulate ubiquitination of the host GTPase Rab10. The evidence supporting the claims of the authors is solid, although it remains unclear how modification of the GTPase Rab10 with ubiquitin supports Legionella virulence and the impact of ubiquitination during LCV formation. The work will be of interest to colleagues studying animal pathogens as well as cell biologists in general.

eLife assessment

This important study outlines a new role for caspases during cellular differentiation. The methodology used is convincing and state-of-the-art. The newly discovered cellular cascade described here uncovers that caspases can achieve high substrate specificity during differentiation. As such, the work will be of broad interest to cell biologists.

eLife assessment

In this valuable study, the authors seek to characterize the role of splicing factor SRSF1 during spermatogenesis with a conditional knockout for Srsf1 in male germ cells. The spermatogenesis phenotype is convincingly supported, but two central claims of the study, that SRSF1 is required for spermatogonial homing and self-renewal and that this function is mediated by regulation of splicing of the gene Tial1, are inadequately supported. Support is inadequate because homing and self-renewal phenotypes were not explicitly tested, and functional data were not provided to support a role for alternative splicing of Tial1 in the fertility phenotype. The work will be of interest to reproduction and stem cell biologists.

eLife assessment

This important study presents findings with broad implications for the use of AlphaFold2 models in ligand binding pose modeling, a common task in protein structure modeling. The computational experiments and analyses provide compelling results for the GPCR protein family data, but the conclusions are likely to apply also to other proteins and they will therefore be of interest to biophysicists, physical chemists, structural biologists, and anyone interested or involved in structure-based ligand discovery.

eLife assessment

This useful study investigates the roles of C. elegans MYRF transcription factors myrf- and myrf-2 in the temporally controlled activation of the miRNA lin-4, a key step in larval developmental timing. While some of the findings are solid, other evidence is incomplete because of concerns about the technical approaches. This study provides information that will be useful to those interested in the regulation of lin-4 expression in C. elegans.

eLife assessment

Resistance of Plasmodium falciparum to artemisinin, which has become a threat to malaria control, has been linked to mutations in the parasite protein K13. This study provides important new insights into the function of K13 in the endocytosis of hemoglobin, a central process for the activation of artemisinin derivatives. Conditional protein mislocalization combined with high-resolution imaging provides convincing evidence that K13 is involved in the formation of cytostomes, the structures involved in the endocytosis of host cytosol. This study will be of interest to scientists working on parasite biology as well as antimalarial drug resistance.

eLife assessment

This paper reports valuable results regarding the potential role and time course of the prefrontal cortex in conscious perception. Although the sample size is small, the results are clear and convincing, and strengths include the use of several complementary analysis methods. The behavioral test includes subject report so the results do not allow for distinguishing between theories of consciousness; nevertheless, results do advance our understanding of the contribution of prefrontal cortex to conscious perception.

eLife assessment

This paper is of interest to researchers and policy makers involved in cervical cancer prevention. The paper provides insight into how the Covid19 pandemic accelerated changes in organized cervical cancer screening. The claim that self-sampling led to a major improvement of test coverage seems somewhat exaggerated and alternative hypotheses to those provided by the authors on the population who chose self-sampling are possible. Nonetheless, this is a valuable piece of work given the scope of the intervention(s) and the precedent it sets i.e. a crisis can in fact accelerate positive changes in screening that have been academic possibilities rather than practical realities.

eLife assessment

This paper addresses the important question of presynaptic homeostasis and convincingly demonstrates antagonistic interactions between Spinophilin and Syd-1 in this process. It also provides a useful hypothesis for the downstream mechanisms.

eLife assessment

Moises and Harel generate an important set of novel molecular tools in African turquoise killifish, an innovative model to study aging biology. The new solid tools described in this paper can boost this buddying model system for broad biotechnological applications. The authors showcase the efficacy of their tools in the context of peptide hormones involved in growth and gonad development. The killifish community will greatly benefit from these novel tools and the relevance of the developed methods will likely go beyond the killifish community.

eLife assessment

This study addresses an important question in the field of antimicrobial chemotherapy: whether combinations of enzyme inhibitors that select for mutations that confer resistance to one inhibitor and at the same time increased sensitization to the other inhibitor can provide a path towards mitigating resistance risks. The authors here investigated one such combination of inhibitors of Plasmodium falciparum DHODH (dihydroorotate dehydrogenase), finding that despite "collateral sensitivity", it was still possible to select a mutation that mediated resistance to both inhibitors without any change in parasite fitness. Additional cross-susceptibility and structural modeling strengthen this study, which is performed to a high technical standard and presents a convincing body of data.

eLife assessment

The valuable study by Dumeaux et al examines the transcriptional response to antifungal treatment in the major opportunistic human fungal pathogen Candida albicans. Using solid methodology, including a novel droplet-based single cell transcriptomics platform, the authors report that fungal cells exhibit heterogeneity in their transcriptional response to antifungal drug treatment. The ability to study the trajectories of individual cells in a high-throughput manner provides a novel perspective on studying the emergence of drug tolerance and resistance in fungal pathogens.

eLife assessment

This manuscript addresses the important issue of hemodynamic response function (HRF) variability across brain areas and will be valuable to researchers who use fMRI and other types of functional imaging that rely on neurovascular coupling. Using simulations and experiments, the authors provide solid evidence that differences in the HRF can impact spectrum-based metrics such as ALFF and fALFF. A better understanding of the variability of the HRF is critical for the proper interpretation of activation onset times and of differences observed in clinical populations where both neural and vascular alterations can be expected.

eLife assessment

This valuable study shows that Rab12 is required for LRRK2 activation. However, while some of the data are compelling, some claims, especially the ones related to LRRK2's membrane association are not supported. Addressing discrepancies between figures (pointed out by reviewers) and re-writing certain sections will greatly improve this manuscript.

eLife assessment

This exceptional work substantially advances our understanding of the mechanics of the Reissner's fibre (RF) by performing in-vivo experiments that track and analyze the behavior of the RF when it is cut and the behavior of ciliated cells touching the RF when contact is interrupted. The data is valuable and the conclusions are compelling. The work will be of broad interest to many research communities including developmental neuroscience and cilia biology.

eLife assessment

This manuscript reports the fundamental finding that an oligomeric protein kinase, CaMKII, can be phosphorylated by another molecule of the holoenzyme in a manner that does not involve subunit exchange. The evidence for the main conclusion is compelling, supported by several independent experiments. If independently confirmed in future, the study will stand as having provided a novel regulatory mechanism for the autophosphorylation of this kinase. The work will be of broad interest to molecular and cellular neuroscientists as well as biochemists.

eLife assessment

This is an important analysis of two sleep datasets in children and adolescents that contributes to our understanding of sleep spindle and slow oscillation dynamics during development and is expected to be of interest to interdisciplinary fields including development and sleep. The analyses are solid and adequately complex to capture the changes in sleep spindle to slow oscillation coupling between the age groups. However, the paper would be strengthened by performing the same analyses in an adult sample to sufficiently characterize the maturation of sleep spindles and their coupling to slow oscillations.

eLife assessment

This study presents a valuable finding on the associations and causal relationship between second primary cancers and the initial diagnosis of a primary cancer via using a large database. The evidence supporting the claims of the authors is solid. The work will be of interest to cancer clinicians.

eLife assessment

This important study combines engineered mesenchymal stem cells together with mouse models of kidney injury to determine the ability of these cells to reduce kidney damage upon acute kidney injury. The evidence supporting the claims is solid, although the inclusion of more than one type of stem cell and the use of male mice which are more prone to acute kidney injury, would strengthen the study. This work will be of interest to both basic scientists and clinicians working on mechanisms of kidney injury and repair.

eLife assessment

This important study identifies the functional consequence of myelination of interneuronal axons on circuit function by showing that 4.1B deletion leads to altered myelination in a subset of interneurons and altered intrinsic and synaptic physiological parameters. The authors' conclusions about how myelination of inhibitory axons affects physiological properties are based on solid evidence using a combination of imaging and electrophysiological approaches.

eLife assessment

This is an important study that uses chromatin accessibility as a measure to determine the impact of neuronal activity on the state of chromatin regulatory elements in striatal neurons. The authors provide convincing evidence of how Pdyn gene expression is highly dependent on a distal regulatory genomic region both at basal and upon neuronal activation in this particular system, a mechanism conserved as well in human neuronal cells. Although some findings are not novel, this paper ties previous findings all together in one place and uses the analysis to then identify a functionally relevant and conserved enhancer for the prodynorphin gene with potential relevance for neuropsychiatric disorders beyond basic cellular neuroscience.

eLife assessment

This is an important study that characterized the activity of optogenetically identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) in mice performing a memory-guided T-maze task. The authors show that subpopulations of dopaminergic and GABAergic neurons exhibited choice-related activity during the delay period, which was enhanced when the task requires short-term memory. The reviewers found that the results are surprising, novel, and convincing, while some relatively minor issues were pointed out regarding the data presentation and analysis.

eLife assessment

This study proposes a deep learning-based segmentation pipeline of fetal brain MRI, with parcellation based on a newly implemented atlas. This represents an important contribution to the field of developmental neuroscience and pediatric neuroimaging, especially as the pipeline and atlas are publicly available. The evidence for the pipeline robustness and atlas relevance is convincing given the extensive validations provided and the very high-quality ground truth dataset. Although beyond the state of the art, the study would benefit from further comparisons with existing methods and additional evaluations of the framework generalizability according to image quality, subject age or brain abnormalities.

eLife assessment

The authors provide a valuable analysis of what neural circuit mechanisms enable varying the speed of retrieval of sequences, as needed for say reproducing motor patterns. Their use of heterogeneous plasticity rules to allow external currents to control speed of sequence recall is a novel alternative to other mechanisms proposed in the literature. They perform a solid characterization of relevant properties of recall via simulations and theory, which would benefit from a better mapping to biologically plausible mechanisms.

eLife assessment

This important study addresses the fundamentally unresolved question of why many thousands of small-effect loci contribute more to the heritability of a trait than the large-effect lead variants. The authors explore resource competition within the transcriptional machinery as one possible explanation with a simple theoretical model, concluding that the effects of resource competition would be too small to explain the heritability effects. The topic and approximation of the problem are very timely and offer an intuitive way to think about polygenic variation, but the analysis of the simple model appears to be incomplete, leaving the main claims only partially supported.

eLife assessment

This is a useful study of the connection between the ubiquitin ligase protein deltex and the wingless signaling pathway. Two different links are inferred from genetic interactions in vivo between loss-of-function mutations and overexpression. While providing useful in vivo physiological context, the approach is necessarily incomplete in so far as it cannot distinguish between direct and indirect mechanisms.

eLife assessment

This study provides an important cell atlas of the gill of the mussel Gigantidas platifrons using a single nucleus RNA-seq dataset, a resource for the community of scientists studying deep sea physiology and metabolism and intracellular host-symbiont relationships. The work, which offers solid insights into cellular responses to starvation stress and molecular mechanisms behind deep-sea chemosymbiosis, is of relevance to scientists interested in host-symbiont relationships across ecosystems.

eLife assessment

The authors provide a fundamental resource, detailing genetic variation of nutrient-responsive islet calcium regulation in mice through the lens of proteomics. The evidence for the mechanisms identified using this resource is compelling and strongly supported by integration with results from genome-wide association studies in humans. The construction of a streamlined and searchable web interface for the data will maximize their accessibility and utilization by the community.

eLife assessment

This study presents a valuable dataset and tool that can aid in arthropathies' assessment, potentially enabling such evaluation to be done outside the lab. There is solid evidence supporting the comparison between the force plate and insole data, which can be strengthened by improvements in cross-validation, but the evidence for distinguishing disease signatures and elimination of walking speed as a factor is inconclusive and would need further analysis. This work will be of interest to physical therapists, clinicians, and researchers in the field of ankle/knee/hip osteoporosis and other lower limb joint diseases.

eLife assessment

This study makes important contributions to our understanding of spinal locomotor circuits by manipulating the function of excitatory and inhibitory V2 interneurons and revelaing their role in locomotor control. The data collected and the methods used by the authors are solid and the authors suggest that V2 excitatory and inhibitory neurons have antagonistic functions in intralimb coordination. This work will be of broad interest for neuroscientists studying development and function of motor circuits.

eLife assessment

This study seeks to determine how synaptic relationships between principal cell types in the olfactory system vary with glomerulus selectivity and is therefore valuable to the sub-field. The methodology is solid, but technical limitations require that claims regarding local interneurons be tempered as they were grouped with other neuron types for analyses, and with only one sample from each glomerulus, it is difficult to assess the import of differences between glomeruli without measures of inter-animal variability.

eLife assessment

This is an important study about the mechanisms underlying our capacity to represent and hold recent events in our memory and how they are influenced by past experiences. A key aspect of the model put forward here is the presence of discrete jumps in neural activity with the posterior parietal region of the cortex. The strength of evidence is largely solid, with some weaknesses noted in the methodology. Both reviewers suggested ways in which this aspect of the model can to be tested further and resolve conflicts with previously published experimental results, in particular the study by Papadimitriou et al 2014 in Journal of Neurophysiology.

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. These findings constitute a fundamental contribution to the field, and the rigor of the analyses make this manuscript compelling.

eLife assessment

This important study utilizes the nematode C. elegans and mammalian cell culture to investigate the role of MML-1/Mondo in conserved regulation of metabolism and aging. The evidence supporting the conclusions is compelling in some areas, such as localization, upstream pathways, and conservation. It is still incomplete in other areas, such as longevity pathway analysis and the link between Mondo and the key downstream mitochondrial metabolic pathways identified. The paper will be of interest to a broad range of biologists studying aging, metabolism, and transcriptional regulation.

eLife assessment

This is an important follow-up study to a previous paper in which the authors reconstituted CO2 metabolism in Escherichia coli (autotrophy). Here, the authors define a set of three mutations that promote autotrophy, highlighting the malleability of E. coli metabolism. The authors make a convincing case that mutations in pgi are loss-of-function mutations that prevent metabolic efflux from the reductive pentose phosphate autocatalytic cycle, but claims about the role of mutations in two other genes - crp and rpoB - are currently incomplete. This research will be particularly interesting to synthetic biologists, systems biologists, and metabolic engineers aiming to develop synthetic autotrophic microorganisms.

eLife assessment

This study presents a valuable deep learning-based model for predicting fracture within the next five years from just a standard distal radius and ulna scan obtained using high-resolution computed tomography images. The evidence supporting the conclusion that the model-predicted fracture prediction score can be used clinically to identify women at risk of fracture more effectively than with the current standard clinical approach is convincing. This work will be of interest to biomechanists and biomedical engineers working on osteoporosis.

eLife assessment

This study provides important findings on the distinct functions of resident and recruited macrophages during cardiac healing after myocardial ischemia. Using state-of-the-art fate-mapping models and genetic and pharmacological targeting approaches, the authors provide solid evidence that the absence of resident macrophages do not influence infarct size but instead alter the immune cell crosstalk in response to injury. However, the functional evaluation of resident macrophages is limited by potential off target effects in ∆FIRE mice. This study should be of interest to the fields of Development, Immunology and Cardiology.

eLife assessment

This manuscript provides novel and important findings regarding the impact of noradrenergic signaling from the locus coeruleus on hippocampal gene expression. The locus coeruleus is the sole source of noradrenaline to the hippocampus and many rapid molecular changes induced by stress are regulated by noradrenaline. This manuscript provides a rigorous investigation into hippocampal genes uniquely regulated by noradrenaline in the presence or absence of stress. Data were collected and analyses were performed using solid methodology, and the results mostly convincingly support the conclusion made with few weaknesses. The study would benefit from a more comprehensive analyses of sex differences.

eLife assessment

This useful study presents data regarding the presence of synaptic proteins in the extracellular vesicle present in the blood of Parkinson's patients and healthy people, trying to correlate changes in such levels with the progression of Parkinson´s symptoms. The results are preliminary, suggesting that these biomarkers might be useful for this purpose. The evidence is incomplete, and more adequate methods to isolate the extracellular vesicles and quantify the proteins are recommended. Also, a better presentation of the results will help the reader to understand the significance of the report, and in addition, more focused Introduction and Discussion sections are recommended.

eLife assessment

This study presents a valuable new behavioral apparatus aimed at differentiating the strategies animals use to orient themselves in an environment. The evidence supporting the claims is solid, with statistical modeling of animal behavior. Overall, this study will attract the interest of researchers exploring spatial learning and memory.

eLife assessment

By combining electrophysiological analysis of mutant channels and molecular dynamics simulations, this important study identifies a common binding site for two structurally distinct activators of KCNQ1-KCNE1 channels. The findings represent an important advance for the field, with convincing functional and computational data to support the claims. The work will be of interest to those studying the binding of small molecule drugs to membrane protein complexes.

eLife assessment

This valuable study describes an interesting synergism between macropinocytosis and Wnt signaling in multiple biological systems. The main claims are at least partially supported with solid evidence. The pharmacological manipulations comes with a number of caveats, and the mechanistic basis of the described synergism remains unclear. The study will be of interest to cell biologists and biomedical researchers, particularly in the Wnt field and in tumor biology.

eLife assessment

This important study uses near full-length HIV-1 sequencing to examine proviral persistence in various tissues derived from three individuals who received antiretroviral therapy until time of death. Intact as well as defective HIV-1 proviruses are found at various anatomical sites including the central nervous system, results that are convincing and relevant for our understanding of latent viral reservoirs, especially in the brain.

eLife assessment

Alpha-synuclein is a synaptic vesicle associated protein that is linked to a number of neurodegenerative disorders. In this manuscript, the authors provide compelling evidence of alpha-synuclein's interaction with E-domain synapsins as the main culprit mediating the suppression of neurotransmitter release and synaptic vesicle recycling by alpha-synuclein. This important work provides molecular mechanisms underlying the pathophysiological functions of alpha-synuclein.

eLife assessment

This useful study presents a genetically encoded barcoding system that could not only advance transcriptomic studies but that also has potential further applications, such as in high-throughput population-scale behavioral measurements. The evidence supporting the claims of the authors are currently inadequate to demonstrate that the method is indeed greatly superior to existing approaches in behavioural and transcriptomic studies.

eLife assessment

The manuscript looks at how dysregulated purine metabolism impacts the behavior, neural circuits and survival of the fruit fly with the possibility of generating a model for Lesch-Nyhan Disease. The study is valuable but the strength of evidence is currently incomplete regarding the use of this model for LND.

eLife assessment

This study presents a valuable analysis of the effects of covariates, such as age, sex, socio-economic status, or biomarker levels, on the predictive accuracy of polygenic scores for body mass index; it also presents approaches for improving prediction accuracy by accounting for such covariates. While the analyses are solid, the study falls short of providing a cogent interpretation of key findings, which could be of great interest and utility. The work will be of interest to people using and developing methods for phenotypic prediction based on polygenic scores.

eLife assessment

Zhao et al describe a novel function for RAPSYN in bcr-abl fusion associated leukemia. They show that RAPSYN stabilizes the oncogenic BCR-ABL fusion protein. Their findings are important and the strength of findings is convincing. The reviewers have made suggestions about further strengthening the rigor by use of more primary samples.

eLife assessment

This study, based on a large-scale data set and established behavioural tasks, has the potential to provide a valuable contribution to the literature if the authors could combine and correlate their behavioural evaluations with neural data and/or clinical assessments. As a standalone dataset, however, the current study appears incomplete because it does not go beyond merely replicating existing findings in a large cohort of children. In order to elevate their study, the authors are encouraged to publish their full dataset and explore the relationship between behavioural and neural or clinical data.

eLife assessment

This valuable study poses a provocative mechanism of channel activation of the mechanically activated ion channel TREK-1. The data provide evidence that the application of shear to cells causes a redistribution of both TREK-1 and an associated enzyme, PhospholipaseD2 in the membrane that increases the enzyme activity. The work offers a new mechanism; however, evidence is incomplete and restricted to the over-expression system used.

eLife assessment

The aim of this valuable study is to identify novel genes involved in sleep regulation and memory consolidation. It combines transcriptomic approaches following memory induction with measurements of sleep and memory to discover molecular pathways underlying these interlinked behaviors. The authors explore transcriptional changes in specific mushroom body neurons and suggest roles for two genes involved in RNA processing, Polr1F, and Regnase-1, in the regulation of sleep and memory. At present, the strength of the evidence is incomplete to support the main claim that these two genes establish a definitive link between sleep and memory consolidation.

eLife assessment

This paper demonstrates that subjective treatment effects are an important and under appreciated element in randomized controlled neurostimulation trials. The authors present compelling evidence that has significance in the context of other modalities of treatment, treatment for other diseases, and plans for future randomized controlled trials. This is an important examination and will help guide the theoretical framework for future inquiry with lessons learned for neurostimulation and other emerging areas of psychiatric research.

eLife assessment

This paper provides a fundamental expansion of our understanding of vestibular compensation into transient and partial dysfunction, as well as insights into the adaptation of visual reflexes in this process. The conclusions are convincingly supported with paired histological and behavioral measurements, which are additionally modeled for further interpretation. This work would be of interest to neuroscientists working in multisensory integration and recovery mechanisms.

eLife assessment

This paper provides useful information regarding visuospatial working memory performance in patients with MS compared to healthy controls using a relatively novel continuous measure of visual working memory. The strength of evidence provided, however, is incomplete reflecting the need for better clarification of inclusion/exclusion criteria and underlying pathophysiology. The paper will be of interest to those working in the field of clinical neuroscience.

eLife assessment

This article describes a useful python-based image-analysis tool for bacteria growing in the 'mother-machine' microfluidic device. This new method for image segmentation and tracking offers a user-friendly graphical interface based on the previously developed, promising environment for image analysis 'Napari'. The authors demonstrate the usefulness of their software and its robust performance by comparing it to other methods used for the same purpose. The comparison provides solid support for the new method, although it would have been even stronger if tested using data sets from other groups. This article will be of interest for scientists who utilize the 'mother machine', not least because it also provides a short overview of how to set up this widely used device.

eLife assessment

This manuscript presents valuable findings about how sphingolipids and membrane contact sites are involved in promoting vacuole fission in S. cerevisiae. While a connection between the levels of sphingolipids and vacuole homeostasis is interesting, the data pertaining to this issue are incomplete and do not fully support the claim for causality between altered lipid composition and organelle dynamics. The work will be of interest to cell biologists working on organelle biogenesis and lipid metabolism.

eLife assessment

In this important study, the rabbit was used as a non-rodent mammalian model to show that DMRT1 has a testicular promoting function as it does in humans. The experiments are meticulous and compelling, and the arguments are clear and convincing. These results may explain the gonadal dysgenesis associated with mutations in the DMRT1 locus in humans and highlight the need for mammalian models other than mice to better understand the process of gonadal sex determination in humans.

eLife assessment

In this valuable manuscript, the authors attempt to examine the role of long non-coding RNAs (lncRNAs) in human evolution, through a set of population genetics and functional genomics analyses that leverage existing datasets and tools. Although the methods are at times inadequate - for example, suitable methods and/or relevant controls are lacking at many points, and selection is inferred sometimes too quickly - the results nonetheless point towards a possible contribution of long non-coding RNAs to the evolution of human biology and they suggest clear directions for future, more rigorous study.

eLife assessment

This paper reports important findings on a potent activator of the YAP pathway, demonstrating its mechanism through alternative splicing changes. The authors provide convincing evidence to support their claims, although more consistent inhibitor concentrations would have strengthened the study. This research is of interest to biologists studying alternative splicing or the Hippo pathway, with significant implications for medical research.

eLife assessment

This important study helps to elucidate the mechanism by which the agr quorum-sensing system in Staphylococcus aureus contributes to virulence. The results are supported by solid evidence using state-of-the-art methods. The linkage of metabolism and virulence in this pathogen will be of interest to the areas of microbiology, infectious diseases and immunology.

eLife assessment

This study adds a valuable new perspective to a long-standing question: What controls the repair of photosystem II (PSII), a key process in maintaining and optimizing photosynthesis? The work supports a role for chemical modification in the recognition and subsequent degradation of a key protein subunit of PSII by a bacterial-type protease, suggesting that tryptophan oxidation of components of the photosynthetic apparatus after high light stress plays a critical role in initiating the PSII repair system. The evidence supporting the authors' conclusions is solid, although their arguments would be strengthened by additional experiments.

eLife assessment

This study provides valuable insights into the dynamic interplay between the starvation and hyper-osmotic stress responses in budding yeast, where the presence of one stress can impact the concurrent effects of another perturbation. Using microfluidic devices and extensive quantitative analyses of time-series responses, the authors applied concurrent (in-phase) or alternate (anti-phase) stresses. Their compelling analyses reveal some unexpected behaviors that could not have been guessed from simpler experimental designs, revealing that investigating complex environmental inputs can reveal new biological insights, even for well-studied systems.

eLife assessment

Cryo-EM has become the dominant method in structural biochemistry, and making more efficient use of expensive microscope time is therefore of broad interest to academic and industrial users. The authors identify a bottleneck in cryoEM data collection, namely path optimization, and provide a valuable machine-learning model to overcome this bottleneck. The solid data presented suggests their model can replace a human operator to automate efficient data collection.

eLife assessment

This study is of fundamental significance, providing compelling data on the mechanism by which ULK4 regulates the transcription factor GLI2 and on the ULK4/STK36 interaction promoting GLI2 phosphorylation and activation of the sonic hedgehog (SSH) pathway. The work will be of interest to cell biologists and the signaling community in general.

eLife assessment

This study presents valuable findings showing the contrasting responses of two bacteria to the phytoplankton-derived compound azelaic acid. Metabolomic and transcriptomic data provide convincing evidence for activation of the assimilation pathway in one marine bacterial species and a stress response in another species. There is also solid evidence for azelaic acid altering marine microbial community structure in mesocosm experiments, but the underlying community-level mechanisms are not investigated in this study.

eLife assessment

In this important paper, the authors report a link between brumation 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 will be of broad interest to ecologists, evolutionary biologists, and those interested in global change biology. While the dataset involves significant field work and advanced statistical analyses, the manuscript would benefit from more explanation of the models, including why frogs are a good model in which to address these questions, and from general improvement in the structure and conciseness.

eLife assessment

This valuable study presents findings on the mode of action of MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c), and its impact on monocyte-derived macrophages. The authors present solid evidence for its increased expression in stimulated monocytes/macrophages, its direct bactericidal functions, as well as its role in the modulation of monocyte differentiation into macrophages. Since most of the data were generated from a cell line (THP1), future work is required to validate observations in primary cells and to further support the claims of this work.

eLife assessment

In this intriguing study, the authors offer a new metric, Codon Adaptation Index of Species (CAIS), which allows one to determine the strength of selection and effective population sizes using data on GC content and amino acid composition. This could be of broad use in molecular evolution, as it could be applied across species. The study offers important findings that may aid in our ability to compute key population genomic parameters from genomic data, and the conclusions are based on solid evidence.

eLife assessment

This important study addresses both the native role of the Plasmodium falciparum protein PfFKBP35 and whether this protein is the target of FK506, an immunosuppressant with antiplasmodial activity. The demonstration of the essentiality of FKBP35 in parasite growth relies on compelling genetic evidence. However, it remains unclear whether FK506 exerts its antimalarial activity through an FKBP35-independent mechanism.

eLife assessment

The adaptation of organs including the heart to chronic stress has interested biologists for a long time. Using an elegant model of overexpression of adenyly cyclase, the authors demonstrate posttranslational modification of the protein by phosphorylation, making an important contribution to approaches for the protection of heart performance in these transgenic mice. The convincing results open a new paradigm in understanding the biological effects of stress.

eLife assessment

This important study shows that a splice variant of the kainate receptor Glu1-1a that inserts 15 amino acids in the extracellular N-terminal region substantially changes the channel's desensitization properties, the sensitivity to glutamate and kainate, and the effects of modulatory Neto proteins. The functional data supporting the role of the 15 amino acid insert are solid, although some clarifications and more data are needed to determine the molecular mechanism by which the insert changes the functional profile of the channel. Even so, these findings substantially advance our understanding of splice variants among glutamate receptors and will be of interest to neuro- and cell-biologists and biophysicists in the field.

eLife assessment

This valuable study provides a comparative interactome analysis of α-arrestin in human and Drosophila. Using convincing methodology that includes affinity purification/mass spectrometry, bioinformatic tools and experimental data in human cells, the authors identify biological roles of protein-protein interactions (PPI) involving α-arrestin in the two species. This study will serve as a broadly relevant resource for understanding the PPI network of human and Drosophila α-arrestins.

eLife assessment

Using a newly developed C. elegans model of Alzheimer's disease that expresses Abeta aggregates extracellularly, the authors provide convincing evidence of a disintegrin and an ortholog of human ADAM9 that participate in removing these extracellular aggregates. The worm model presented in this important paper may be very useful to the Alzheimer Disease field.

eLife assessment

This important paper reveals distinct dynamics of two meiosis-specific cohesin complexes containing either REC-8 or CHO-3/4 in C. elegans: REC-8-cohesin is essential for sister chromatid cohesion in meiosis I and DNA double-strand break repair, while COH-3/4-cohesin, whose binding to meiotic chromosomes is stabilized by the cohesin accessory protein SCC-2, is necessary for loop-axis formation. The experimental evidence in the paper is solid based on cytological analysis using a conditional depletion of the gene. The work will be of interest to researchers working on meiosis and chromosome dynamics.

eLife assessment

This important manuscript, which describes the largest genetic association study to date, uses broadly compelling methods to address the genetic susceptibility to tuberculosis infection. A strength of the paper is that this multi-ancestry meta-analysis of genetic association studies than is more powerful than what has been done before. A weakness is that its main result is difficult to interpret due to the complexity of the genetic association signal.

eLife assessment

This is an important study on learning strategy differences in autism vs typically developing controls. The study identifies similar learning rates but different learning strategies. The evidence provided by the authors is convincing, relying on well-done tasks and fMRI analyses.

eLife assessment

This important work provides evidence regarding the impact of the COVID-19 pandemic on cervical cancer screening and precancer treatments in the USA. As there are few screening registries, the study provides solid evidence using a survey of health providers' impressions to assess whether cervical cancer screening services declined during the pandemic. The work will be of interest to public health professionals working in cancer prevention.

eLife assessment

Salmonella invades and survives in host cells via SPI-1 and SPI-2 type III secretion system mechanisms, with the SPI-2 system allowing for intracellular survival in Salmonella-containing vacuoles, which have a low-pH environment. Transcription of SPI-2 genes at low pH is activated by the DNA-binding SsrB protein, which sits at the top of the SPI-2 regulatory hierarchy. This study provides important insights as to how SsrB is allosterically affected by pH resulting in acid-dependent DNA binding. However, there are concerns about some experiments, and the evidence presented is not fully conclusive.

eLife assessment

This paper reports the fundamental discovery of adrenergic modulation of spontaneous firing through the inhibition of the Na+ leak channel NALCN in cartwheel cells in the dorsal cochlear nucleus. This study provides unequivocal evidence that the activation of alpha-2 adrenergic or GABA-B receptors inhibit NALCN currents to reduce neuronal excitability. The evidence supporting the conclusions is compelling, the electrophysiological data is high quality and the experimental design is rigorous.

eLife assessment

In this useful study, the authors explore regulatory cascades governing mammalian cochlear hair cell development and survival. They confirm previous studies that the transcription factors Pou4f3 and Gfi1 are necessary for hair cell survival, and use compelling evidence to demonstrate that the RNA binding protein gene RBM24 is regulated by Pou4f3, but not Gfi1. These findings will be of interest to those working on hearing loss, and hold significance for viral gene delivery methods aiming to manipulate gene expression.

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 convincing 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 provides valuable insights into how the brain parses the syntactic structure of a spoken sentence. A unique contribution of the work is to use a large language model to quantify how the mental representation of syntactic structure updates as a sentence unfolds in time. Solid evidence is provided that distributive cortical networks are engaged for incremental parsing of a sentence, although the contribution could be further strengthened if the authors would further highlight the main results and clarify the benefit of using a large language model.

eLife assessment

This paper describes important advances from the results of studies on atypical language lateralisation and how this might impact language behaviour, as well as its associations with reading skills and the prevalence of schizotypy and autistic traits. Despite most of the conclusions of this paper being supported by evidence, several aspects including the characteristics of participants tested, hypotheses/predictions, and data analysis, are incomplete and/or need some clarification. The work has implications for evolutionary hypotheses and our understanding of the effects of brain damage on distinct cognitive functions.

eLife assessment

This fundamental work substantially advances our understanding of retinol transport through the blood-brain barrier. The evidence supporting the conclusions is compelling, with rigorous biochemical assays. In general, the work is of broad interest to cell biologists, biochemists and neuroscientists.

eLife assessment

This valuable study provides a comprehensive assessment of cell-free DNA methylation to explore the ability of a newly-developed so-called "multimodal" predictive model in detecting malignancies and discriminating tumor of origin. The strength of evidence is solid and the logic beneath this study is well-organized. The study sheds insights into the early detection of malignancies with noninvasive methods using a large sample size with external validation cohort. This study will be of interest to cancer geneticists and oncologists for early diagnosis of cancer.

eLife assessment

This important study advances our understanding of the ways in which different types of communication signals differentially affect mouse behaviors and amygdala cholinergic/dopaminergic neuromodulation. Researchers interested in the complex interaction between prior experience, sex, behavior, hormonal status, and neuromodulation should benefit from this study. Nevertheless, the data analysis is incomplete at this stage, requiring additional analysis and description, justification, and - potentially - power to support the conclusions fully. With the analytical part strengthened, this paper will be of interest to neuroscientists and ethologists.

eLife assessment

This study provides a valuable tool for predicting binding between immune cells receptors and antigens based on protein sequence data. Its improvement over existing methods is supported by solid analysis, though more details on data, architectures and benchmarking are needed to fully justify this claim. This study will be of interest to immunologists and computational biologists.

eLife assessment

In Drosophila melanogater, 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 transcription factor. Although the findings reported here are important, the evidence supporting some of the claims is incomplete.

eLife assessment

This manuscript supports the intriguing idea that some aspects of novel learning can occur during sleep and outside of awareness. The authors provide solid evidence that presenting participants with novel words and their translations during sleep, especially during slow oscillation troughs, leads to the ability to categorize the semantic meaning of those words during awake testing 36 hours later. These findings represent a valuable contribution to the literature on unconscious processing and learning during sleep, although the claim that the results reflect episodic memory formation, in particular, deviates from typical use of this term in the literature.

eLife assessment

In this manuscript, Chakraborty et al address the role of IP3R1 in regulating store-operated calcium entry in neurons and neural progenitors. Long-standing observations in non-neuronal cells have shown that IP3Rs are not required for SOCE. In contrast to those findings, this manuscript determines that in neuronal cells, knockdown of IP3R1 suppresses SOCE by disrupting ER-plasma membrane contact sites. The paper supports a novel role for IP3R1 as a tether in promoting membrane contact sites which would have broad implications for a range of physiological processes including SOCE and lipid metabolism.

eLife assessment

This study reports valuable behavioral and computational observations regarding how passive exposure to auditory stimuli can facilitate auditory categorization. The combination of behavioral results in mice with a study of artificial neural network models provides solid evidence for the authors' conclusions. This paper will likely be of broad interest to the general neuroscience community.

eLife assessment

This is an important study on the role of the Ras/MEK/Erk signaling cascade in brain development, with both theoretical and practical implications in multiple fields. The authors reveal functional redundancy and shared function for Erk1 and Erk2 in determining medial ganglionic eminence derived glial number, and exclude a role for Erk1 and Erk2 in the regulation of GABAergic neuron number or initial specification of GABAergic identity. They combine multiple methods including Ribotags, electrophysiology, and chemogenetic stimulation using DREADDs towards comprehensive conclusions. Reviewers expressed concerns about the coherence of the findings, and about the selection of controls mouse lines. Heterozygous ERK1/2 mice are used as 'het controls' throughout the manuscript, however, reviewers felt that there was not sufficient evidence that ERK levels in heterozygous mice are similar to wildtype mice. Nevertheless, these compelling findings will be of interest to a broad readership, and especially readers interested in kinase function and neurodevelopmental syndromes.

eLife assessment

The work examines the effect of transcranial alternating current stimulation on the perception of specific features in sound: gaps in a frequency modulated noise. Several theories link the phase of brain oscillations to perception: the work is important in suggesting direct support for the link. The work is technically well executed on a good size cohort. Still one reviewer raised concerns that the effect seen might be an artifact of the analysis used, so the strength of evidence is incomplete at this stage . We encourage the authors to respond to this issue.

eLife assessment

fMRI was used to address an important aspect of human cognition - the capacity for structured representations and symbolic processing - in a cross-species comparison with non-human primates (macaques); the experimental design probed implicit symbolic processing through reversal of learned stimulus pairs. The authors present solid evidence in humans that helps elucidate the role of brain networks in symbolic processing, however the evidence from macaques was incomplete (e.g., sample size constraints, potential and hard-to-quantify differences in attention allocation, motivation, and lived experience between species).

eLife assessment

The manuscript by Bull et al provides valuable information on the relationship between metabolic features, in particular different lipoproteins and fatty acids, and colorectal cancer. They use solid methods and combine different data sources to analyze forward and reverse Mendelian Randomizations that support their claims.

eLife assessment

This paper provides a useful set of data examining the role of PTPMT1, a mitochondria-based phosphatase, in mitochondrial fuel selection. The data were collected and analyzed using solid methodology and can be used as a starting point for further studies that build on the findings here.

eLife assessment

This valuable study provides solid evidence that the stability and function of the Eph-B2 receptor (EPHB2) are affected by interactions with the multifunctional MYCBP2 and Fbxo45 proteins, extending our knowledge of how members of this key family of receptors are regulated, in particular in regard to their forward signaling. The biochemical binding evidence is generally convincing, but the evidence from the C. elegans experiments is still incomplete.

eLife assessment

This study presents the valuable finding that a cleaved form of METTL3 (termed METTL3a) has an essential role in regulating the assembly of the METTL3-METTL14-WTAP complex. The evidence supporting the claims of the authors is solid, and the work will be of interest to medical biologists working on breast cancer.

eLife assessment

This valuable study provides the community with a set of clearly interpretable computational methods to identify new pioneer transcription factors (PTFs) from which thirty two putative PTFs were predicted. The authors used multiple approaches to validate their predictions, and the evidence to support their claims is solid. This work will be of interest to computational and molecular biologists working on transcription factors.

eLife assessment

This valuable study combines in vitro experiments with simulations to identify the mechanisms governing modulation of microtubule dynamics by GTP hydrolysis. The authors introduce a solid new approach by using a mixed GDP/GMPCPP lattice and varying GDP concentration to reveal that the nucleotide at the interface of two tubulin dimers determines the strength of the interaction between two dimers. Overall, the findings will be of interest to biophysicists and cell biologists, especially in the field of microtubule biology.

eLife assessment

The study presents patterns of cancer care disruption in southern Illinois and eastern Missouri in the summer of 2020. Survey results show factors that impact cancer care during the COVID-19 pandemic, including group differences by race. The important findings provide solid evidence about variation in cancer care disruptions and opportunities to improve return to care.

eLife assessment

This valuable work presents new results to characterize the relationship between electrical excitation and torque generation in stick insect joints. The evidence supporting this work is a series of torque-voltage measurements across individuals. The strength of evidence is solid in supporting the outcomes, but some details of the methodology, which could potentially shed light on the sources of this variation, are missing.

eLife assessment

This important study reports selective CDKL5 inhibitors that may be of high interest to investigate the role of this kinase in disease (particularly, in CDKL5 deficiency disorder) and to address unsolved issues of inconsistency in the phenotypic characterization of CDKL5-deficient knockout mice. The evidence supporting the conclusions is convincing, with rigorous biochemical, in vitro and ex vivo assays. The work will be of interest to cell and medical biologists and epileptologists working in the fields of epilepsy and neural excitation.

eLife assessment

This study presents a valuable finding on the combination treatment of ONC201/TIC10 with everolimus for metastatic ER+ breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer.

eLife assessment

This study demonstrates an important method that drastically improves the precision of ultrasound localization in interacting mice. The authors present convincing evidence of the usefulness of the method for quantifying vocal behavior in various situations and demonstrate an interesting vocal dominance phenomenon between males. This tool will be of great interest to all scientists interested in vocal behavior in small animals.

eLife assessment

This important study reports selective CDKL5 inhibitors that may be of high interest to investigate the role of this kinase in disease (particularly, in CDKL5 deficiency disorder) and to address unsolved issues of inconsistency in the phenotypic characterization of CDKL5-deficient knockout mice. The evidence supporting the conclusions is convincing, with rigorous biochemical, in vitro and ex vivo assays. The work will be of interest to cell and medical biologists and epileptologists working in the fields of epilepsy and neural excitation.

eLife assessment

This study presents a valuable finding on the optimal prioritization in different malaria transmission settings for the distribution of insecticide-treated nets to reduce the malaria burden. The evidence supporting the claims of the authors is solid, although the authors have made various simplifications to enable the identification of optimal strategies. The work will be of interest from a global funder perspective, though somewhat less relevant for individual countries.