eLife assessment

This important work illuminates the dynamics of BRAF in both its monomeric and dimeric forms, with or without inhibitors, combining traditional techniques and sophisticated computational analyses. The evidence presented is convincing and suggests a potential allosteric effect, though substantiating the exact mechanism will require further studies. The work has implications for understanding kinase signaling and the development of potential drug candidates. This study will be of interest to structural biologists, medicinal chemists, and pharmacologists.

eLife assessment

This study presents valuable findings on the ligand- and ion-dependent structural dynamics of a transcriptional riboswitch. The single-molecule data presented are solid and prompts intriguing hypotheses and models, which will undoubtedly stimulate future structural analyses. These findings are of considerable interest to biochemists and biophysicists engaged in the study of RNA structure and riboswitch mechanisms.

eLife assessment

This study presents a valuable finding on the relationship between brain activity related to sustained attention and substance use in adolescence/early adulthood with a large longitudinal dataset. The evidence supporting the claims of the authors is solid, although the inclusion of more details of methods, results, and data analyses would have strengthened the study. The work will be of interest to cognitive neuroscientists, psychologists, and clinicians working on substance use or addiction.

eLife assessment

This interesting study reports that muscle contains fibro-adipogenic progenitor cells (FAPs) that promote regeneration following injury of peripheral neurons. These novel results indicate that several known growth factors are involved in the process of regeneration. This is an important contribution, however the analysis is incomplete since additional experimental data is needed to support the main conclusions.

eLife assessment

Cancer treatments are not just about the tumor - there is an ever-increasing need for treating pain, fatigue, and anhedonia resulting from the disease. Using an implantable oral tumor model in the mouse, the authors provide valuable information showing that nerve fibers are transmitting sensory signals to the brain that reduce pleasure and motivation. These findings are in part supported by anatomical and transcript changes in the tumor that suggest sensory innervation, neural tracing, and neural activity measurements; however, the study is incomplete in its current form.

eLife assessment

The authors show that short bouts of chemical ischemia lead to presynaptic changes in glutamate release and long-term potentiation, whereas longer bouts of chemical ischemia lead to synaptic failure and presumably cell death (which could be confirmed experimentally). This solid work relies on rigorous electrophysiology/imaging experiments and data analysis. It is valuable as it provides new mechanistic details on chemical ischemia, though its implications for ischemic stroke in vivo remain to be determined.

eLife assessment

This important study sheds new light on cargo movement within the Golgi apparatus, challenging the cisternal progression model by providing convincing evidence for a velocity decrease from cis to trans Golgi and variable speeds within cisternae, suggesting a more stable compartmental nature. While these findings propose refinements to the classic model, they prompt further exploration of recent models like rapid partitioning and rim progression, necessitating additional experimental approaches to account for cargo expression variations and HeLa cell-specific effects.

eLife assessment

This important work provides interesting datasets of myofiber differentiation. The evidence supporting the involvement of SRF2 in selected biological processes is convincing, however, additional evidence to pin-point the major action of SRF2 during muscle differentiation is appreciated. The work will be of broad interest to developmental biologists in general and molecular biologists in the field of gene regulation.

eLife assessment

This study describes the application of machine learning and Markov state models to characterize the binding mechanism of alpha-Synuclein to the small molecule Fasudil. The results suggest that entropic expansion can explain such binding. However, the simulations and analyses in their present form are inadequate.

eLife assessment

This valuable study establishes a method for live-cell imaging, tracking, and quantification of Alu elements marking euchromatic regions of the nucleus. The method will help characterize the relationship between chromatin dynamics and transcriptional activity. While the findings are largely consistent with previous reports, characterization of the technique is incomplete and could benefit from additional controls.

eLife assessment

This study provides valuable initial characterization of a verterbrate embryonic system that demonstrates aspects of an optogenetically inducible hyperplasia model. Although the evidence provided is incomplete to conclude that the system is demonstrating tumor initiation from a single cell that is metastasizing that can be quantitatively assessed, the authors propose a mechanism whereby reactivation of re-programming factors correlates with the increased likelihood of a mutant cell undergoing malignant transformation. This work will be of interest to developmental and cancer biologists mainly for the novel genetic tools described.

eLife assessment

The authors show in vitro that TAK1 overexpression reduces tumor cell migration and invasion, while TAK1 knockdown promotes a mesenchymal phenotype and enhances migration and invasion. The work is a valuable addition to the field of tumor biology of esophageal squamous cell carcinoma. Although minor limitations exist, the overall evidence is solid. The data aligns with previous findings by the same researchers and others.

eLife assessment

In the current study, the authors describe how sex and age affect the consequence of traumatic brain injury in Drosophila. They find that females are more sensitive than males, and mated females are sensitive whereas virgin females are not. This fundamental work substantially advances our understanding of how sex-dependent response to traumatic brain injury occurs, by identifying the Sex Peptide and the immune system as modulators of sex differences. The authors provide a compelling set of results, showing that female Sex Peptide signaling in Drosophila adversely affects late-life neurodegeneration after early-life exposure to repetitive mild head injury.

eLife assessment

This manuscript describes an AI-automated microscopy-based approach to characterize both bacterial and host cell responses associated with Shigella infection of epithelial cells. The methodology is compelling and should be helpful for investigators studying a variety of intracellular pathogens. The authors have acquired valuable findings regarding host and bacterial responses in the context of infection, which should be followed up with further mechanistic-based studies.

eLife assessment

This valuable work characterized a new set of small molecules targeting the interaction between ELF3-MED23, with one of the reported compounds representing a promising novel therapeutic strategy, The evidence supporting the conclusions is solid, although including characterization with breast and lung cancer cell models would strengthen the study. This article will be of interest to medical and cell biologists working on cancer and, particularly, on HER2-overexpression cancers.

eLife assessment

This manuscript describes a method for genetic manipulation of Leishmania species which should be sufficiently efficient to enable genome-wide genetic screens. The authors improved numerous aspects of their previously described method, which is based on sequence-specific genome editing to introduce premature stop codons using a CAS9-cytidine deaminase variant. The work is thoroughly described, with convincing data, and will be very important for Leishmania researchers, as well as perhaps suggesting the use of similar approaches in other organisms in which genetic manipulation is challenging.

eLife assessment

This important chronobiological study in mice suggests that light modulated activity of Cdk5 activity on the PKA-CaMK-CREB signaling pathway provides missing molecular mechanistic details to understand light- induced circadian clock phase delays during the early night, but not for phase advances in the morning. The authors provide overall convincing evidence bridging from behavioral to molecular/cellular experiments to neural activity imaging.

eLife assessment

This paper presents H3-OPT, a deep learning method that effectively combines existing techniques for the prediction of antibody structure. This work, supported by convincing experiments for validation, is important because the method can aid in the design of antibodies, which are key tools in many research and industrial applications.

eLife assessment

This important study, using three bioactive compounds as a model, demonstrates that estimating the intake of food components based on food composition databases and self-reported dietary data is highly unreliable. The authors present convincing data showing the differences in the estimated quantile of intake of three bioactive compounds between biomarker and 24-hour dietary recall with food-composition database. The work will be of broad interest to the clinical nutrition research community.

eLife assessment

This useful article provides evidence of the potential neuropathogenicity of Bacillus cereus serovar anthracis in wild chimpanzees. The authors provide an extensive characterization of four chimpanzees that died acutely from anthrax. The study provides incomplete traditional histopathologic evidence of neuroinvasion since the meninges could not be evaluated, which weakens the authors' conclusions. The work will be of interest to infectious disease researchers.

eLife assessment

This valuable biomechanical analysis of kangaroo kinematics and kinetics across a range of hopping speeds and masses is a step towards understanding a long-standing problem in locomotion biomechanics: the mechanism for how, unlike other mammals, kangaroos are able to increase hopping speed without a concomitant increase in metabolic cost. Based on their suggestion that kangaroo posture changes with speed increase tendon stress/strain and hence elastic energy storage/return, the authors imply (but do not show quantitatively or qualitatively) that the greater tendon elastic energy storage/return counteracts the increased cost of generating muscular force at faster speeds and allows for the invariance in metabolic cost. The methods are impressive, but there is currently only limited evidence for increased tendon stress/strain at faster speeds, and the support for any conclusion metabolic energy expenditure is inadequate.

eLife assessment

This important manuscript follows up on previous findings from the same lab supporting the idea that deficits in learning due to enhanced synaptic plasticity are due to saturation effects. Compelling evidence is presented that behavioral learning deficits associated with enhanced synaptic plasticity in a transgenic mouse model can be rescued by manipulations designed to reverse the saturation of synaptic plasticity. In particular, the finding that a previously FDA-approved therapeutic can rescue learning could provide new insights for biologists, psychologists, and others studying learning and neurodevelopment.

eLife assessment

This study conducted fMRI experiments in an inbred rat model of absence seizures. The results provide new information suggesting reduced brain responsiveness during this type of seizure. The reviewers had divergent opinions but on average thought the study was valuable and the conclusions were solid.

eLife assessment

In this manuscript, the authors tested the hypothesis that Aβ42 toxicity arises from its proven affinity for γ-secretases. The authors provide useful findings, showing convincingly that human Abeta42 inhibits gamma-secretase activity. The data will be of interest to all scientists working on neurodegenerative diseases.

eLife assessment

This important study explores infants' attention patterns in real-world settings using advanced protocols and cutting-edge methods. The presented evidence for the role of EEG theta power in infants' attention is solid. The study will be of interest to researchers working on the development and control of attention.

eLife assessment

This valuable manuscript reveals sex differences in bi-conditioning Pavlovian learning and conditional behavior. Males learn hierarchical context-cue-outcome associations more quickly, but females show more stable and robust task performance. These sex differences are related to cellular activation in the orbitofrontal cortex. Although the evidence for the claims is convincing, the claim of sex differences in context-dependent discrimination behaviour is overstated in places. Nevertheless, the results will be of interest to many behavioural neuroscientists, particularly those who investigate sex-specific behaviours.

eLife assessment

This important study shows that a high autism quotient in neurotypical adults is associated with suboptimal motor planning and visual updating after eye movements, suggesting a disrupted efference copy mechanism. The implication is that abnormal visuomotor updating may contribute to sensory overload - a key symptom in autism spectrum disorder. The evidence presented is convincing, with few limitations, and should be of broad interest to neuroscientists at large.

eLife assessment

This study offers a useful advance by introducing a cord blood DNA methylation score for maternal smoking effects, with the inclusion of cohorts from diverse backgrounds. However, the overall strength of evidence is deemed incomplete, due to concerns regarding low exposure levels and low statistical power, which hampers the generalisability of their findings. The study provides an interesting basis for future studies, but would benefit from the addition of more cohorts to validate the findings and a focus on more diverse health outcomes.

eLife assessment

This important manuscript shows that axonal transport of Wnd is required for its normal degradation by the Hiw ubiquitin ligase. These are interesting findings supported by solid data. However, the summary and conclusions are over-interpreted and how Rab11 is involved in Golgi processing or axonal transport of Wnd is not resolved and would require additional experiments to support the claims. Alternatively, the authors should dial back on their interpretation.

eLife assessment

Manley and Vaziri introduce an important new method for brain-wide imaging of cellular activity in zebrafish and provide evidence for the applicability of this technique. They use this method to explore the question of how neural variability gives rise to variability in behavior. The analyses used are mostly convincing, with some central results that are currently incomplete and difficult to interpret.

eLife assessment

This is a potentially valuable study suggesting that neuronal-specific loss of function of the RNA splicing factor Ptbp1 in striatal neurons induces dopaminergic markers and alleviates motor defects in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's Disease. If properly replicated, the claims of the manuscript are remarkable and identify a straightforward mechanism with therapeutic relevance for the treatment of motor deficits in Parkinson's Disease. However, while the rescue of motor deficits with Ptbp1 manipulation is solid, the strength of the evidence supporting the induction of a dopaminergic neuronal identity is incomplete. The study nevertheless addresses recent controversial literature on cell reprogramming in Parkinson's Disease and will be of interest to researchers with a focus on the application of gene therapy to rescue neurodegeneration.

eLife assessment

This valuable study provides insights and strategies for assessing laminar structure in vivo in the visual cortex of the macaque monkey with high-density linear electrode arrays. The paper provides solid evidence demonstrating that signals in higher frequency bands, related to the discharge of action potentials, are of substantially better use for achieving well-resolved cortical layer identification than are signals in lower frequency bands typically associated with local field potentials and standard-practice Current Source Density (CSD) analyses. These findings are of interest to electrophysiologists seeking to make comparisons between cortical layers.

eLife assessment

This important study uses state-of-the-art, multi-region two-photon calcium imaging to characterize the statistics of functional connectivity between visual cortical neurons. The evidence supporting the conclusions is incomplete; currently, alternative interpretations of the results cannot be ruled out. With new analyses strengthening the conclusions, the work would be of broad interest to neuroscientists interested in the visual cortex and inter-area communication.

eLife assessment

The authors expand the concept of a new layer to training immunity, which is currently being highlighted by several colleagues in the field. The work provides important hints to understand end-stage renal disease. Overall, the rational approach leads to experimental results that are solid.

eLife assessment

This important study expands generally upon our understanding of the role of hnRNP proteins in lncRNA function through analysis of ASAR genes that are present on all chromosomes and of profound significance. The findings provide convincing evidence linking ASARs with the phenomenon of RNA retention on chromosomes, including X inactivation, thereby providing an expanded context for studies in these areas. This manuscript will be of interest to researchers studying gene regulation and the interactions and functional roles of hnRNP and lncRNAs.

eLife assessment

The author use an approach that is in principle useful, comparative meta-analysis, to contribute to our understanding of life history evolution. The advance remains limited, as both the meta-analysis and the theoretical model are incomplete, and proper statistical and mechanistic descriptions of the simulations are lacking. A major concern is that the interpretation does not properly take into account the effect of well-characterised complexities in the relationship between clutch size and fitness in birds.

eLife assessment

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

eLife assessment

This useful studying implicates TRPV4 as a mediator of sweat, potentially based on TRPV4's expression and function on sweat glands. The data and methods are solid, with some limitations in terms of the approach. Overall, the work lends new insight into the physiologic basis of sweating using data from mice and humans.

eLife assessment

This study provides a useful set of experiments showing the relative contribution of the Neurodrenergic system in reversing the sedation induced by midazolam. The evidence supporting the claims of the authors is solid, although specificity issues in the pharmacology and neural-circuit investigations narrow down the strengths of the conclusions. After dealing with these limitations, the paper will be of interest to medical biologists working on the neurobiology of anesthesia.

eLife assessment

Münker and colleagues use an optical tweezer setup to apply oscillatory forces to endocytosed/phagocytosed glass beads over a wide frequency range (from ~1 to 1000 Hz) and probe cytoplasmic material properties at multiple time scales in six different cell types. Using statistical methods and principal component analysis, they find that the active and passive mechanical properties of cells can be described by 6 parameters (from power law fits) that allow characterizing the viscous and elastic nature of the cytoplasmic material as well as an effective active energy driven by cellular metabolism. Overall, this is very well done and important work, using convincing and state-of-the-art methods, albeit with some limitations related to the way the beads are internalized.

eLife assessment

This valuable manuscript sets out to identify sleep/arousal phenotypes in larval zebrafish carrying mutations in Alzheimer's disease (AD)-associated genes. The authors provide detailed phenotypic data for F0 knockouts of each of 7 AD-associated genes and then compare the resulting behavioral fingerprints to those obtained from a large-scale chemical screen to generate new hypotheses about underlying molecular mechanisms. The data presented are solid, although extensive interpretation of pharmacological screen data does not necessarily reflect the limited mechanistic data. Nonetheless, the phenotypic characterization presented is comprehensive, and the authors develop a well-designed behavioral analysis pipeline that will provide considerable value for zebrafish neuroscientists.

eLife assessment

This study addresses an important, understudied question using approaches that link molecular, circuit, and behavioral changes. The findings that Netrin-1 and UNC5c can guide dopaminergic innervation from the nucleus accumbens to the cortex during adolescence are solid. The data showing that the onset of Unc5 expression is sexually dimorphic in mice, and that in Siberian hamsters environmental effects on development are also sexually dimorphic are also solid. Reviewers identified significant gaps in evidence for specificity of Netrin-1 expression, which, if filled, would strengthen the evidence for some of the claims. Future work would also benefit from Unc5C knockdown to corroborate the results and investigation of the cause-effect relationship. This paper will be of interest to those interested in neural development, sex differences, and/or dopamine function.

eLife assessment

van Vliet and colleagues show a correlation between internal states of a convolutional neural network (CNN) trained on visual word stimuli with three specific components of evoked MEG potentials during reading in humans. The findings are useful, but the current results remain incomplete, without evidence that the CNN can produce any of the phenomena that the human visual system is known to have (e.g., feedback connections, sensitivity to word frequency), or that the model has comparable performance to human behaviour (i.e., similar task accuracy with a comparable pattern of mistakes).

eLife assessment

This study provides useful insights for anyone focusing on exonic regions when looking into the investigation of DNA fragmentation patterns (fragmentomics) for circulating tumor DNA (ctDNA) data for cancer detection. The method expands the DELFI method of Cristiano and colleagues (2019), but the datasets chosen are not ideal and the analysis remains incomplete.

eLife assessment

Supported by solid evidence, this work provides valuable insights into theanine metabolism and regulation at single-cell resolution. The study paves the way for addressing the multicellular compartmentation of secondary metabolites in various plant systems, making it a valuable resource for future research.

eLife assessment

The authors present an important resource to quantify mitochondrial function across many organs in mice. The convincing conclusions are supported by the identification of processes that specifically differ between young and old, or between male and female mice. All reviewers point to the merit of this study in providing a comprehensive resource to contextualize mitochondrial functions across the body. Some further suggestions are made to clarify conclusions in terms of data normalization, interpretations of comparative analyses between organs.

eLife assessment

This valuable study partially succeeds in providing evidence to support the therapeutic potential of the plant-derived compound eugenol for ameliorating symptoms associated with Type 1 Diabetes, identifying Nuclear factor E2 - related factor (Nrf2) as a mediator of the effects induced by eugenol. Although the study provides some interesting data, the evidence for the proposed mechanism is currently incomplete.

eLife assessment

This valuable simulation study proposes a new coarse-grained model to explain the effects of CpG methylation on nucleosome wrapping energy and nucleosome positioning. The evidence to support the claims in the paper looks solid, although the novelty of the findings should be discussed in connection with the previous works. This work will be of interest to the researchers working on gene regulation and mechanisms of DNA methylation.

eLife assessment

This study presents valuable findings linking circHMGCS1 and miR-4521 in diabetes-induced vascular endothelial dysfunction. The evidence supporting the claims of the authors is solid, but addressing concerns around how certain experiments were performed and controlled could enhance clarity and further strengthen the study. The work will be of interest to biomedical scientists working with cardiovascular and/or RNA biology, particularly those studying diabetes.

eLife assessment

This useful manuscript presents an interesting multi-modal omics analysis of lung adenocarcinoma patients with distinct clinical clusters, mutation hotspots, and potential risk factors identified in cases linked to air pollution. The findings show potential for high clinical and therapeutic impact. However, some of the conclusions are incomplete as they are based on correlative or suggestive findings, and would benefit from further functional investigation and validating approaches.

eLife assessment

This valuable work provides novel insights into the substrate binding mechanism of a tripartite ATP-independent periplasmic (TRAP) transporter. The structural analysis is convincing, but evidence to support some of the conclusions regarding the mechanism is incomplete. This study will be of interest to the membrane transport and bacterial biochemistry communities.

eLife assessment

This important manuscript presents several structures of the Kv1.2 voltage-gated potassium channel, based on state-of-the-art cryoEM techniques and algorithms. The authors present solid evidence for structures of DTX-bound Kv1.2 and of Kv1.2 in potassium-free solution (with presumably sodium ions bound within the selectivity filter). These structures advance our knowledge of the molecular basis of the channel inactivation process.

eLife assessment

This structural and biochemical study of the mouse homolog of acidic mammalian chitinase (AMCase) enhances our understanding of the pH-dependent activity and catalytic properties of mouse AMCase, and it sheds light on its adaptation to different physiological pH environments. The methods and analysis of data are solid, providing several lines of evidence to support the development of mechanistic hypotheses. While the findings and interpretation will be valuable to those studying AMCase in mice, the broader significance, including extension of the results to other species including human, remain less clear.

eLife assessment:

This paper characterises a novel gene (Spar), and presenting valuable findings in the field of insect biology and behaviour. The experiments are well designed, with attention to detail, showcasing the potential of the Drosophila melanogaster model and the use of online resources. The mixed approach presents a convincing argument for a genetic interaction between Alk and Spar.

eLife assessment

Receptor tyrosine kinases such as ALK play critical roles during appropriate development and behaviour and are nodal in many disease conditions, through molecular mechanisms that weren't completely understood. This manuscript identifies a previously unknown neuropeptide precursor as a downstream transcriptional target of Alk signalling in Clock neurons in the Drosophila brain. The experiments are well designed with attention to detail, the data are convincing, and the findings will be valuable to those interested in events downstream of signalling by receptor tyrosine kinases.

eLife assessment

The authors present evidence suggesting that MDA5 can substitute as a sensor for triphosphate RNA in a species that naturally lacks RIG-I. The key findings are potentially important for our understanding of the evolution of innate immune responses. Compared to an earlier version of the paper, the strength of evidence has improved but it is still partially incomplete due to a few key missing experiments and controls.

eLife assessment

The authors provide compelling evidence that MSP1 inhibition (leading to chromosomal instability or CIN in the cancer cells) increases phagocytosis and that tumors with CIN respond better to macrophage therapeutics. In this important study, they demonstrate particularly impressive survival rates for mouse models of CIN B16 tumors treated with adoptively transferred macrophages, CD47-SIRPα blockade, and anti-Tyrp1 IgG.

eLife assessment

This article presents important results describing how the gathering, integration, and broadcasting of information in the brain changes when consciousness is lost either through anesthesia or injury. They provide convincing evidence to support their conclusions, although the paper relies on a single analysis tool (partial information decomposition) and could benefit from a clearer explication of its conceptual basis, methodology, and results. The work will be of interest to both neuroscientists and clinicians interested in basic and clinical aspects of consciousness

eLife assessment

This article presents important results describing how the gathering, integration, and broadcasting of information in the brain changes when consciousness is lost either through anesthesia or injury. They provide convincing evidence to support their conclusions, although the paper relies on a single analysis tool (partial information decomposition) and could benefit from a clearer explication of its conceptual basis, methodology, and results. The work will be of interest to both neuroscientists and clinicians interested in basic and clinical aspects of consciousness.

eLife assessment

This study presents a useful pipeline for de novo design of antimicrobial peptides active both against bacteria and viruses. The method is based on deep learning, using a GAN generator and a regression tasked to predict antimicrobial activity. The evidence supporting the conclusions is promising but incomplete: three generated peptides are studied experimentally in vitro, and one is then tested in vivo in mice; the comparisons to other design methods could also be strengthened. This work will be of interest to the community working on machine learning for biomedical applications and specifically on antimicrobial peptides.

eLife assessment

This fundamental study addresses discrepancies in determining bacterial burden in osteomyelitis as determined by culture and enumeration using DNA. The authors present compelling data demonstrating the emergence of discrepancies between CFU counts and genome copy numbers detected by PCR in Staphylococcus aureus strains infecting osteocyte-like cells. The observations represent a substantial addition to the field of musculoskeletal infection, with possible broad applicability and clinical benefit to other infectious diseases.

eLife assessment

This manuscript by Vuong and colleagues reports on the kinetics of viremia in a large set of individuals from Vietnam. In the large cohort, all 4 dengue serotypes are represented and the authors try to correlate viraemia measured at various days from illness onset with thrombocytopaenia and severe dengue, according to the WHO 2009 classification scheme. These are fundamental findings that provide compelling evidence of the importance of measuring viremia early in the phase of the disease. These data will help to inform the design of studies of antiviral drugs against dengue.

eLife assessment

This study presents an important finding on how lentiviral infection has driven the diversification of the HIV/SIV entry receptor CD4. Using a combination of molecular evolution approaches coupled with functional testing of extant and ancestral reconstructions of great ape CD4, the authors provide solid evidence to support the idea that endemic simian immunodeficiency virus infection in gorillas have selected for gorilla CD4 alleles that are more resistant to SIV infection. Expanding the study to interrogate the evolution and function of additional primate CD4 sequences could yield more convincing evidence.

eLife assessment

The humanized model of EAE represents a valuable model in which to evaluate mechanisms that may drive EAE-like processes in vivo. The data are solid given the revisions and expansion of numbers of mice to yield more statistical rigor. This model will be used by the greater community studying EAE.

eLife assessment

In this valuable study, the authors use a computational model to investigate how recurrent connections influence the firing patterns of grid cells, which are thought to play a role in encoding an animal's position in space. The work suggests that a one-dimensional network architecture may be sufficient to generate the hexagonal firing patterns of grid cells, a possible alternative to attractor models based on recurrent connectivity between grid cells. However, the support for this proposal was incomplete, as some conclusions for how well the model dynamics are necessary to generate features of grid cell organization were not well supported.

eLife assessment

This study presents a valuable insight into a computational mechanism of pain perception. The evidence supporting the authors' claims is compelling. The work will be of interest to pain researchers working on computational models and cognitive mechanisms of pain in a Bayesian framework.

eLife assessment

This useful study reports how neuronal activity in the prefrontal cortex maps time intervals during which animals have to wait until reaching a reward and how this mapping is preserved across days. However, the evidence supporting the claims is incomplete as these sequential neuronal patterns do not necessarily represent time but instead may be correlated with stereotypical behavior and restraint from impulsive decision, which would require further controls (e.g. behavioral analysis) to clarify the main message. The study will be of interest to neuroscientists interested in decision making and motor control.

eLife assessment

This study presents a useful exploration of the complex relationship between structure and function in the developing human brain using a large-scale imaging dataset from the Human Connectome Project in Development and gene expression profiles from the Allen Brain Atlas. The evidence supporting the claims of the authors is solid, although the inclusion of more systematic analyses of structural and functional connectivity with respect to myelin measures and oligodendrocyte-related genes, and also more details regarding the imaging analyses, cognitive scores, and design and validation strategies, would have strengthened the paper. The work will be of interest to developmental biologists and neuroscientists seeking to elucidate structure-function relationships in the human brain.

eLife assessment

This study addresses an important, understudied question using approaches that link molecular, circuit, and behavioral changes. The novel findings that Netrin-1 and UNC5c can guide dopaminergic innervation from the nucleus accumbens to the cortex during adolescence are solid. The data showing that the onset of Unc5 expression is sexually dimorphic in mice, and that in Siberian hamsters environmental effects on development are also sexually dimorphic are also solid. Reviewers identified some gaps in evidence for specificity of Netrin-1 expression, which, if filled, would strengthen the evidence for some of the claims. Future work would also benefit from Unc5C knockdown to corroborate the results and investigation of the cause-effect relationship. This paper will be of interest to those interested in neural development, sex differences, and/or dopamine function.

eLife assessment

The authors present a valuable computational platform, which aims to automate the workflow for coarse-grained simulations of biomolecules in the framework of the popular MARTINI model. The capability of the platform has been convincingly demonstrated by the application to a large number of proteins as well as macrocycles and polymers. On the other hand, because the developments have largely been based on the MARTINI model, some might argue that the general impact on the multi-scale simulation community is limited, leaving the support for the claimed significance incomplete.

eLife assessment

This important study of artificial selection in microbial communities shows that the possibility of selecting a desired fraction of slow and fast-growing types is impacted by their initial fractions. The evidence, which relies on mathematical analysis and simulations of a stochastic model, is convincing. It highlights the tension between selection at the strain and the community level. This study should be of interest to researchers interested in ecology, both theoretical and experimental.

eLife assessment

This important study implicates Sempharon 4a in both mice and humans as a key suppressor of psoriatic inflammation. The data are in parts incomplete in defining the precise functionally relevant cellular source and mechanism. Nonetheless, this study brings new insight into psoriasis pathogenesis and a potential new therapeutic target.

eLife assessment

This study presents a valuable finding on the cell composition in mouse spleen depleted for the CD47 receptor and its signaling ligand Thrombospondin in hematopoietic differentiation. The supporting evidence is convincing with analytical improvements on the individual contributions of the signaling components and with functional studies. This work has implications for the role of CD47/Thsp in extramedullary erythropoiesis in mouse spleen and will be of interest to medical biologists working on cell signaling, transfusion medicine, and cell therapy.

eLife assessment

This valuable study describes a new type of NAD+ and Zn2+-independent protein lysine deacetylase in prokaryotes. These results extend the understanding of regulatory mechanisms related to bacterial lysine acetylation modifications however, the experimental evidence is incomplete and does not fully support the conclusions made. The work will be of interest to microbiologists studying metabolism and post-translational modifications.

eLife assessment

This paper reports a large drug repurposing screen based on an in vitro culture platform to identify compounds that can kill Plasmodium hypnozoites. This valuable work adds to the current repertoire of anti-hypnozoites agents and uncovers targetable epigenetic pathways to enhance our understanding of this mysterious stage of the Plasmodium life cycle. The data presented here are based on solid methodology and represent a starting point for further investigation of epigenetic inhibitors to treat P. vivax infection. This paper will be of interest to Plasmodium researchers and more broadly to readers in the fields of host-pathogen interactions and drug development.

eLife assessment

The manuscript by Yang and coworkers presents valuable evidence that an in vitro brain blood barrier composed of endothelial cells, astrocytes, and neuroblastoma cells of human origin, would resemble better the in vivo condition. The presented results constitute solid evidence that GDNF induces the expression of VE-Cadherin and Claudin-5. Further, silencing of GDNF in the brain of mice altered brain blood barrier properties. This provides a new perspective on the interaction between neurons and endothelial cells and this model can be used to screen the permeability of the brain blood barrier to different drugs.

eLife assessment

This valuable paper first demonstrated that RGS10 was identified as a biomarker to evaluate the prognosis of breast cancer. To prevent the loss of RGS10 theoretically provide a new strategy for the treatment of breast cancer. The evidence supporting the claims of the authors is solid, although inclusion of a larger number of patient samples and an animal model would have strengthened the study. The work will be of interest to clinicians working on breast cancer.

eLife assessment

This study investigates the role of the Cadherin Flamingo (Fmi) in cell competition in developing tissues in Drosophila melanogaster. The findings are valuable in that they show that Fmi is required in winning cells in several competitive contexts. The evidence supporting the conclusions is solid, as the authors identify Fmi as a potential new regulator of cell competition, however, they don't delve into a mechanistic understanding of how this occurs.

eLife assessment

This manuscript reports a valuable new mechanism of regulation of the glutamine synthetase in the archaeon Methanosarcina mazei and clarifies the direct activation of glutamine synthetase activity by 2-oxoglutarate, thus introducing a novel understanding of how 2-oxoglutarate serves as a central indicator of carbon and nitrogen sensing. The authors provide solid evidence using mass photometry, specific activity measurements, and single particle cryo-EM data. This study is of interest to biologists working on the regulation of metabolism.

eLife assessment

This landmark work by Lewis and Hegde represents the most significant breakthrough in membrane and secretory biogenesis in recent years. Their work reveals with outstanding clarity how nascent transmembrane segments can pass through the gate of Sec61 into the ER membrane through the coordinated motions of a conformationally and compositionally dynamic machine. Among many other insights, the authors discovered how a new factor, RAMP4, contributes to the formation and function of the lateral gate for certain substrates. The technical quality of the work is exceptional, setting the bar appropriately high.

eLife assessment

The manuscript describes a valuable method to boost WNT signaling in a tissue-specific manner. The work extends previous data from the authors based on fusing an RSPO2 mutant protein to an antibody that binds ASGR1/2. In the current manuscript, two new antibodies with similar effects are described, that expand this solid approach and provide alternatives for potential future clinical applications. This manuscript will be of interest to all scientists studying protein engineering and cellular targeting.

eLife assessment

This important research article provides a novel approach to measure imaginal disc growth and uses this approach to explore the roles of Fat and Dachsous, two conserved protocadherins, in late larval development. The authors have addressed all referee concerns and the evidence supporting the authors' findings overall are compelling.

eLife assessment

This is a valuable study that develops a new model of the way muscle responds to perturbations, synthesizing models of how it responds to small and large perturbations, both of which are used to predict how muscles function for stability but also how they can be injured, and which tend to be predicted poorly by classic Hill-type models. The evidence presented to support the model is solid, since it outperforms Hill-type models in a variety of conditions. Although the combination of phenomenological and mechanistic aspects of the model may sometimes make it challenging to interpret the output, the work will be of interest to those developing realistic models of the stability and control of movement in humans or other animals.

eLife assessment

This study provides a valuable contribution to our understanding of the mechanisms underlying the limited capacity to process rapid sequences of visual stimuli by reporting convincing evidence that the attentional blink affects neurally separable processes of visual detection and discrimination. The motivation for some of the analyses and the connection to previous empirical and theoretical work can be improved. The study will be of interest to neuroscientists and psychologists investigating perception and attention.

eLife assessment

This study employs a modified protocol for single-nuclei RNA sequencing of adipose tissue that preserves RNA quality and nuclei integrity. Using this protocol, the study provides valuable insights into the cellular heterogeneity and molecular landscape of murine adipose tissue from lean mice and mice with diet-induced obesity. The study is solid in its approach and analysis, providing a comprehensive description of a dysfunctional hypertrophic adipocyte subpopulation that emerges in association with obesity.

eLife assessment

This valuable study shows how an intersecting network of regulators acting on genes with differences in their RNA metabolism explains why the loss of some regulators of RNAi in C. elegans can selectively impair the silencing of some target genes. The evidence presented is convincing, as the authors use a combination of computational modeling and RNAi assays to support their conclusions.

eLife assessment

This work investigated the mechanisms by which sperm DNA is excluded from the meiotic spindle after fertilization. The finding that kinesin-13, katanin and Ataxin-2 proteins are involved in this process is useful in uncovering the mechanisms underlying healthy embryo formation. The overall conclusions of the work are supported by solid evidence obtained by microscopy and RNAi experiments, though more robust data analyses and rescue experiments would have strengthened the study.

eLife assessment

This important study identifies biallelic variants of DNAH3 in four unrelated infertile men. In addition, it reports that DNAH3 knockout (KO) mice are infertile, and that compromised DNAH3 activity decreases the expression of IDA-associated proteins in the spermatozoa of human patients and the KO mice. Of note, the infertility of both can be rescued by intracytoplasmic sperm injection (ICSI). In aggregate, the work provides solid evidence to demonstrate that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and male infertility . It will be of substantial interest to clinicians, reproductive counselors, embryologists, and basic researchers working on infertility and assisted reproductive technology.

eLife assessment

This work presents valuable information on the structure of the spirosome's native extended conformation as the active form of the enzyme aldehyde-alcohol dehydrogenase (AdhE). However, the data supporting this claim are incomplete.

eLife assessment

This manuscript presents important observations on the early changes in calcium signaling, TMEM16a activation, and mitochondrial dysfunction in salivary gland cells in an inflammation murine model of autoimmune Sjögren's disease. Convincing changes are shown in saliva release, calcium signaling, TMEM16a activation, mitochondrial function, and sub-cellular morphology of the endoplasmic reticulum following DMXAA treatment. The work will be of strong interest to physiologists working on secretion, calcium signaling, and mitochondria.

eLife assessment

Gain-of-function mutations and amplifications of PPM1D are found across several human cancers and are associated with advanced tumor stage and worse prognosis. Thus far, the clinical translation has not been possible due to the lack of PPM1D inhibitors with favorable pharmacokinetic properties. This useful study leverages CRISPR/Cas9 screening to determine that loss of SOD1 and is synthetic lethal with PPM1D mutation in leukemia. The mechanistic analyses are still incomplete.

eLife assessment

This important study expands our understanding of the role of two axon guidance factors in a specific axon guidance decision. The strength of the study is the compelling axonal labeling and quantification, which allows the authors to establish precise consequences of the loss of each guidance factor or receptor.

eLife assessment

This study presents an important finding on the structural role of glycosylation at position N343 of the SARS-CoV-2 spike protein's receptor-binding domain in maintaining its stability, with implications across different variants of concern. The evidence supporting the claims of the authors is convincing, since appropriate and validated methodology in line with current state-of-the-art has been approached. The work will be of interest to evolutionary virologists.

eLife assessment

This study presents potentially valuable insights into the role of climbing fibers in cerebellar learning. The main claim is that climbing fiber activity is necessary for optokinetic reflex adaptation, but is dispensable for its long-term consolidation. There is evidence to support the first part of this claim, though it requires a clearer demonstration of the penetrance and selectivity of the manipulation. However, support for the latter part of the claim is incomplete owing to methodological concerns, including unclear efficacy of longer-duration climbing fiber activity suppression.

eLife assessment:

This important study combines experiments that rely on the use of target-agnostic memory B cell sorting and screening approaches and thorough characterization of antibodies with specificities to the sexual stages of Plasmodium falciparum. The authors present solid findings that one antibody, B1E11K, is cross-reactive with multiple proteins containing glutamate-rich repeats. B1E11k binds to the repeats through homotypic interactions, similar to what has been observed for Plasmodium circumsporozoite protein repeat-directed antibodies. Despite the importance of the findings beyond the field of malaria, the writing, in several places, lacks clarity.

eLife assessment

This study presents an important study of the relationship between morphogen signaling and cell fate choices in the forming zebrafish neural tube, addressing a topical question in developmental biology. The authors provide a solid characterization of the precision limit for gene regulatory networks interpreting Shh, with single-cell resolution and state-of-the-art in vivo approaches. However, the analyses are at times incomplete and would benefit from a higher number of cell traces. With the analyses strengthened, this work will be of interest to developmental biologists interested in cellular decision-making.

eLife assessment

The authors address key assumptions underlying current models of the formation of value-based decisions. They provide solid evidence that the subjective values human participants assign to choice options change across sequences of multiple decisions and establish valuable methods to detect these changes in frequently used behavioral task designs. That said, the description of the fMRI results requires further elaboration in order to support the claim that the authors' algorithm reveals neural valuation processes better than the current standard approach.

eLife assessment

This landmark paper introduces the generation and analysis of a connectome resource of the entire ventral nerve cord of a fruit fly which is one of the top model organisms to investigate how a nervous system forms and functions. The work introduces new and improved approaches - from tissue preparation to automated reconstruction - to generate a detailed connectome from a complex adult ventral nerve cord. This extensive new dataset provides cell type and lineage annotations, putative neurotransmitter expression information, and the potential to link to genetic driver lines, with compelling evidence to support the claims made.

eLife assessment

Work described in this manuscript reveals the importance of the zinc transporter SLC30A1 in the antimicrobial function of macrophages, specifically against Salmonella. Cell-targeted deletion of the zinc transporter increased susceptibility of mice to systemic infection with Salmonella, leading to decreases in several cell functions such as nos2 expression. The authors argue that zinc homeostasis promotes macrophage cell function that is not conductive to the intracellular proliferation of Salmonella. This study provides novel and supportive evidence for a new pathway in nutritional immunity.

eLife assessment

Serotonin is an important neurotransmitter and its synaptic concentration is controlled by re-uptake by the sodium-coupled serotonin transporter SERT. The manuscript by Chan et al reports results from a systematic deep mutagenesis approach to study the surface expression and APP+ (5HT analogue) transport mechanism of the human serotonin transporter. The authors complement this experimental evidence with large-scale molecular simulations of the transporter in the presence of APP+. The use of deep mutagenesis and large-scale adaptive sampling simulations is impressive, and could contribute to understanding the structural requirements for folding and how transporters evolve to recognize different substrates.

eLife assessment

The authors provide a high quality genome of the xenacoelomorph worm Xenoturbella bocki and discuss its structure and evolution. Understanding the genomic structure of this group provides important insights into bilaterian evolution. The authors make a solid case that the data they present can support the placement of Xenacoelomorpha within the deuterostomes rather than as a sister group to all other bilaterians, but do not unequivocally reject the competing scenario.

eLife assessment

The study presents a valuable finding on quantifying the orientation and organization of chondrocyte columns in the prenatal and postnatal growth plate cartilage using advanced 3D imaging and a sophisticated image analysis pipeline. The evidence supporting the authors' conclusions regarding the lack of columns in the fetal growth plate is considered inadequate due to technical caveats, inconsistencies in the data and corresponding model, and failure to correctly put the findings in context.

eLife assessment

This fundamental work advances our understanding of the central coding and control mechanisms regulating sympathetic nervous system efferent signals to bone. The evidence supporting the conclusion is mostly convincing, although the inclusion of higher resolution images for certain data and further discussions would strengthen the study. This paper holds potential interest for skeletal biologists and neuroscientists who study the brain-bone sympathetic neural circuits.

eLife assessment

This paper is valuable in that it provides a critical missing link between measures of structural connectivity and rhythmic tapping abilities, pointing to some interesting possibilities for how tapping synchronization is carried out. The methodology and findings are solid, and of interest to those studying the neural mechanisms of timing.

eLife assessment

This investigation marks an important advancement in our understanding of motor thalamus connectivity, illustrating a complex integration of inputs that reshapes previous models. The study utilizes compelling methodologies that expose a dynamic synaptic network, although the evidence of triple-input convergence on individual neurons and for multiple driver type inputs onto motor thalamic neurons remains incomplete. Despite this, the findings provide a persuasive rationale for revisiting our perceptions of the thalamic role in motor control, with a call for further studies to substantiate the breadth of these functional interactions.

eLife assessment

This paper presents a new method for separating organelles in an unbiased way. The method is applied to the separation of distinct subpopulations of insulin vesicles. There are concerns around whether the vesicles measured are in fact insulin vesicles and whether the observed changes in vesicle populations upon glucose stimulation are biologically meaningful, and thus it is difficult to assess at this stage how well the technique performs. This paper is likely to be of wide interest to cell biologists studying a variety of compartments, as well as to researchers in the beta cell field.

eLife assessment

Using continuum theory of elastic solids the authors present evidence that periodic muscle contraction leads to elongation of C. elegans embryos by storing elastic energy that is subsequently released by extending the embryo's long axis. This important finding could apply to other developmental processes and be exploited in soft robotics. The presented evidence is convincing on the phenomenological level adopted in the work. How bending energy is converted into elongation on a more microscopic level remains to be worked out.

eLife assessment

This is an important computational study that applies the machine learning method of bilinear modeling to the problem of relating gene expression to connectivity. Specifically, the author attempts to use transcriptomic data from mouse retinal neurons to predict their known connectivity with promising results. On revision, the approach was tested against a second data set from C. elegans. A limited number of genes studied in this second dataset may have resulted in performance that matched but did not exceed prior models. However, taken together, the results were felt to provide solid evidence for the value of the approach.

eLife assessment

In this important study, the authors report a novel measurement of the Escherichia coli chemotactic response and demonstrate that these bacteria display an attractant response to potassium, which is connected to intracellular pH level. The experimental evidence provided is convincing and the work will be of interest to microbiologists studying chemotaxis.

eLife assessment

This study presents a cellular automaton model to study the dynamics of virus-induced signalling and innate host defense against viruses such as SARS-CoV-2 in epithelial tissue. The simulations and data analysis are convincing and represent a valuable contribution that would be of interest to researchers studying the dynamics of viral propagation.

eLife assessment

This study uses numerical simulations to characterize and compare variants of two widely used mathematical models and then applies those models to inferring evolutionary parameters from breast cancer data. The copious numerical results will be of some interest to mathematical biologists working with similar models. The finding that many breast cancer mutations are mildly deleterious is valuable but the evidence supporting this claim is incomplete because the mathematical modelling and statistical methods are insufficiently justified and inadequately validated.

eLife assessment

This valuable study reports that actin-related proteins may be involved in transcriptional regulation during spermatogenesis. The supporting data remain incomplete, and more extensive disentanglement from the canonical role of these actin-related proteins and the experimental validation of in silico predictions are required. This work will be of interest to reproductive biologists and other researchers working on non-canonical roles of actin and actin-related proteins.

eLife assessment

The authors develop a novel genetic strategy for specific and comprehensive labeling of axo-axonic cells, also referred to as chandelier cells, in the mouse brain. The approach and analysis are rigorous such that the data convincingly support the key conclusions, including the expanded distribution of axo-axonic cells throughout the brain. This study provides important new information about the distribution of a significant neuronal cell type, as well as new tools for future studies. This work will be of broad interest to neuroscientists who work on the anatomical and functional organization of neural circuits.

eLife assessment

This useful study provides a novel method to detect sleep cycles based on variations in the slope of the power spectrum from electroencephalography signals. The method, dispensing with time-consuming and potentially subjective manual identification of sleep cycles, is supported by solid evidence and analyses but some aspects could be better illustrated and the source of the discrepancies between classical and fractal cycles should be identified. This study will be of interest to researchers and clinicians working on sleep and brain dynamics.

eLife assessment

This useful manuscript challenges the utility of current paradigms for estimating brain-age with magnetic resonance imaging measures. It presents solid evidence to support the suggestion that an alternative approach focused on predicting cognition may be more beneficial. This work will be of interest to researchers working on brain-age and related models.