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 proof-of-concept study focuses on an A->G DNA base editing strategy that converts CAG repeats to CAA repeats in the human HTT gene, which causes Huntington's disease (HD). These studies are conducted in human HEK293 cells engineered with a 51 CAG canonical repeat and in HD knock-in mice harboring 105+ CAG repeats. The findings of this study are valuable for the HD field, applying state-of-the-art techniques; however, the key experiments have yet to be performed in neuronal systems or brains of these mice: actual disease-rectifying effects relevant to patients have yet to observed.

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 study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

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.

eLife assessment

This work explores the role of one the most abundant circRNAs, circHIPK3, in bladder cancer cells, showing with convincing data that circHIPK3 depletion affects thousands of genes and that those downregulated (including STAT3) share an 11-mer motif with circHIPK3, corresponding to a binding site for IGF2BP2. The experiments demonstrate that circHIPK3 can compete with the downregulated mRNAs targets for IGF2BP2 binding and that IGF2BP2 depletion antagonizes the effect of circHIPK3 depletion by upregulating the genes containing the 11-mer. These important findings contribute to the growing recognition of the complexity of cancer signaling regulation and highlight the intricate interplay between circRNAs and protein-coding genes in tumorigenesis.

eLife assessment

The authors aim to develop a CRISPR system that can be activated upon sensing an RNA. As an initial step to this goal, they describe RNA-sensing guide RNAs for controlled activation of CRISPR modification. Many of the data look convincing and while several steps remain to achieve the stated goal in an in vivo setting and for robust activation by endogenous RNAs, the current work will be important for many in the field.

eLife assessment

This study presents valuable findings describing how two brain regions, the midbrain periaqueductal gray matter and basolateral amygdala, communicate when a predator threat is detected. Though the periaqueductal gray is usually viewed as a downstream effector, this work contributes to a growing body of literature from this lab showing that the periaqueductal gray produces effects by acting on the basolateral amygdala. The experimental design, data collection and analysis methods provide solid evidence for the main claims. Although anatomical and immediately early gene results suggest the paraventricular nucleus of the thalamus may serve as a mediator of dorsolateral periaqueductal gray to basolateral amygdala neurotransmission, this finding would benefit from a functional assessment. This study will appeal to a broad audience, including basic scientists interested in neural circuits, basic and clinical researchers interested in fear, and behavioral ecologists interested in foraging.

eLife assessment

This valuable work describes a new protein factor that is required for filamentous phage assembly. Convincing evidence is provided for the binding of PSB15 to the packaging signal of the single-stranded DNA, Trx, and cardiolipin, and a mechanism for how the phage DNA is targeted to the assembly site in the bacterial inner membrane is presented. The work will be of interest to microbiologists.

eLife assessment

This study presents important data describing cell states of olfactory ensheathing cells, and how these cell states may relate to repair after spinal cord injury. While the overall framework used for characterizing these cells is solid, the quantification and contextualization of results are incomplete, given that measurements, significance statistics, and discussion of both previous work and experimental methods that would be necessary to support several claims are not provided. With more thorough quantification and discussion, this work will be of interest to stem cell biologists and spinal cord injury researchers.

eLife assessment

This study presents valuable research comparing three different species of extant cartilaginous fishes and describes new data on ratfish. The methods are convincing although the reviewers noted that standardized methods are essential when comparing numerical datasets. This study would be of interest to skeletal biologists working on the evolution of chondrichthyan skeletons.

eLife assessment

This useful study reports that epididymal proteins are required for embryogenesis after fertilization. The data presented are generally convincing, but the study is incomplete because it does not investigate in detail how those proteins cause DNA fragmentation and compromised embryonic development. This work will be of interest to reproductive biologists and andrologists.

eLife assessment

This important work advances our understanding of how brains flexibly gate actions in different contexts, a topic of great interest to the broader field of systems neuroscience. Recording neural activity from several sensory and motor cortical areas along a sensorimotor pathway, the authors found that preparatory activity in motor cortical areas of the mouse depends on the context in which an action will be carried out, consistent with previous theoretical and experimental work. Furthermore, the authors provide causal evidence that these changes support flexible gating of actions. The carefully carried out experiments were analyzed using state-of-the-art methodology and provide convincing conclusions.

eLife assessment

This fundamental study provides insights into the interplay of endogenous orienting and the planning of goal-directed gaze shifts (saccades). Using an elegant experimental protocol and detailed analyses of the time course of saccadic choices, the authors provide compelling evidence for independent mechanisms that guide early, reflexive eye movements and later, voluntary gaze shifts. This work will be of interest to neuroscientists and psychologists working on vision and motor control and to those researching decision-making across disciplines.

eLife assessment

This important study provides evidence for a combination of the latest generation of Oxford Nanopore Technology long reads with state-of-the art variant callers enabling bacterial variant discovery at accuracy that matches or exceeds the current "gold standard" with short reads. The evidence supporting the claims of the authors is convincing, although the inclusion of a larger number of reference genomes would further strengthen the study. The work will be of interest to anyone performing sequencing for outbreak investigations, bacterial epidemiology, or similar studies.

eLife assessment

The study, from the group that pioneered migrasome, describes a novel vaccine platform derived from this newly discovered organelle. Using these cleverly engineered migrasomes – that behave like natural migrasomes – as a novel vaccine platform has the potential to overcome obstacles such as cold chain issues for vaccines like messenger RNA. Although the findings are important with practical implications for the vaccine technology, and the evidence, based on appropriate and validated methodology is convincing and is in line with current state-of-the-art, there are some critical issues that need to be addressed. These include a head-to-head comparison with proven vaccine platforms, for example, a SARS-CoV-2 mRNA vaccine or an adjuvanted recombinant spike protein.

eLife assessment

This important study reports the deep evolutionary conservation of a core genetic program regulating spermatogenesis in flies, mice, and humans. The data presented are supportive of the main conclusion and generally convincing. This work will be of interest to evolutionary and reproductive biologists.

eLife assessment

This important study reports the developmental dynamics and molecular markers of the rete ovarii during ovarian development. However, the data supporting the main conclusions remain incomplete. This study will be of interest to developmental and reproductive biologists.

eLife assessment

The authors combined human genetic analysis with zebrafish experiments to produce evidence that alleles that impair the function of EPHA4 cause idiopathic scoliosis (IS), a common spinal deformity. The significance of the findings is important because the cellular and molecular mechanisms that contribute to IS remain poorly understood. The human genetic data are quite convincing whereas the zebrafish data, although supportive, are incomplete.

eLife assessment

This useful manuscript describes the second earliest known winged ovule without a capule in the Famennian of Late Devonian. Using solid mathematical analysis, the authors demonstrate that three-winged seeds are more adapted to wind dispersal than one-, two- and four-winged seeds. The manuscript will help the scientific community to understand the origin and early evolutionary history of wind dispersal strategy of early land plants.

eLife assessment

This work is important because it attempts to elucidate how immune cells migrate across the blood brain barrier. The authors developed a convincing framework to visualize, recognize and track the movement of different immune cells across primary human and mouse brain microvascular endothelial cells without the need for fluorescence-based imaging using microfluidic devices. The data gathered are solid, and this work will be of interest to the cancer biology, immunology and medical therapeutics fields.

eLife assessment

This fundamental study provides a modeling regime that provides new insight into the energy-preservation parameters among schooling fish. The strength of the evidence supporting observations such as distilled dynamics between leading and lagging schooling fish which are derived from emergent properties is convincing. Overall, the study provides exciting insights into energetic coupling with respect to group swimming dynamics. Some potential improvements to strengthen the study include clarification regarding degrees of freedom and parameter ranges in the model.

eLife assessment

This is a valuable study that describes the effects of T. pallidum on neural development by applying single-cell RNA sequencing to an iPSC-derived brain organoid model. The evidence supporting the claims of the authors is solid, although further evidence to understand the differences in infection rates would strengthen the conclusions of the study. In particular, the conclusions would be strengthened by validating infection efficiency as this can impact the interpretation of single-cell sequencing results, and how these metrics affect organoid size as well as comparison with additional infectious agents. Furthermore, additional functional validations of downstream effectors could be insightful.

eLife assessment

This fundamental study reports differential expression of key genes in full-term placenta between Tibetans and Han Chinese at high elevations, which are more pronounced in the placenta of male fetus than in female fetus. The gene expression data were collected and analyzed using solid and validated methodology, although there is limited support for hypoxia-specific responses due to a lack of low-altitude samples. Several of the placental genes found in this study have been previously reported to show signatures of positive selection in Tibetans, pointing to a potential mechanism of how human populations adapt to high elevation by mitigating the negative effects of low oxygen on fetal growth. The work will be of interest to evolutionary and population geneticists as well as researchers working on human hypoxic response.

eLife assessment

This study aggregates across five fMRI datasets and reports that a network of brain areas previously associated with response inhibition processes, including several in the basal ganglia, are more active on failed stop than successful stop trials. This study is valuable as a well-powered investigation of fMRI measures of stopping. However, evidence for the authors' conclusions regarding the role of subcortical nodes in stopping is incomplete, due to the limitations in the fMRI analysis.

eLife assessment

This important study provides a new perspective on why preparatory activity occurs before the onset of movement. The authors report that when there is a cost on the inputs, the optimal inputs should start before the desired network output for a wide variety of recurrent networks. The authors present convincing evidence by combining mathematically tractable analyses in linear networks and numerical simulation in nonlinear networks.

eLife assessment

The valuable findings by Dasgupta et al demonstrate the role of Sema7a in fine tuning the morphology of the microcircuit between afferent axons and sensory hair cells in the lateral line organ. The loss and gain of function evidence provides solid support for a role for Sema7a in this process. Additional work is needed to determine the role for different isoforms in Sema7a-mediated synapse formation and chemoattraction as well as cell type specificity.

eLife assessment

This important work provides convincing data on neuronal heterogeneity in the dorsal raphe nucleus (DRN), focusing on their electrophysiological properties, morphology, and susceptibility to the neurodegeneration of noradrenaline and dopamine systems in the Parkinsonian state. These findings suggest a significant interplay between catecholaminergic systems in healthy and parkinsonian conditions, as well as neuronal structure and function. Such findings provide a strong foundation for basic scientists as well as pre-clinical researchers interested in the role of dorsal raphe neurons in Parkinson's disease.

eLife assessment

The authors use point light displays to measure biological motion (BM) perception in children (mean = 9 years) with and without ADHD, and relate it to IQ, social responsiveness scale (SRS) scores and age. They report that children with ADHD were worse at all three BM tasks, but that those tasks loading more heavily on local processing relate to social interaction skills and those loading on global processing relate to age. There are still some elements of the results that are unclear, but nevertheless, the important and solid findings extend our limited knowledge of BM perception in ADHD, as well as biological motion processing mechanisms in general.

eLife assessment

This fundamental study significantly advances our understanding of the role of water influx and swelling on neutrophil migration in response to chemoattractant. The evidence supporting the conclusions, based on a genome-wide CRISPR screen and high quality cellular observations, is compelling. This paper will be of interest to cell biologists and biophysicists working on cell migration.

eLife assessment

Despite the well-known facilitatory effect that integration across the senses has on behavioural measures, standard neuroimaging approaches have not yet produced reliable and precise neural correlates. In this paper, Buhman et al. harness the decoding of EEG responses, beyond univariate approaches, to capture these correlates in a robust, clear fashion. If confirmed, this approach could be important for estimating multisensory integration in humans across a wide range of different domains. However, the strength of evidence to support these claims is still incomplete because of the potentially confounding factor of eye movements, which the authors themselves identify in their data, and because of the discrepancies between the behavioural and EEG data.

eLife assessment

Following synaptic vesicle fusion events at release sites, vesicle remnants will need to be cleared in order to allow new rounds of vesicle docking and fusion. This fundamental study of Mahapatra and Takahashi examines the role of release site clearance in synaptic transmission during repetitive activity in two types of central synapses, the giant calyx of Held and hippocampal CA1 synapses. The study uses pharmacological approaches to interfere with release site clearance by blocking membrane retrieval (endocytosis). The results also show how pharmacological inhibition of scaffold proteins affects short-term plasticity. The data presented make a compelling case for fast endocytosis as necessary for rapid site clearance and vesicle recruitment to active zones. The data reveal an unexpected, fast role for local site clearance in counteracting synaptic depression.

eLife assessment

This paper provides valuable insights into the neural substrates of human working memory. Through clever experimental design and rigorous analyses, the paper provides compelling evidence that the working memory representation of stimulus orientation is a reformatted version of the presented stimulus, though more work is needed to establish more generally that visual working memories are abstractions of percepts. This work will be of broad interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife assessment

This useful experiment seeks to better understand how memory interacts with incoming visual information to effectively guide human behavior. Using several methods, the authors report two distinct pathways relating visual processing to the default mode network: one that emphasizes "semantic" cognition, and the other, spatial cognition. Despite the impressive array of methods employed, the evidence supporting a clear distinction is currently incomplete.

eLife assessment

The study presents a useful investigation of the relation between pupil size and saccade decision in human observers. Based on the premise that pupil size is a reliable proxy of "effort", the authors conclude that less costly saccade targets are preferred. The data were collected and analyzed using solid and validated methodology, but the evidence supporting the claim that effort drives saccade target selection is incomplete and alternative explanations are not ruled out.

eLife assessment

This is a fundamental study that advances our understanding of the contribution of somatic variations in microglia that may contribute to the onset or progression of neurodegenerative disease. Specifically, during Alzheimer's disease, somatic mutations were identified in the MAPK pathway genes. The findings presented here are backed by compelling evidence drawn from a patient cohort, along with mechanistic proof-of-concept studies. Collectively, this research will be of interest to a wide audience, particularly those involved in the study of somatic mutations, neurodegeneration, immunology, and cell signalling.

eLife assessment

This study could pose an important step forward in understanding brain network embedding of beta oscillations, advancing our circuit-level understanding of the pathophysiology associated with frontal beta or dopaminergic alterations in psychiatric or neurological disorders. The study provides compelling evidence that beta oscillations across the neocortex and basal ganglia map onto shared functional and structural networks that show significant positive correlations with dopamine receptors.

eLife assessment

This study employed a comprehensive approach to examining how the MT+ region integrates into a complex cognition system in mediating human visuo-spatial intelligence. While the findings are useful, the experimental evidence is incomplete and the study design, hypothesis, analyses, writing, and presentation need to be improved. The work will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife assessment

This study offers a valuable description of the layer-and sublayer specific outputs of the somatosensory cortex based on convincing evidence obtained with modern tools for the analysis of brain connectivity, together with functional validation of the connectivity using optogenetic approaches in vivo. Beyond bridging together, in one dataset, the results of disparate studies, this effort brings new insights on layer specific outputs, and on differences between primary and secondary somatosensory areas. This study will be of interest to neuroanatomists and neurophysiologists.

eLife assessment

Abbasi and colleagues use Granger causality to explore the cortico-subcortical dynamics during speaking and listening. They find valuable evidence for bi-directional connectivity in distinct frequency bands as a function of behaviour, but currently offer incomplete support for the validity of their analyses and the predictive coding interpretation of their results.

eLife assessment

This a useful study that reports a genetic regulatory network that accounts for altered lipid metabolism in response to two different bacterial diets of C. elegans. The proposed mechanism, linking vitamin B12, S-adenosyl methionine (SAM), phosphatidylcholine (PC), and neutral lipid levels, is solid but has been previously demonstrated by other studies using similar assays. The evidence to support a new layer of regulation, via the production of phospho-choline by ASM-3/acid sphingomyelinase, requires further substantiation.

Editors Assessment:

This work is part of a series of papers from the Hong Kong Biodiversity Genomics Consortium sequencing the rich biodiversity of species in Hong Kong. This example presents the genome of the golden birdwing butterfly Troides aeacus (Lepidoptera, Papilionidae). A notable and popular species in Asia that faces habitat loss due to urbanization and human activities. The lack of genomic resources impedes conservation efforts based on genetic markers, as well as better understanding of its biology. Using PacBio HiFi long reads and Omni-C a 351Mb genome was assembled genome anchored to 30 pseudo-molecules. After reviewers requested more information on the genome quality it seems there was high sequence continuity with contig length N50 = 11.67 Mb and L50 = 14, and scaffold length N50 = 12.2 Mb and L50 = 13. Allowing a total of 24,946 protein-coding genes were predicted. This study presents the first chromosomal-level genome assembly of the golden birdwing T. aeacus, a potentially useful resource for further phylogenomic studies of birdwing butterfly species in terms of species diversification and conservation. This evaluation refers to version 1 of the preprint