eLife assessment

This study is of fundamental importance, addressing the regulation of the carbon concentrating mechanism in cyanobacteria. It is a well-controlled investigation of low affinity regulatory binding of small molecules, processes that are typically difficult to examine. The work provides compelling evidence that the adenylate pool, rather than any single metabolite, regulates a key bicarbonate transporter (SbtA) to provide efficient bicarbonate supply while preventing futile cycling that can result from escape of unfixed CO2.

eLife assessment

This is a fundamental work identifying the components of the N6-methyladenosine methyltransferase complexes in yeasts and showing its major differences with the same complexes in mammals and flies. The evidence supporting the conclusions is convincing, with rigorous high-throughput sequencing approaches and detailed functional analysis. This work will be of broad interest to those in the RNA modification and meiosis fields.

eLife assessment

This is an important study that addresses the interesting question of whether stimulation of Ventral midbrain input to prefrontal cortex (PFC) during adolescence can be used to rescue genetic defects in PFC function. The conclusions are solidly supported by the data and will of interest to a broad group of neuroscientists.

eLife assessment

The authors provide an important demonstration that pharmacologically enhanced catecholamine levels and increased voluntary spatial attention have largely dissociable effects on perceptual decision making. Their findings provide solid evidence that neuromodulatory arousal and selective spatial attention shape perception in qualitatively different ways.

eLife assessment

This important study expands on current knowledge of allosteric diversity in the human kinome by C-terminal splicing variants using as a paradigm DCLK1. The authors provide solid evolutionary and some mechanistic evidence how C-terminal isoform specific variants generated by alternative splicing can regulate catalytic activity by means of coupling specific phosphorylation sites to dynamical and conformational changes controlling active site and substrate pocket occupancy, as well as protein-protein interactions. The data will be of interest to researchers in the kinase and signal transduction field.

eLife assessment

This important study combines extensive phenotyping of genome-wide deletion mutants and machine learning-based prediction to generate a large scale resource for understanding the functions of thousands of fission yeast protein-coding genes. This resource is supported by compelling phenotyping data and state-of-the-art bioinformatic analyses.

eLife assessment

This manuscript provides important findings on the role of individual cysteine residues of FGF2 in its unconventional secretion through the plasma membrane. The experimental results are of generally high quality and solid. The work should interest researchers working on protein trafficking and secretion.

eLife assessment

This work presents a valuable online platform designed to facilitate the exploration of genes and genetic pathways implicated in human aging. Leveraging a new inference methodology, the tool enables the identification and visualization of key genes and tissues impacted by aging, facilitating scientific discovery. However, since the methods have not been fully explained, there is only incomplete support for the platform, which could be improved upon for usability and reproducibility.

eLife assessment

This useful manuscript presents a new approach to transform multi-omics datasets into images and to exploit Deep Learning methods for image analysis of the transformed datasets. As an example, the method is applied to multi-omics datasets on different cancers, but the evidence for the method working as advertised is currently incomplete.

eLife assessment

This study offers important insights into the transcriptional regulatory networks driving female gametocyte maturation in rodent malaria parasites. The carefully designed and executed experiments convincingly show how two female-specific transcription factors, AP2-FG and PFG (aka Fd2), co-operate to up-regulate the expression of genes required for development after fertilization occurs in the mosquito midgut. This study will be of interest to scientists working on sexual differentiation and gene regulation in Plasmodium and other apicomplexan parasites.

eLife assessment:

This fundamental study provides evidence that de novo beige adipogenesis from Pdgfra+ adipocyte progenitor cells is blocked during early aging in subcutaneous fat. The depth of the data at early ages is compelling, with rigorous cell tracing methodology employed. The study will aid in identifying new approaches to switch dormant adipocytes into an active thermogenic phenotype, and should be of interest to cell biologists at large.

eLife assessment

The study by O'Reilly and Delis provides a valuable data-driven framework for extracting task-related muscle synergies in a step towards the understanding and practical use of synergies in real scenarios (e.g., evaluation of patients in a clinical environment). The approach is incomplete since the authors did not compare their method with classical physiologically grounded approaches for assessing muscle synergies. In this sense, the comparisons with classical approaches would clarify if physiological assemblies were preserved and were not altered to incorporate task space variables. Despite limitations, the proposed framework would interest motor control and neural engineering researchers.

eLife assessment

The authors report that an interaction between the sodium-activated potassium channel Slack and Nav1.6 sensitizes Slack to inhibition by quinidine. This is an important finding because it contributes to our understanding of how the antiseizure drug quinidine affects epilepsy syndromes arising from mutations in the Slack-encoding gene KCNT1. The results are largely compelling, although additional data would strengthen the claims of a direct channel-channel interaction in vivo.

eLife assessment

This study presents a valuable finding on developing a generative model of brain electrophysiological signals to explain temporal decoding matrices that have been widely used in cognitive neuroscience. The evidence supporting the claims of the authors is convincing, although adding more neurobiological interpretation of signal properties and the underlying brain mechanism would have strengthened the study. The work will be of interest to cognitive neuroscientists using electrophysiological recordings.

eLife assessment

This valuable study combines chronic widefield calcium imaging of dorsal cortex activity at the mesoscale level with electrical recording of single neurons in specific cortical and subcortical locations. This work provides compelling evidence for recording neuronal activity at multiple temporal and spatial scales by combination of optical and electrophysiological methods. This work will be of broad interest to system neuroscientists studying neural circuits.

eLife assessment

This study addresses an important 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 solid. While this work is novel and on an interesting, understudied topic, the reviewers also identified significant gaps in experimental data and agree that support for the main claims is incomplete.

eLife assessment

This valuable work provides a near-complete description of the mechanosensory bristles on the Drosophila melanogaster head and the anatomy and projection patterns of the bristle mechanosensory neurons that innervate them. The data presented are solid. The study has generated numerous invaluable resources for the community that will be of interest to neuroscientists in the field of circuits and behaviour, particularly those interested in mechanosensation and behavioural sequence generation.

eLife assessment

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

eLife assessment

This important paper advances our ability to understand feeding behavior in fruit flies and begins to address the challenging question of motivation. With innovative methods based on the detailed monitoring of interactions between foods of different qualities at different hunger states, they present compelling evidence for non-homeostatic feeding not driven by metabolic need.

eLife assessment

This is an important paper that combines methods ranging from agronomy and plant breeding to Arabidopsis functional genetics, to construct a plausible argument that polymorphism in a single gene affects crop yield by affecting root cell elongation and drought stress resilience in a poorly studied crop. The overall argument is plausible but rests on a diverse set of claims that are supported by solid, but also partly incomplete evidence.

eLife assessment

This study presents Bactabolize, a useful tool for the rapid genome-scale reconstruction of bacteria, applied here to strains of Klebsiella pneumoniae. Using a solid and validated methodology, the tool takes reference reconstructions as the input and can generate new reconstructions for target strains from these. However, the evidence to substantiate all of the justifications and practical applications of the models produced is still incomplete, and the work would benefit from more rigorous approaches regarding the accuracy of the predicted models.

eLife assessment

This paper describes useful tools for the light-induced degradation of proteins in bacteria, which will be appreciated by the community. The methods and data analyses are solid but the strength of evidence for the tool working as advertised is still incomplete. The study will be of interest to colleagues in the fields of microbiology and synthetic biology.

eLife assessment

This is a valuable investigation of the chromatin dynamics throughout the cell cycle by using fluorescence signals and patterns of GFP-PCNA and CY3-dUTP, which labels newly synthesized DNA. The authors report reduced chromatin mobility in S relative to G1 phase. The technology and methods used are solid, but the significance of the work is reduced by the model system employed, the HeLa cell line, which has a greatly abnormal genome.

eLife assessment

This manuscript provides useful information on the evolution of gene expression levels and plasticity in tissues impacted by hypoxia during colonization of a high-altitude environment. The strength of evidence is still inadequate because of limitations in the methods and analyses. The work will be of interest to biologists working at the interface of ecology and evolution.

eLife assessment

This important study describes the protective role of group 2 innate lymphoid cells (ILC2s) in tissue physiology and contributes to immunity, inflammatory pathology, and metabolism in maintaining homeostasis during pregnancy. The authors provide convincing evidence that ILC2s have new roles distinct from parasite protection and allergy inducers. Uterine ILC2s are key immune cells during normal and complicated pregnancies.

eLife assessment

This study presents valuable new insights into the role of the extracellular matrix component (ECM) Perlecan in axon integrity, with downstream consequences for the maintenance of synaptic structures. The evidence for Perlecan's role in this process is solid, although negative results for Perlecan's mechanism of action should be strengthened with the addition of appropriate controls centered on the relevant pathways and mechanisms involved as well as more careful analyses and interpretations. The authors provide convincing data identifying and describing the cellular sequence from ECM perturbations to axonal and synaptic degeneration, but additional data pinpointing the requirements of Perlecan for axonal maintenance would further improve the impact of this study.

eLife assessment

The present study offers valuable insights into the remodeling of Merkel cells and their innervating sensory axons in the skin. This remodelling seems to be mostly played out independently between the two synaptic partners revealing significant Merkel cell turnover and axonal plasticity. The authors employed live imaging and quantification tools using genetic models in which parts of the mechanosensory organs of the skin are labelled with distinct fluorescent proteins. While most of the data, and their interpretations are solid, the analyses of Merkel cell number homeostasis remain incomplete.

eLife assessment

This study offers an inventory of proteins and their phosphorylated sites that are up- and down-regulated in the adipose tissue and skeletal muscle of women with PCOS. The data were collected and analyzed using rigorous and validated methodology, making it a useful resource for identifying targets and strategies for future PCOS treatments. However, even though some of the predicted targets are compelling, further functional validation is required to ensure the accuracy of these identified targets. If confirmed, the findings of this study would be of significant interest to a wide range of readers.

eLife assessment

In this useful study, Holzinger et al. present compelling evidence that scorpionfish bactericidal/permeability-increasing protein (scoBPI) exhibits remarkable antibacterial activity against multi-drug resistant Pseudomonas aeruginosa. These findings open new avenues of research for identifying novel chemotherapies to treat Pseudomonas infections and have broader implications in developing chemotherapies against other drug-resistant Gram-negative bacterial infections. The work will be of interest to individuals investigating novel cystic fibrosis antimicrobials.

eLife assessment:

This important paper highlights the clonal organization of the dorsal telencephalon, a major region of the vertebrate brain, and analyzes the distinctive gene expression and chromatin accessibility present in each clonal using the adult teleost fish medaka. High-quality data were collected using convincing and solid methods and these were used to identify synaptic genes with a distinct chromatin landscape and expression in one of the regions of the dorsal pallium, with the goal of ascribing an evolutionary origin to these neurons.

eLife assessment

This paper is of potential interest to both the hippocampal and computational neuroscience fields because it provides a framework for understanding how adult-born granule cells in the hippocampus contribute to network processing. It contains novel interesting ideas, such as the analysis of input-output transformation by SRM models and the establishment of "greedy networks". However, not all major conclusions are sufficiently supported by the data. The paper demonstrates that mixed networks show better encoding performance than pure networks, but the differences are small and only visible with specific performance metrics. Intuitive explanations are not provided.

eLife assessment

In this study, the authors use high-speed and high-resolution imaging to investigate the role of the yeast syntaxin homolog Tlg2p in endocytic vesicle sorting. They obtain compelling data to show that the Tlg2p-residing compartment within the trans-Golgi network functions as an early/sorting compartment, where endocytic cargos are sorted to either the recycling pathway or the endo-lysosomal pathway. The authors also describe additional molecular details of this sorting process, and overall provide important insights into the mechanism of endocytic vesicle sorting in budding yeast.

eLife assessment

This valuable study shows that new, virulent genotypes of Xanthomonas oryze pv. oryzae, that are similar to strains present in east Asia, cause outbreaks of bacterial blight of rice in Tanzania. The authors' use of CRISPR-based gene editing on multiple pathogen targets in an elite African rice variety to create lines resistant to both endemic and emerging pathogen strains in Africa makes for a compelling contribution to meet this alarming development. The work describing the new strains of the pathogen is solid but could be stronger if there were genome sequence data for all strains examined and a clearer presentation of recent disease outbreaks and their severity.

eLife assessment

The findings in this study are important, as this brainstem region is implicated in a multitude of functions. The experimental procedures are difficult to implement and the preparation used and the skill required are impressive. The methods and data are solid, however, some analyses are incomplete, and the strength of evidence is also incomplete because the claims are only partially supported by the data. This work will interest those who study respiration, airway protection, and other oral behaviors.

eLife assessment

This manuscript explores the potential regulatory role of a previously unstudied phosphorylation site in the Src kinase SH3 domain. A mutant intended to mimic the phosphorylation of this site, Y90E, shows enhanced activity and transforming capacity, reduced mobility in the lipid bilayer, and a more open catalytic structure. In general, these findings are supported by compelling evidence. The paper will be of interest to biochemists and structural biologists studying new mechanisms that are capable of modulating the allosteric regulation of multi-domain protein kinases.

eLife assessment

Using chemogenetic manipulation, the authors induce or suppress activity in D1 spiny neurons in the dorsomedial striatum of mice. The results effectively demonstrate that excitation or inhibition of this class of neurons results in a consistent behavioral effect that is linked to an impact on local dynamics in thalamic regions that project to this part of the thalamus, as well as cortical regions that can be more readily defined as unimodal as identified by a classification approach. This work has clear relevance to the field of neuroimaging, getting at the broader hemodynamic signatures of direct pathway stimulation in the striatum, but requires critical revisions to justify their main conclusions.

Using chemogenetic manipulation, the authors induce or suppress activity in D1 spiny neurons in the dorsomedial striatum of mice. The results effectively demonstrate that excitation or inhibition of this class of neurons results in a consistent behavioral effect that is linked to an impact on local dynamics in thalamic regions that project to this part of the thalamus, as well as cortical regions that can be more readily defined as unimodal as identified by a classification approach. This work has clear relevance to the field of neuroimaging, getting at the broader hemodynamic signatures of direct pathway stimulation in the striatum, but requires critical revisions to justify their main conclusions.

eLife assessment

This paper reports a detailed functional analysis of the Rab1 effector Uso1, and it provides a fundamental advance in our understanding of how ER-derived vesicles deliver their cargo. The authors provide compelling evidence that the key function of Uso1 is promoting SNARE complex formation rather than tethering vesicles as generally assumed. These insights will be of interest to cell and structural biologists who study membrane traffic.

eLife assessment

This study makes an important effort to observe and quantify synaptic integration in a large and active network of cultured neurons, using simultaneous patch-clamp and large-scale extracellular recordings. They developed a method to distinguish excitatory and inhibitory contributions, showing compelling evidence that the subthreshold activity of these neurons is dominated by few presynaptic neurons. They provide basic statistics about connectivity and network dynamics, but their statistical analysis of the interplay between excitatory and inhibitory inputs is incomplete, mainly showing examples and averages, with little quantification of variability and therefore requiring additional analysis to better support their claims.

eLife assessment

This important study details an enrichment of the IL-6 signaling pathway in human tendinopathy, and applies transcriptional profiling to an advanced in vitro model to test IL-6 specific phenotypes in tendinopathy. Overall, the strength of evidence is solid yet incomplete, as transcriptomic measurements provide clarity, though functional studies including analysis of proliferation are needed to confirm these findings. This work will be of interest to stem cell biologists and immunologists.

eLife assessment

This paper describes useful results from studies investigating circuits in the brain that underlie behavioral responses in fearful situations. They identified a role for a class of neurons that are sufficient to cause these stereotyped behaviors including freezing behaviors. These solid studies will increase our understanding of brain pathways regulating these types of behaviors.

eLife assessment

This study is important as it examined the role of Perk (Protein kinase RNA-like endoplasmic reticulum kinase) and Atf4 (Activating Transcription Factor-4) in the integrated neurodegenerative and regenerative responses following the optic nerve injury. The evidence is convincing as the authors relied on both newly generated transcriptomic data and publicly available databases to support their research. While there are some limitations in data quality and interpretations, the study is likely to be of interest to researchers studying optic neuropathies and axonal regeneration.

eLife assessment

This is a very interesting and important study that convincingly demonstrates a descending pathway for the control of nociception in non-mammalian organisms.

eLife assessment

This important paper reports recent improvements and extensions to stdpopsim, a community-driven resource that is built on top of powerful software for performing simulations of population genomic data and provides a catalog of species with curated genomic parameters and demographic models. In addition to describing the new features and species in stdpopsim, the authors provide a set of practical guidelines for implementing realistic simulations. Overall, this convincing manuscript serves as an excellent overview of the utility, challenges, common pitfalls, and best practices of population genomic simulations. It will be of broad interest to population, evolutionary, and ecological geneticists studying humans, model organisms, or non-model organisms.

eLife assessment

This valuable paper informs on the role of type I PRMTs in programming muscle stem cell identification. The evidence presented is mostly solid, with some weaknesses in the evidence regarding the proposed mechanism. The paper will be of particular interest to those who study skeletal muscle satellite cell biology.

eLife assessment

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

eLife assessment

This paper describes an important new marine reptile specimen. A solid ostelogical description of the saurosphargid Prosaurosphargis yingzishanensis, the earliest known member of this group, combined with a large-scale phylogenetic analysis enhances our understanding of the affinities of a wide range of Triassic reptiles. As such the relevance of this paper goes far beyond the immediate importance of this remarkable fossil - it also sheds light on the position of several important Triassic groups, including Testudinata and Archosauromorpha.

eLife assessment

Vocalizations are controlled by neural circuits connecting the amygdala and periaqueductal gray. This study presents valuable measures of the neurons that suppress vocalization in appropriate contexts using a rich variety of behavioural, imaging, optogenetic, and tracing methodologies. The evidence supporting the claims of the authors is solid, although their results only hint at the mechanisms that could underlie the hierarchical control of vocalization. The work will be of interest to neurobiologists working on motor control and vocalization.

eLife assessment

This study presents valuable findings on the risk factors of avascular osteonecrosis in patients with Gaucher disease. The evidence supporting the claims of the authors is convincing. The work will interest clinicians who treat patients with inborn errors of metabolism.

eLife assessment

This study presents valuable findings regarding the functional diversification of flavodoxins from diatoms, a protein initially described as an Fe-sparing substitute for ferredoxin in Fe-poor open ocean environments. The evidence supporting the claims of the authors is solid, although the study could be strengthened by using a wider gradient of oxidative stress in the experiments and using Fe limitation methodology, which allows more certain differentiation between a low Fe and oxidative stress response.

eLife assessment

This valuable study combines population genetic theory and deep learning approaches to estimate the extent of assortative mating and sex bias in modern admixed populations in the Americas. The new approach provides solid evidence for their main conclusions that socially constructed hierarchies have influenced mating behaviors, though certain results would benefit from further consideration. This paper would be of interest to human population geneticists and social scientists, particularly those studying demographic processes.

eLife assessment

This compelling study brings together two earlier observations: that Ca2+ influx can trigger exosome release from multivesicular bodies, and that plasma membrane repair after wounding requires Ca2+ and involves Ca2+-binding annexin proteins. This important work takes these earlier findings in an interesting new direction by showing that exosome release from MVBs is also triggered by Ca2+ influx during plasma membrane wounding and requires the annexin isoform ANX6. The study suggests a few possible mechanisms (such as Ca2+-dependent tethering of MVBs to the plasma membrane by ANX6) and raises the interesting possibility that cell injury and repair may contribute to the release of exosomes into biological fluids.

eLife assessment

This manuscript reports an important finding that spermatogenic defects in Parl KO mice, a genetic model for Leigh syndrome, may result from mitochondrial defects leading to ferroptosis. The finding, if confirmed, would be of great significance because male germ cell ferroptosis has not been well characterized. However, the criteria for determining male germ cell ferroptosis were vague, and the supporting data were inadequate.

eLife assessment

This study presents important findings on the decision-making capacities of honey bees in controlled conditions. The evidence supporting the study is solid, however, the explanation of the methods, importance, and novelty of the study requires further clarification. With a deeper development of the relevance of this study, the reader will have a clear idea of how this study contributes to the field.

eLife assessment

This paper will be of broad interest to immunologists that study T cell responses and formation of the peripheral T cell compartment. Using elegant live imaging approaches, the authors provide convincing evidence in support of a revised model for how positive-selected thymocytes are called to the thymus medulla to interact with distinct antigen-presenting cells. The work makes an important contribution to the field by identifying previously unappreciated complexities related to cellular movement during T cell generation.

eLife assessment

This study presents valuable findings on how gender-neutral vaccination against human papillomavirus can help improve program resilience in the case of vaccination disruptions. The evidence supporting the claims of the authors is convincing, although the results are only applicable to India and other countries with a similar HPV context; researchers can adapt the model for their local context and use it as a starting point for future research.

eLife assessment

This paper reports on the role of RIF1 during early stages of zebrafish embryonic development, with the important finding that Rif1 seems to be required predominantly to establish the correct embryonic transcriptional program first, followed by a switch to a more replication-timing centered later function. The evidence is convincing, with the major strength being the elegant system and the possibility to also address the problem of the maternal pool of Rif1. A weakness is that the study remains descriptive and the presentation slightly disconnected, with limited mechanistic insight. The work will be of interest for researchers both in the transcription and the replication field, especially for scientists investigating the interplay between the two processes.

eLife assessment

This important study reports a novel mechanism linking DHODH inhibition-mediated pyrimidine nucleotide depletion to antigen presentation. Alternative means of inducing antigen presentation provide therapeutic opportunities to augment immune checkpoint blockade for cancer treatment. While the solid mechanistic data in vitro are compelling, in vivo assessments of the functional relevance of this mechanism are still incomplete.

eLife assessment

Gap junctions, formed from connexins, are important in cell communication, allowing ions and small molecules to move directly between cells. By determining the Cryo EM structure of the structure of connexin 43 in a putative closed state involving lipids, the study makes an important contribution to the development of a mechanistic model for connexin activation. The connexin 43 structure is solid and its presentation will appeal to the channel and membrane protein communities.

eLife assessment

This important study provides an unprecedented overview of the subcellular organization of proliferative blood stage malaria parasites. The localization of multiple parasite organelles is comprehensively probed using three-dimensional super-resolution microscopy throughout the entire intraerythrocytic development cycle. This work provides a compelling framework to investigate in future more deeply the unconventional cell biology of malaria-causing parasites.

eLife assessment

This valuable paper reports the development of SCA-seq, a nanopore-based multiOME mapping method for simultaneously measuring chromatin accessibility, genome 3D and CpG DNA methylation. The methods, data and analyses are solid and largely support the claims. This new tool to interrogate genome structure-function relationships will be of broad interest to geneticists and many others.

eLife assessment

The authors set out to study the development of high altitude polycythemia, which affects mice in a hypoxia chamber and humans staying at a hypoxic atmosphere at high altitude. The findings are useful both for initiating the discussion of the hypothesis that splenic red pulp macrophages, central to red cell survival, are impacted by hypoxia, and for providing some data that partially supports this hypothesis. However, the current data are inadequate to fully support the authors' conclusions.

eLife assessment

This important paper reports data on the cellular response to a single site-specific replication fork block in human MCF7 cells. Compelling evidence shows the efficacy of the bacterial Tus-Ter system to stall replication forks in human cells, with fork stalling leading to lasting ATR-dependent phosphorylation of histone H2AX but not of ATR itself and its downstream targets RPA and CHK1. The work will be of broad interest to students of DNA replication.

eLife assessment

This valuable study uses multiple large neuroimaging data sets acquired at different points through the lifespan to provide solid evidence that birthweight (BW) is associated with robust and persistent variations in cortical anatomy, but less-substantial influences on cortical change over time. These findings, supported by robust statistical methods, illustrate the long temporal reach of early developmental influences and carry relevance for how we conceptualize, study, and potentially modify such influences more generally. The paper will be of interest to people interested in brain development and aging.

eLife assessment

This valuable study revisits the effects of substitution model selection on phylogenetics by comparing reversible and non-reversible DNA substitution models. The authors provide evidence that 1) non time-reversible models sometimes perform better than general time-reversible models when inferring phylogenetic trees out of simulated viral genome sequence data sets, and that 2) non time-reversible models can fit the real data better than the reversible substitution models commonly used in phylogenetics, a finding consistent with previous work. However, the methods are incomplete in supporting the main conclusion of the manuscript, that is that non time-reversible models should be incorporated in the model selection process for these data sets.

eLife assessment

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

eLife assessment

This important study provides novel strategies to overcome certain limitations when investigating the metabolism of hematopoietic stem cells, mainly due to their low abundance. The study provides some solid evidence suggesting that hematopoietic stem cells mainly use glycolysis (rather than mitochondrial OXPHOS or TCA cycle) as their primary energy source, when proliferating in response to hematopoietic stress, as opposed to homeostasis. With the evidence further strengthened by more direct links between metabolic features and cell proliferation, and after consideration of alternative energy sources, this study would be of great interest to stem cell biologists.

eLife assessment

This important study uses CRISPRi to silence multiple effectors in the pathogen Legionella pneumophila. The paper provides a technique that will allow researchers to address functional redundancy amongst effectors, a problem that has persisted even after decades of study. The methodology used is convincing, and further improvement can lead to the identification of novel virulence factors.

eLife assessment

This important study unifies our current understanding of phosphate homeostasis and starvation responses in different eukaryotes, in which the nutrient messenger 1,5-InsP8 binds to one or several cellular SPX receptors, which in turn regulate very different, species-specific PHO pathway components. The evidence is compelling and supported by biochemical analyses, protein localization by fluorescence, and genetic approaches, but could still be strengthened by additional experiments. The work will be of interest to a broad community working on nutrient signalling in eukaryotes.

eLife assessment

This important study addresses both the native role of the Plasmodium falciparum protein PfFKBP35 and whether this protein is the target of FK506, an immunosuppressant with antiplasmodial activity. The genetic evidence for the essentiality of FKBP35 in parasite growth is compelling. However, the conclusion that the role of FKBP35 is to secure ribosome homeostasis and the claim that FK506 exerts its antimalarial activity independently of FKBP35 rely on incomplete evidence.

eLife assessment

The current manuscript investigates the energy landscape of the mammalian sugar porter GLUT5 using enhanced molecular dynamics simulations and biochemical assays. The approach generates important insights into the mechanism of GLUT5 conformational change, and into mechanistic diversity among the GLUT sugar porters more generally. The overall strategy is solid, but without an additional error analysis, the computational components remain incomplete. These findings will be of interest to the transporter and membrane biology communities.

eLife assessment

This useful study adapts methods from causal inference to develop analytical tools for determining the causal influence of single cells on downstream neurons. The simulation evidence is solid, suggesting that these causal methods produce better estimates under biologically-relevant confounds given enough data, although the practical application of the method and the biophysics it relies on is unclear. Nonetheless, this application of causal methods developed in econometrics and other fields could suggest new ways to think about largely observational datasets in neuroscience.

eLife assessment

Hyperpolarised-activated and Cyclic Nucleotide-gated (HCN) channels are the only mammalian channels to open under hyperpolarisation, being important for their roles in cardiac and neuronal cells. The authors of this study use atomistic simulations to enforce changing interaction distances that have been identified from a cryoEM structure and a homology model based on the hERG channel. The simulations suggest state-dependent interactions involving pore and voltage sensor helices, as well as with lipids, leading the authors to propose a domino-like mechanism of activation. These findings will be of considerable interest to the ion channel community.

eLife assessment

This is a comprehensive approach to understanding the genetic requirements of the VEGF family in the generation of brain capillary structure in zebrafish. The manuscript combines vascular brain/meningeal anatomy revealed with a variety of reporter lines, with mutants for Wnt/β-catenin signaling and angiogenic cues. In particular revealing genetic redundancy in VEGF receptor family in an essential function in vasculature development.

This paper is significant because it provides compelling evidence that features methods, data, and analyses more rigorous than the current state-of-the-art in analysis of brain vasculature development. The data derived from the reporter lines are convincing, and the germline mutations allow for solid visualization and quantification of results.

eLife assessment

This important study provides continuous maps of human brain gene expression and explores their relationship with a large variety of microscopic and macroscopic aspects of brain organisation. The authors provide convincing evidence for a relationship between gene expression maps with various aspects of the anatomy of adult brains, during development, and in the case of mental disorders. The data and methods introduced can be an important tool for neuroimaging research.

eLife assessment

These valuable findings will be of interest for the study of dystroglycanopathies and in the general area of axon migration and synapse formation. This work provides solid conclusions about how a range of dystroglycan mutations alter CCK interneuron axonal targeting and synaptic connectivity in the forebrain, and seizure susceptibility.

eLife assessment

This work represents an important contribution to our understanding of how phenomena associated with the theta rhythm in the hippocampus could be generated even in the absence of theta. This convincing computational work provides a parsimonious continuous attractor network model of how hippocampal place cell networks can briefly sweep forward to represent future locations and then sweep back, even in animal species in which theta oscillations are only weakly (or not at all) present.

eLife assessment

The study expands our understanding of the neural circuitry downstream of the cerebellum by describing pathways between the deep cerebellar nuclei and the nucleus accumbens. The authors use a combination of in vivo electrophysiology, electrical and optogenetic stimulation, and both anterograde and retrograde tracing to demonstrate two functional neural pathways. The experiments convincingly support the claims. The finding extends previous investigations about the connections between these two brain areas, and are important for elucidating the role of the cerebellum in influencing functions supported by the nucleus accumbens, such as motivation and reward.

eLife assessment

This important work presents an interesting perspective for the generation and interpretation of phase precession in the hippocampal formation. Through numerical simulations and comparison to experiments, the study provides solid evidence for the role of the DG-CA3 loop in generating theta-time scale correlations and sequences, which would be reinforced through the clarification of the concepts introduced in the study, in particular the notion of intrinsic and extrinsic sequences. This study will be of interest for the hippocampus and neural coding fields.

eLife assessment

This important paper reveals how cells in adjacent tissues use the extracellular matrix to establish mechanical connections. Through a series of crisp genetic manipulations and quantitative image analyses, the authors provide compelling evidence to show how an essential adhesion between the uterus and the seam cells in the nematode C. elegans is formed. The assembly of type IV collagen triggers internalization of a cell surface receptor, which then signals from endocytic vesicles to strengthen the connection.

eLife assessment

This important study shows that lipid degradation is critical for spermatogenesis, with data supporting relevance of this finding across phyla. The authors contribute to a growing realization that lipid droplets have critical roles during differentiation and can influence cell fate, and use convincing methods to analyze the effects of loss of the lipase Brummer on germ line differentiation. This paper will be of interest to developmental and cell biologists working on gametogenesis.

eLife assessment

The important paper describes the structure of a single alpha helix in the large subunit of the Chromatin Assembly Factor 1 (CAF-1) that binds DNA. The single alpha-helix DNA interaction is novel and, combined with the CAF-1 Winged Helix Domain, is required for CAF-1 function in vivo for gene silencing and DNA damage response. The data are convincing, but there are additional analyses that may be considered.

eLife assessment

This study reports of a new signaling pathway in hippocampal neurons by which alpha-1 receptors for norepinephrine regulates Cav1.2 calcium channels; activation of alpha-1 receptors enhances a form of long-lasting synaptic plasticity that is dependent on L-type calcium channels. The experiments are comprehensive and well executed although additional data are warranted to compellingly support the main conclusions. The work has significance for the field of neuroscience in general and for cellular mechanisms of neuroregulation in particular.

eLife assessment

Modi et al. investigate the question of how learned information guides behavior. They combine optogenetic conditioning in Drosophila to spatially restrict the formation of olfactory memory traces in mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning and follow up with behavioral studies and physiological analysis to examine how flies use these 'minimal memories' during learned olfactory discrimination. They discover that MBONs' responses predict behavioral outcomes, with odor responses showing physiological differences under conditions where broadly similar odorants must be discriminated. Thus, flies use olfactory memory templates flexibly to suit their behavioral needs. Modi et al. conclude that a hitherto unknown mechanism downstream of mushroom body output neurons creates these context-specific responses at the MBONs. Overall, the experiments provide convincing physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall, which constitutes a fundamentally important advance in our understanding of the neurobiology of memory retrieval, however, the authors need to more deeply consider caveats to their arguments, more deeply discuss differences and similarities with prior publications and bolster their data by including a few controls that are currently missing.

eLife assessment

The authors set out to characterize a function of Drosophila glia that form an expansion of myelin-like membranes that might facilitate rapid nerve conduction. A combination of Drosophila genetics, antibody staining, and electron microscopy is used to characterize this "myelin" and the role of glial wrapping in clustering of sodium/potassium channels at motor exit points. The results are valuable, as they would point to Drosophila as a new, genetically accessible model organism to study myelin evolution. While the results are interesting, the strength of the evidence provided is incomplete due to inadequate quantification of the data provided.

eLife assessment

This manuscript is of interest for the fields of ageing, mRNA translation and C. elegans biology, as it provides new insights into the regulation of lifespan by alternate mechanisms that modulate mRNA translation in selected environmental contexts. While overall the main conclusions are supported by the data and of interest, the work would be stronger with control experiments that more fully and more consistently support all the conclusions. Furthermore, data presentation and interpretation need some attention.

eLife assessment

The important work presented here provides findings that substantially advance our understanding of a major research question into how bicarbonate/CO2 signaling regulates cardiac mitochondrial energy supply. The methods, data, and analyses broadly support the claims with only minor weaknesses concerning the exact spatial location of the enzymes involved. The work will be of broad interest to cell biologists and biochemists interested in metabolic control.

eLife assessment

This study presents an important description on the dynamics of histone variant exchange controlling the organization of the chromatin state of the Arabidopsis genome, combining the analysis of histone variants, histone modification, and chromatin states. The evidence supporting the claims of the authors is compelling, but some of the main claims are only partially supported experimentally. This work will be of great interest to those in the field of epigenetics and chromatin biology.

eLife assessment

This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. The strength of the evidence supporting the claims is solid, although many computational details are still missing, and the are concerns about the repeatability of the results across replicates, the dynamics of evaporation in their experiment, and the termites' ability to sense humidity.

eLife assessment

This paper describes a useful analysis tool for quantitative assessment of sarcomere structures in healthy and perturbed cardiomyocytes. The work is solid, and the methods, data and analyses broadly support the claims with only minor weaknesses. The tool will be of interest to biologists working on sarcomere structure, function and development.

eLife assessment

This useful manuscript challenges the utility of current paradigms for estimating brain-age with magnetic resonance imaging measures, but presents inadequate evidence to support the suggestion that an alternative approach focused on predicting cognition is more useful. The paper would benefit from a clearer explication of the methods and a more critical evaluation of the conceptual basis of the different models. This work will be of interest to researchers working on brain-age and related models.

eLife assessment

This study presents important findings that set a new standard for generating and maintaining monosomic yeast lines, and is the first, to our knowledge, to assess gene expression in yeast monosomies. The research offers an innovative approach to evaluate epistasis between genes on the same chromosome; however, the strength of evidence supporting the conclusions on positive epistasis for fitness is still incomplete due to the need for clarification for the exact calculation method of expected fitness without epistasis, as well as due to a lack of molecular mechanisms. Additionally, the interpretation of transcriptome results would benefit from a more comprehensive consideration of previous studies on genomic balance and the inclusion of further analyses and experiments.

eLife assessment

This valuable manuscript provides a single-cell RNA sequencing analysis of adult pig skin from different species and anatomical regions. The evidence supporting the conclusions is compelling, with identification molecular and cellular differences in pig skin, yet the analyses are incomplete in the analysis of regional- or species-based differences.

eLife assessment

This is an important study that defines cell type changes upon the expression of a mutant tau protein and put it into context of human postmortem tissue. Technically, the single cell mRNA sequencing data are convincing but the loss of neurons already at the earliest stages assessed in this model may rather suggest there are also elements of developmental toxicity.

eLife assessment

This fundamental study substantially advances our understanding of how aging and stress resilience across an organism is determined by identifying a new player in this process and uncovering its mode of action. The evidence is solid as the methods, data and analyses broadly support the claims with only minor weaknesses. The work will be of broad interest to the field of aging and protein homeostasis.

eLife assessment

Studies of prey behavior have the potential to provide insight into the chemical encoding of stress in the brain and the mechanisms by which this generates behavioral plasticity. In this important work, the authors identify a novel predation-evoked behavior in the nematode C. elegans and implicate dopamine in its implementation. While the support for some claims in the current paper is incomplete, this work provides an exciting foundation for future studies of behavioral plasticity in this powerful system.

eLife assessment

The toxin mycolactone is produced by mycobacterium ulcerans which is responsible for the Buruli ulcer. The authors performed a valuable study showing the effects of mycolactone on blood vessels integrity. This convincing data provide new therapeutic targets to accelerate healing of Buruli ulcers.

eLife assessment

This paper is of interest to neuroscientists studying the effects of sex hormones on neural and behavioral plasticity, and more specifically to researchers studying the neural mechanisms underlying birdsong plasticity. The experimental design is excellent, and the work provides a comprehensive resource for understanding the intersection between testosterone's influence on gene expression and behavior. However, the work also makes claims concerning cellular effects and gene regulatory mechanisms that extend beyond the data and under the current analyses are not rigorously supported.

eLife assessment

This study is an excellent example of how one can use high-throughput technologies to address animal evolution from a cell-type perspective. The authors present a beautiful analysis of single-nucleus RNA-seq data from three embryonic stages in a sea star; this is the first single-cell data from this large group of echinoderms and the first single-nucleus transcriptomic study in any echinoderm. The authors demonstrate the presence of unique as well as previously unnoticed homologous cell types between a sea star and a sea urchin, discovery very intriguing to echinoderm developmental biologists, which will also be of great interest to scientists in the broad fields of evolution and development.

eLife assessment

The findings of this study yield important new insights into the relationship between the number of close friends and mental health, cognition, and brain structure. Due to the large sample sizes, the evidence is solid but would have been improved if both of the analyzed datasets contained more closely matched measures. This work advances our understanding of how the friendship network relates to young adolescents' mental well-being and cognitive functioning and their underlying neural mechanisms.

eLife assessment

This potentially important work proposes a novel approach, based on co-evolution analysis, machine-learning protocols and molecular dynamics simulations, to predict structures and energetics of the main states of the alternating access cycle of a family of membrane transporters, the sugar porters. The approach is compelling, especially the application of co-evolution and Alphafold to generate highly accurate models in different conformational states of a given protein, but the work is currently incomplete due to shortcomings in the calculation of the energy landscape. With this aspect strengthened, the manuscript will be of interest to the transporter and computational modeling communities.

eLife assessment

This study presents useful structural and functional connectivity profiles of patients receiving deep brain stimulation in the posterior hypothalamus for severe and refractory aggressive behavior. The inclusion of data from multiple centers is compelling. However, the imaging analysis is incomplete and the interpretation of the findings is not solid.

eLife assessment

This study reports a joint experimental and computational investigation of the structural features of biomolecular condensates formed by a specific intrinsically disordered protein. The authors also adapt emerging rules to discuss and physico-chemical determinants of these structures of condensates. Specifically, the authors adapt the analysis of fractal structures, co-opted from the field of colloidal chemistry / physics, and generate important insights regarding the network-like organization of disordered proteins within in silico facsimiles of condensates. The usage of these analyses in the context of studying all atom models for multi-chain assemblies intended to mimic the internal organization of condensates is very interesting. The work is of relevance to cell biology and structural biology.

eLife assessment

The study of Thiery et al. details the heterogeneous expression of a very large number of genes presumably associated with cell fate decisions in the ectoderm at the neural plate border in early avian embryos. The authors mostly succeed in presenting their very complex strategy of data analysis in a clear way but the work is incomplete with some conceptual weaknesses in how the authors describe and interpret their results. By focusing on one of the earliest cell fate decisions in the ectoderm of a vertebrate embryo, this study will be valuable to a broad range of developmental biologists.

eLife assessment

This study presents a useful application of a prior model published by the authors to a new dataset. The results from this approach were interesting and solid but the conclusions that one can make from the application of the model to only one paper are limited in scope and would depend on further probing to know if the model itself has face validity as a model of ventral visual stream function.

eLife assessment

Protein and lipid homeostasis are important for maintaining cellular functions but their crosstalk remains largely unknown. This important manuscript deals with this interesting topic and applies the powerful unbiased tools of somatic cell genetics to discover evidence suggesting a link between sphingolipids/cholesterol ester metabolism and lysosomal protein aggregation. However, in our view the experimental evidence in support of the paper's stated conclusions remains incomplete and measures that (i) go beyond reliance on the ProteoStat stain as the sole metric for aggregation and proteostatic challenge, (ii) biochemically back up the results and provide plausible mechanistic insights into the connection of lysosomal lipid handling and protein aggregation are needed.

eLife assessment

This paper introduces the python software package Pynapple and a separate package of more advanced routines (Pynacollada) to the Neuroscience/Neural Engineering community. Pynapple provides a set of data objects and methods that have the potential to simplify data analysis for neural and behavioral data types. This represents a valuable contribution to the field. The evidence was judged to be incomplete due to the fact that key details were missing.

eLife assessment

This is an important paper that revises the canonical model of how olfactory sensory neurons choose which odor receptor to express. The data presented in the paper are convincing and the model proposed is provocative and likely to enable important future work.

eLife assessment

This important study combines state-of-the art proteomics and genetic manipulation of Chlamydia trachomatis to study the function of a chlamydial effector, Cdu1, with deubiquitination and acetylation activities. Solid evidence is provided to show that Cdu1 is able to protect itself and three other chlamydial effectors, which are involved in the control of chlamydial egress from host cells, from ubiquitin-mediated degradation, and that this depends on the acetylation activity of Cdu1, but not on its deubiquitination activity. This work should be of interest to microbiologists and cell biologists studying host cell-pathogen interactions.

eLife assessment

This work presents an important methodological advance for single-molecule force spectroscopy of membrane proteins providing a new robust design of the linkage between a target single molecule and solid support. The data provide compelling evidence of the improved mechanical stability of the pulling system. Allowing more statistically reliable force measurements of biomolecules, this method may be broadly applicable in the field of single-molecule biophysics.

eLife assessment

The authors present an exciting idea about how to integrate morphogens into a gene regulatory network with the dynamics of morphogenesis and cell movement. It represents a novel methodology, but in its current form the hypotheses, data and relationships described do not provide a sufficiently compelling model to disentangle cause and effect or elucidate the impact of cell movements on differentiation dynamics the zebrafish mesoderm.

eLife assessment

This important work investigates how two distinct processes, morphological changes and synaptic plasticity, contribute to the final shape of neuronal dendrites and the spatial structure of their synaptic inputs. The modelling is solid and could be broadly applied to other similar questions. Some of the findings are a direct result of how the model is constructed, which limits the impact. The work will be of interest to neuroscientists studying dendritic development and connectivity at a single-cell level.

eLife assessment

This paper presents important findings on the hexametric structure of MCM8/9, which potentially explain its role as a DNA helicase in homologous recombination. Due to the lack of DNA in the complex and the invisibility of HROB the current data only provide an incomplete model of the function of the MCM8/9 complex. This work will be of interest to biologists studying DNA transactions.

eLife assessment

The authors present a useful analysis of different factors that are required for release of the lipid-linked morphogen Shh from cellular membranes. The evidence is currently still incomplete as experiments rely on over-expression of Shh in a single cell line and are sometimes of a correlative nature. The study confirms and extends previous findings and will be of interest to developmental biologists who work on Hedgehog signaling.

eLife assessment:

This study introduces a valuable paradigm in the filed of adipose biology field: blocking triglyceride storage in adipose tissue does not lead to lipodystrophy and impaired glucose homeostasis but instead improves metabolic health. The evidence supporting these claims are convincing, with the authors providing a comprehensive metabolic analysis. However, mechanistic studies, which are currently incomplete, would strengthen the study and its impact. Regardless, this study will be of high interest to those in the adipose tissue biology and metabolism fields.

eLife assessment

This study presents an important open-source resource for high-throughput behavioral screening. The protocols employ inexpensive, off the shelf hardware, and carry out real-time analysis of hundreds of behaving flies. Although these protocols were developed using Drosophila melanogaster, they could easily be applied to other model systems. The evidence in support of the conclusions is solid although more details on the algorithms used for phenotyping would be helpful in order to better assessing the overall robustness of the platform.

Within the pantheon of types of notes there are: - paraphrasing notes, which one can use to summarize ideas for later recall and review as well as to check one's own knowledge and understanding of what an author has said. - commentary notes, which take the text and create a commentary on them, often as part of having a conversation with the text. These can be seen historically in the Midrashim tradition of commenting on Torah.

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separately also: - productivity notes - to do lists, reminders of work to be done, often within or as part of a larger complex project