eLife assessment

This valuable study reports a new method based on batch active learning to optimize the biological and pharmaceutical properties of small molecules of pharmaceutical interest. The new method seems compelling, but the theoretical analysis is incomplete and the reproducibility and impact of the article would benefit from disclosing the code and datasets used in the study. With these aspects strengthened, this paper would be of interest to computational and medicinal chemists and scientists working in the drug discovery field.

eLife assessment

This important study advances existing approaches for demographic inference by incorporating rapidly mutating markers such as switches in methylation state. The authors provide a solid comparison of their approach to existing methods, although the work would benefit from some additional consideration of the challenges in the empirical use of methylation data. The work will be of broad interest to population geneticists, both in terms of the novel approach and the statistical inference proposed.

eLife assessment

This important study combines in vitro and in vivo experiments to investigate the reciprocal regulation between mitochondria-associated membranes and Notch signaling in skeletal muscle atrophy, with implications beyond the single subfield of muscle atrophy. The methods, data, and analyses convincingly support most of the claims. There are minor weaknesses, with the analysis of gene and protein expression in some parts being incomplete.

eLife assessment

This important study makes a bold step towards understanding what fraction of DNA that is liberated from different tissues in a healthy human is found in circulation as cell-free DNA. Unfortunately, the evidence for the conclusions is presently incomplete, but with additional controls, this could become a major achievement for reference in understanding changes in cell-free DNA in disease states.

eLife assessment

This study provides valuable findings on a causative relationship between LRRC23 mutations and male infertility due to asthenozoospermia. The evidence supporting the conclusions is solid despite a lack of analyses of the effects of the mutations detected on the flagellar structure of human sperm. This work will be of interest to biomedical researchers who work on sperm biology and non-hormonal male contraceptive development.

eLife assessment

The authors provide the first investigation of the role of the lateral habenula in vocal learning in the songbird. This study provides important insights into the conserved connectivity of the lateral habenula with dopaminergic reinforcement circuits and presents a potential role of this circuit in zebra finch song learning. The results stem from a careful anatomical and functional mapping and from a rigorous behavior analysis that, together, implicate a previously undescribed analog between mammals and songbirds. Although many aspects of the manuscript - like the analysis of song behavior - are exceptional, the evidence linking behavior to selective lesions of the lateral habenula is, at this point, incomplete, leaving the interpretation of key results difficult.

eLife assessment:

This important study sheds light on several apparent discrepancies observed across animal studies examining neuroimaging biomarkers of functional recovery following focal ischemia. Using 2-photon imaging of calcium activity in awake mice, the authors show solid evidence that deficits in neuronal activity and functional connectivity after photothrombosis occur within a very small distance from the infarct (<750 microns) whereas these measures were relatively unaltered more distally, even those typically implicated with functional remapping of the forelimb representation in anaesthetized animals. These findings reveal a complex spatiotemporal relationship between perilesional neuronal network function and behavioral recovery that is more nuanced than previously reported, and motivates the need for better criteria for what is considered remapping.

eLife assessment

In this work, the authors make a valuable contribution based on convincing evidence that children 6-to-7-years-old improve in 2 years of development towards utilising more optimal value-based decision-making strategies while performing a reinforcement learning task. They found that delayed feedback learning was associated with volume in the hippocampus while immediate feedback learning was not. Striatal volume was associated with both forms of learning, in contrast to prior research funding in adults. Brain-behaviour correlations were stable across the 2-year period, despite the hippocampus increasing in volume and striatal volume remaining stable.

eLife assessment

This study presents useful findings regarding how a particular class of neurons within a brain region respond to threatening stimuli and their role in fear processing in male and female mice; these results are solid as they uncover the role functional of this brain region (BNST) in this particular type of processing and expand this knowledge by highlighting the function of a specific class of neurons (CRF) showing that their role in fear depends on the sex of the animal. However, the analysis is incomplete and can certainly benefit from additional (for example locomotor) controls and from clarifying interpretability issues with respect to sex differences in fear expression and to a precise role of these neurons. The work will be of interest to neuroscientists studying the biological basis of fear processing.

eLife assessment

This important study identifies and characterizes a broad peptidergic network that coordinates nutrient-specific consumption needs for food or water. Using state-of-the-art methodology the authors combine a well-balanced set of exploratory anatomical analyses with rigorous functional experimental approaches to examine how ingestion is regulated based on internal needs. These significant and convincing new findings are of broad interest to the neuroscience field.

eLife assessment

In this potentially useful study, the authors employ concepts and algorithms associated with induced subgraph in graph theory to automate several key but non-trivial steps in the development of coarse-grained models. These developments can help to model complex biomolecular systems at the coarse-grained level., but given the limited number of examples explicitly discussed, the demonstration of the general applicability of the approach to biomolecular systems is considered incomplete.

eLife assessment

This valuable study presents reports on the role of the transcription factor BATF and its target PD1 in lipid metabolism including a model of nonalcoholic fatty liver disease (NAFLD). Overall, the evidence supporting the conclusions is convincing. The work will be of interest to medical biologists working on NAFLD.

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. With more examples and as a live coding notebook, the evidence was judged to be compelling.

eLife assessment

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

eLife assessment

This paper conducts human and rodent experiments of non-invasive diffusion MRI estimates of axon diameter with the aim to establish whether these estimates provide biologically specific markers of axonal degeneration in MS. It will be of interest to researchers developing quantitative MRI methods and scientists studying neurodegeneration. The experiments provide evidence for the sensitivity of these markers, but do not directly validate axon diameter and do not reflect common pathological mechanisms across rodents and humans.

eLife assessment

The authors have improved a method to differentiate human iPSC-derived microglial cells with immune responses and phagocytic abilities; and through transplantation into the adult mouse retina, the authors further demonstrated their integration and occupation of native microglial cell space, and functional response to retinal injuries. The study is important for potential microglial replacement therapy to treat retinal and CNS diseases. Overall, the data are solid, but there is a need to improve writing, figure-making, and data interpretation.

eLife assessment

This valuable study informs whether diminishing BDNF expression or alterations in the activity of BDNF-containing neurons in the paraventricular nucleus of the hypothalamus contributes to metabolic alterations in individuals with reduced RAI1 function, including those afflicted with Smith-Magenis syndrome (SMS). The evidence supporting the conclusions is compelling in that RAI1 deficits in BDNF-containing neurons partly contribute, with prominent effects on glycemic control and modest effects on feeding and body weight regulation, however, the histological analyses of BDNF and TrkB expressions are inadequate. This study would be of interest to neuroscientists and medical biologists working on metabolic disorders such as obesity and diabetes, as the findings in this study further links SMS-associated obesity with reduced Bdnf gene expression in the PVH and shed light on the role of the Rai1 gene in the PVH Bdnf neurons and offer a basis for future therapeutic strategies for managing obesity in SMS.

eLife assessment

This study has the potential to provide valuable insights that connect the way humans and non-human primates (Rhesus monkeys) perform visuomotor control for a simplified, virtual task that involves stabilizing an unstable system (analogous to pole balancing). Thus, the paper provides the potential, in future studies, to make new discoveries in the neural mechanisms that underly behavior. However, the evidence (including inferring control strategies on a single-trial basis) was incomplete. Overall, the question and approach are potentially valuable in informing future studies, but more evidence is needed to support the primary claims of the paper.

eLife assessment

In this potentially useful study, the authors attempt to use comparative meta-analysis to advance our understanding of life history evolution. Unfortunately, both the meta-analysis and the theoretical model is inadequate and proper statistical and mechanistic descriptions of the simulations are lacking. Specifically, the interpretation overlooks the effect of well-characterised complexities in the relationship between clutch size and fitness in birds.

eLife assessment

This paper represents a valuable single-cell level analysis of tendon enthesis development. It will allow further understanding of this specific process with clinical implications. Specifically, the authors provided convincing evidence for the heterogeneity of postnatal enthesis growth and the molecular dynamics and signaling networks during enthesis formation.

eLife assessment

The authors make the case that the assembly of MreB from Geobacillus, a Gram-positive organism differs substantially from MreB from the Gram-negative model organism, Escherichia coli. Although the conclusion of this valuable study would represent a major advance if correct, the evidence is currently incomplete, and significant additional work is necessary to ensure both rigor and impact.

eLife assessment

This fundamental study addresses the role of miRNA-218 in circuit development, seizure susceptibility, and behavior. The supporting experimental evidence provided by the authors is solid, although more mechanistic insight into how miRNA-218 controls neuronal cell type function during circuit development to then impact seizures and behavior would have strengthened the study. This work has broad implications for researchers working on the role of neuronal microRNA in neurodevelopmental and neurological diseases.

eLife assessment

The authors use a previously described technology of designing soluble transmembrane-targeting peptides, to interfere with the receptor function of the T cell receptor (TCR), which provides useful insights into the molecular mechanism of T cell activation. The designed PITCR peptide has functional effects, but the evidence for the proposed mechanism is still incomplete. With further data to support the conclusion, results from this study will be of interest to those studying the TCR as well as those seeking to use the TCR or its derivatives in synthetic biology studies and immunotherapy.

eLife assessment

This important research uses complementary CRISPR screening strategies to reveal novel pathways that prevent T cells from killing tumor cells. The evidence presented to support the claims is solid, although some additional assays defining the features of these novel pathways and their clinical relevance are still required. Overall, this work will be of broad interest to immunologists, cancer biologists, and those interested in cell adhesion and cell-cell communication.

eLife assessment

This useful paper examines changes (or lack thereof) in birds' fear response to humans as a result of COVID-19 lockdowns. The evidence supporting the primary conclusion is currently inadequate, because the model used does not properly account for many potentially confounding factors that could influence the study's outcomes. If the analytic approach were improved, the findings would be of interest to urban ecologists, behavioral biologists and ecologists, and researchers interested in understanding the effects of COVID-19 lockdowns on animals.

eLife assessment

The study presents important findings on the timing and movement of crops in the Near East. The authors provide convincing data supporting a predominant contribution of Roman Agricultural Diffusion to the spread of a number of cultigens in the region. The work will be of interest to those thinking about the timing and movement of the diffusion of agricultural crops post-domestication.

eLife assessment

The present study shows that the expression of some inhibitory receptors (IRGs) on CD8 T cells is increased in people living with HIV (PLWH) and remain elevated even after years of viral suppression by antiretroviral therapy. The authors further report that inhibition of TGIT partially restores the ability of CD8 T cells to produce CD107a but not the other functions. Altogether, the results provide some valuable insights into our understanding of inhibitory receptor expression in the HIV infected individuals but some evidence seems incomplete.

eLife assessment

This important study combines experiments and computational approaches to understand the effects of influenza H1N1 infection on hypothalamic cells. The methodology and analysis are solid and raise questions around how a respiratory virus affects the central nervous system.

eLife assessment

This valuable study provides high-quality epigenome data in Drosophila testes and purified germ cells. The analyses are solid and will help to understand and appreciate the dramatic chromatin structure change during spermatogenesis in Drosophila. The work will be of interest to students of epigenetic modifications and reproductive biologists.

eLife assessment

This is an important study using 3D mapping of neuronal activation throughout the brain after pair-bonding in the monogamous vole, which can be broadly applied to other species and behaviors. The authors provide compelling evidence that there is some synchrony in the male and female partners in a pair bond and that number of ejaculations is the most important variable. Same-sex pairs are also examined and found to have activation in the same brain regions. An overall low level of sex differences is observed, which was unexpected.

eLife assessment

This useful study tests the hypothesis that Mycobacterium tuberculosis infection increases glycolysis in monocytes, which alters their capacity to migrate to lymph nodes as monocyte-derived dendritic cells. The authors conclude that infected monocytes are metabolically pre-conditioned to differentiate, with reduced expression of Hif1a and a glycolytically exhaustive phenotype, resulting in low migratory and immunologic potential. Unfortunately, the evidence for the conclusions is currently incomplete, as the use of dead mycobacteria will affect bioenergetic readouts. The study will be of interest to microbiologists and infectious disease scientists.

eLife assessment

This valuable study presents a modification of earlier imputation methods for clinical data, effectively addressing missing values with a slight improvement over previous techniques. The methodology and results for the classical case are solid, although the evidence for the claim of a practical advantage in 'next generation' quantum computers is not validated. This work will be of value to scientists dealing with datasets involving imputation for classification tasks, particularly in clinical studies.

eLife assessment

How macro-ecological patterns of microbiomes depend on the taxonomic level across a wide range of taxa and ecosystems, and that correlations in richness across taxonomic scales are largely created by variation in sample size, are valuable findings. The authors present convincing evidence that a stochastic logistic growth model is a more appropriate choice as null model than one that is based on the neutral theory of biodiversity. The work will be of interest to microbial ecologists and those interested in general ecological patterns.

eLife assessment

This study reports that a water-soluble analog of heliomycin, 4-dmH, induces protein degradation of not only SirT1 but also tNOX, unlike heliomycin, which induces degradation of SirT1 but not tNOX, a difference that could in principle explain why 4-dmH induces apoptosis while heliomycin induces autophagy. Although the data showing that 4-dmH binds to and induces degradation of tNOX are solid, it is unclear whether the differences in binding partners between heliomycin and 4-dmH could explain the different biological outcomes after treatment with these compounds. Thus, the strength of the evidence is incomplete and the main findings, while useful, are only partially supported.

eLife assessment

This compelling and novel mathematical method assesses drug pro-arrhythmic cardiotoxicity by examining the electrophysiology of untreated cardiac cells. It will be valuable for future drug safety design.

eLife assessment

This valuable study links natural variation in steroidal glycoalkaloid production to disease and insect resistance in potato species. The study design is straightforward and thorough, and the evidence supporting the main conclusions is solid. The work will be of interest to plant biologists and breeders.

eLife assessment

This valuable study advances our understanding of the forces that shape the genomic landscape of transposable elements. By exploiting both long-read sequencing of mutation accumulation lines and in vivo transposition assays, the authors offer compelling evidence that structural variation rather than transposition largely shapes transposable element copy number evolution in budding yeast. The work will be of interest to the transposable element and genome evolution communities.

eLife assessment

This work reports important findings regarding the evolution of proteins and heat shock proteins in particular. The evidence supporting the conclusions is solid. The work will be of interest to evolutionary biochemists.

eLife assessment

The authors have developed a compelling coarse-grained simulation approach for nucleosome-nucleosome interactions within a chromatin array. The data presented are solid and provide new insights that allow for predictions of how chromatin interactions might occur in vivo, but some of the claims should be tempered. The tools will be valuable for the chromosome biology field.

eLife assessment

This manuscript reports important 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. Fork stalling let to lasting ATR-dependent phosphorylation of histone H2AX but not of ATR itself and its downstream targets RPA and CHK1.

eLife assessment

This paper provides potentially useful insight into why long-term consolidation of visuospatial memories may differ between children (5-7 years of age) and adults. The work suggests developmental differences in neural engagement during the retrieval of recent and remote memories. However, there are several issues with the experimental design and analyses that render the evidence supporting the authors' main claims currently incomplete.

eLife assessment

This manuscript provides valuable findings that the underlying mechanism for the reduction in BDNF-TrkB signaling in Spinocerebellar ataxia 6 (SCA6) is due to defective endolysosomal trafficking. The findings will be significant in understanding underlying pathology, but the data supporting the hypothesis is not comprehensive and the strength of the data is incomplete in some instances, in that there may be multiple mechanisms that explain the findings.

eLife assessment

This important work identifies electrophysiologically and morphologically distinct subpopulations of dorsal raphe nucleus neurons, which are in turn, differentially impacted in a toxin-based mouse model of Parkinson's disease. The inclusion of several thoughtful controls and rigorous exclusion criteria makes the presented results highly convincing. 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

This paper, on the role of calcium and integrin-binding protein 2 and 3 in the hair-cell in the mechano-electrical transduction (MET) apparatus, is a mix of confirmatory studies with new and important data. Reviewers noted that the modeling data are the most novel. The presented structural modeling and simulations are regarded as necessary and convincing, although functional analyses already imply that the TMC(1/2)-CIB(2/3) association takes place.

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

This study presents a useful description of transcriptional responses in adult zebrafish olfactory bulb microglia and neurons following exposure to infectious hematopoietic necrosis virus. This solid work advances our understanding of central nervous system responses to viral infection and provides an inventory of gene expression changes in particular cell types that can be used as hypothesis generators for future studies. Experiments to assess behavioral and neural responses to the virus in adults and larvae are inadequate and would benefit from a clearer conceptual framework that connects these avenues of investigation both to published literature and to the authors' single cell RNA sequencing results.

eLife assessment

This is an important technical method paper that details the development and quality assessment of a 3D MERFISH method to enable spatial transcriptomics of thick tissues. The evidence presented is strong and solid. The work represents a major step forward in the technical capacity of the MERFISH.

eLife assessment

This study uses experimentally calibrated biophysical modelling and analysis to predict the influence of axonal action potentials on neighbouring membranes. A solid analysis predicts that annihilating action potentials induce large transients in the external electric field, which is predicted to be large enough to induce detectable membrane potentials in a neighbouring, postsynaptic cell. The work is valuable for motivating future experimental work, which may reveal a new mechanism for transmitting synaptic potentials via electrical coupling.

eLife assessment

This study provides fundamental imaging evidence from two independent functional imaging datasets, for a rostral-caudal gradient of locus coeruleus connectivity, which changes across the lifespan. The gradient approach is well-established and convincing results were obtained and validated using large 3T and 7T fMRI datasets. This work will be of interest to clinical and cognitive neuroscientists.

eLife assessment

This important study provides a quantitative characterization and understanding of firing collective patterns in P. Carolinus fireflies. The work significantly contributes to fill the gap between observations and mechanistic models, with convincing experimental evidence and solid theoretical modeling. This work will be of interest to readers curious about collective behavior, biological rhythms, and models of synchronized oscillations.

eLife assessment

This study provides a valuable computational tool for analyzing and deconvoluting a pool of plasmids sequenced without barcoding using nanopore long-read sequencing. While the authors provide convincing validation, this tool might still present limitations concerning practical applications. The work will be of interest to researchers in need of rapid and cost-effective verification of plasmid sequences.

eLife assessment

This is an important study that leverages a human-chimpanzee tetraploid iPSC model to test whether cis-regulatory divergence between species tends to be cell type-specific. The evidence supporting the study's primary conclusion--that species differences in gene regulation are enriched in cell type-specific genes and regulatory elements--is compelling, although attention to biases introduced by sequence conservation is merited, and the case that is made for cell type-specific changes reflecting adaptive evolution is incomplete. This work will be of broad interest in evolutionary and functional genomics.

eLife assessment

This important manuscript demonstrates, with a carefully-collected dataset and compelling analyses, detailed links between societal and academic interest and natural species across the globe. In doing so, the authors reveal biases that may be diminishing our abilities to care for the species on our planet that may need our care the most. While some parts of this manuscript reflect previously published work, the authors are to be commended for putting all the pieces of the puzzle together for the first time. Their work highlights our uneven knowledge of biodiversity and its potential causes.

eLife assessment

This study presents valuable findings about synaptic connectivity among subsets of unipolar brush cells (UBCs), a specialized interneuron primarily located in the vestibular lobules of the cerebellar cortex. The evidence supporting the claims are interesting although incomplete in some areas. The work will be of interest to cerebellar neuroscientists as well as those focussed on synaptic properties and mechanisms. Substantial work remains to be conducted in order for the hypothesis and predictions of the manuscript to play out in the actual brain circuit and how it would impact the processing of feedback or feedforward activity that would be required to promote behavior.

eLife assessment

This valuable study uses passive acoustic monitoring to evaluate the impact of human activity on three species: hooded crow, rose ring parakeet, and graceful prinia. It emphasizes the significance of micro-habitats for species coexisting with humans, revealing the influence of human activity on behavior and habitat preferences during pandemic-related restrictions. While the data themselves are convincing and offer valuable insight into post-lockdown responses of urban wildlife, they are inadequate to support the conclusions as they are currently stated.

eLife assessment

In this important contribution, the authors demonstrate that the infusion of NAD+ may prevent death and reduce disease severity from lethal experimental bacterial sepsis, possibly through inflammasome inhibition, without reducing bacterial load. They provide solid evidence for these protective effects of NAD+, though the evidence for the mechanisms involved remains incomplete, with somewhat suboptimally presented data, and needs further clarification and support. The core findings may well have clinical implications but, in addition to mechanistic clarifications, contextualised interpretation as metabolic adaptation to sepsis as a way to disease tolerance via reduction in immunopathology would create wider interest.

eLife assessment

This study advances our understanding of the allosteric regulation of anaerobic ribonucleotide reductases (RNRs) by nucleotides, providing valuable new structural insight into class III RNRs containing ATP cones. The cryo-EM structural characterization of the system is solid, but other aspects of the manuscript, which are incomplete, could be improved by including additional functional characterization and more evidence for the proposed mechanism of inhibition by dATP. The work will be of interest to biochemists and structural biologists working on ribonucleotide reductases and other allosterically regulated enzymes.

eLife assessment

This is a valuable analysis of the structure of Roseiflexus castenholzii native and carotenoid-depleted light harvesting complexes. The authors have investigated the relationship between Carotenoid pigment depletion in the photosynthesis-related light harvesting complex, the assembly of the prokaryotic reaction center LH complex, and quinone exchange in Roseiflexus castenholzii, a chlorosome-less filamentous anoxygenic phototroph that forms the deepest branch of photosynthetic bacteria. The evidence supporting the claims is solid, with application of rigorous biochemical and biophysical techniques, including cryo-electron microscopy of the purified of the RC-LH complexes with or depleted of carotenoids. This study will be of interest to biologists working on the evolution and diversity of prokaryotic photosynthetic apparatus.

eLife assessment

The study presents important findings for public health authorities and policymakers to enable them to make evidence-based decisions when deciding on how to manage the effect of HPV vaccination disruptions. This study is particularly relevant in light of the efforts of the WHO to achieve global elimination of cervical cancers. The findings are convincing and the model used is appropriate.

eLife assessment

This study addresses a pertinent and important topic related to prolonged delays in cervical cancer screening and the need to maintain routine and timely screening services in a large health maintenance network in Boston. The findings provide a solid, yet incomplete roadmap for implementing simple strategies to help patients return to essential health services.

eLife assessment

By recording simultaneously from premotor and primary motor cortical nuclei in singing birds, this paper provides compelling evidence that premotor activity covaries with primary activity with the temporal specificity necessary to promote learning and drive adaptive vocal variation. As the first study to record from two distant sites at once in singing birds, this study also provides exceptional evidence for temporally precise coordination between two motor areas in the service of vocal learning.

eLife assessment

This Pentz et al study potentially provides fundamental insight into the evolution of multicellularity by experimentally demonstrating that yeast strains that form clonal groups evolve stronger group traits than ones that aggregate into non-clonal groups. While the repeatability of their experiments, supported by genomic analyses and models is compelling, the experimental design may be inadequate and would need to be extended to better support the main claims.

eLife assessment

This study presents an important finding that high-sugar diet-induced behavioral changes can be transmitted to the offspring through the maternal germline. Using genetic and molecular biology approaches in the fruit fly model, the authors argue that this Lamarckian inheritance is mediated by germline-inherited chromatin and is regulated by the general activity of a histone methylase, and H3K27me3 modification plays a critical role in this transgenerational effect. The behavioral data are convincing, while the underlying molecular and neural mechanisms need to be strengthened. The work will be of great interest to behaviorists and epigeneticist.

eLife assessment

This valuable study describes the development of a new structure-based learning approach to predict transcription binding specificity and its application in the modeling of regulatory complexes in cis-regulatory modules. The authors developed a structure-based learning approach to predict TF binding features and model the regulatory complex(es) in cis-regulatory modules, integrating experimental knowledge of structures of TF-DNA complexes and high-throughput TF-DNA interactions. The validation presented by the authors is currently incomplete, with a large variability in the performance of the method on the different TF families tested.

eLife assessment

This manuscript investigates thalamocortical communication and cross-frequency coupling in humans and animal models under anesthesia and the effects of the serotonergic psychedelic compound 5-MeO-DMT. These findings are exciting because they put two different perturbations of brain functions - anesthesia and psychedelic stimulation - into a single modeling framework. The framework describes anesthesia and psychedelic stimulation as opposing perturbations from normal brain function that respectively reduce and enhance thalamocortical communication.

eLife assessment

This important study combines conditional mutagenesis with proximity labeling to evaluate alterations in a sub-cellular proteome upon a perturbing event. The approach is applied to the deletion of a kinase involved in trafficking of adhesins to the malaria parasite-infected erythrocyte surface and the evidence supporting the conclusions is compelling. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

In the present study, authors generate a new formulation built upon a previous nanoparticle platform to generate a new system termed bicontinuous nanospheres (BCN), allowing for the dual incorporation of lipid and protein antigens. Authors generate mycolic acid (MA)-loaded BCN perform a series of characterization studies to demonstrate the superior performance of this new formulation relative to the original one in term of antigen persistence, a quality needed to sustain responses after vaccination. This work provides important new insights relevant to the TB vaccine field and it suggest that alternative antigens to proteins could be used in TB vaccine formulations. The data is convincing and will be interesting to individuals working on tuberculosis, vaccines and basic immunology.

eLife assessment

This is an important contribution to the origins and translational consequences of the relatively low rate of translation elongation in the first ∼30-50 codons of genes in most organisms. The authors provide convincing evidence that the prevalence of rare codons in the first ~40 codons in yeast is due to the relatively recent evolution of these coding sequences, or of lower purifying selection operating on them, and that a preponderance of codons encoded by rare tRNAs near the N-terminus is not associated with higher translational efficiency in the manner proposed by the "translational ramp" hypothesis. There are, however, several incomplete aspects of the study: it neglects to discuss extensive published work providing different explanations for the slow rate of elongation at the start of open reading frames; it does not consider such effects in interpreting the reporter data produced for the current study; it does not resolve the apparent discrepancy posed by the lack of slow elongation observed despite poor sequence conservation of C-terminal coding regions; and it does not measure reporter mRNA levels to evaluate translational efficiencies.

eLife assessment

In this important study, the authors present a human telencephalon-eye organoid model that exhibits remarkable pathfinding and growth of retinal ganglion cell (RGC) axons. The identification of cell-surface markers for RGCs could have value for understanding the molecular mechanisms involved in RGC axon development and regeneration. The strength of evidence is compelling for future studies to investigate RGC neurite outgrowth and brain-eye connectivity in humans.

eLife assessment

This important study elucidates the molecular divergence of caspase 3 and 7 in the vertebrate lineage. Convincing biochemical and mutational data provide evidence that in humans, caspase 7 has lost the ability to cleave gasdermin E due to changes in a key residue, S234. However, the physiological relevance of the findings is incomplete and requires further experimental work.

eLife assessment

Host cell death is an effective strategy to protect against infection, which is believed to function primarily by the elimination of the intracellular niche for pathogen replication. Abele and colleagues address a fundamental question: does the mode of cell death affect its effectiveness in pathogen clearance? Consistent with prior observations, the authors provide compelling evidence that the answer can depend on the cell type and/or tissue involved.

eLife assessment

This work presents some valuable information regarding the molecular mechanisms controlling the regeneration of pancreatic beta cells following induced cell ablation. However, the study lacks the critical lineage tracing result to support the conclusion about the origin of the regenerated beta cells. The results of the pharmacological manipulation of CaN signaling are also incomplete. In particular, these manipulation are not cell-specific, making it difficult to interpret and thus genetic approach is recommended.

eLife assessment

This manuscript provides a useful characterization of penumbral microvascular flow disturbances over the first hours after ischemia onset in a rat model of middle cerebral artery occlusion. This work suggests that there are microscopic changes (including directionality of capillary blood flow and formation of capillary stalls) during the peri-ischemic timeframe but the data are incomplete and not sufficient to support the claims.

eLife assessment

This study investigated transcriptional profiles of midbrain dopamine neurons using single nucleus RNA (snRNA) sequencing. The authors found more nuanced subgroups of dopamine neurons than previous studies, and identified some genes that are preferentially expressed in subpopulations that are more vulnerable to neurochemical lesions using 6-hydroxydopamine (6OHDA). The reviewers found the results are solid, and the study is overall valuable, providing critical information on the heterogeneity and vulnerability of dopamine neurons although the scope is somewhat limited because the result with snRNA is similar to previous results and cell deaths were induced by 6OHDA injections.

eLife assessment

This useful modeling study explores how the biophysical properties of interneuron subtypes in the basolateral amygdala enable them to produce nested oscillations whose interactions facilitate functions such as spike-timing-dependent plasticity. The strength of evidence is currently viewed as incomplete because the relevance to plasticity induced by fear conditioning is viewed as insufficiently grounded in existing training protocols and prior experimental results, and alternative explanations are not sufficiently considered. This work will be of interest to investigators studying circuit mechanisms of fear conditioning as well as rhythms in the basolateral amygdala.

eLife assessment

This study addresses how protein synthesis in activated lymphocytes keeps up with their rapid division, with important findings that are of significance to cell biologists and immunologists endeavouring to understand the 'economy' of the immune system. The work is supported by solid data but because it proposes non-conventional mechanisms, it requires additional explanation and justification to align with the current understanding in the field.

eLife assessment

This manuscript describes a unique humanized model of MS/EAE-like pathology and provides a valuable new model that incorporates enhanced susceptibility related to HLA type. The data are modestly incomplete to solid in terms of supporting their claims that this model improves upon prior models. Overall, these claims could be further supported by a more comprehensive quantification of the immune infiltrate, a better assessment of peptide sensitization requirement, and an assessment of CNS/spinal cord pathology.

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 a convincing theoretical framework explaining the segregation of sequences reflecting navigation and sequences reflecting internal dynamics in the DG-CA3 loop. This study will be of interest for researchers in the spatial navigation and computational neuroscience fields.

eLife assessment

This valuable 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. While the evidence in this specific case is solid, whether the method is working as advertised in other settings is not yet known.

eLife assessment

This is an important study highlighting how a single protein transporter dysfunction can significantly alter brain biochemistry, potentially playing a crucial role in the intellectual disability in creatine transporter deficiency (CTD) patients. The evidence is compelling that the new in vitro CTD model using CTD patient's brain organoid cultures will be widely applicable. Despite minor areas for further exploration, the study significantly enhances our understanding of CTD, offering potential therapeutic targets and a robust foundation for continued research in the field.

eLife assessment

This fundamental study advances our understanding of seabird responses to environmental conditions, with implications for movement ecology, flight biomechanics, animal foraging, and bio-energetics. Animal-borne data-loggers are used to generate a compelling high quality dataset on animal movement and environmental conditions. The study will interest ornithologists, comparative bio-mechanists, ocean ecologists and those interested in technological advances in animal sensors.

eLife assessment

This important study reports how swallowtail butterflies pattern structures composed of chitin at the nanometer scale to produce structural colors. The work uses state-of-the-art microscopy techniques to convincingly show that F-actin is utilized in these butterflies in a novel way to produce structure, paving the way for further studies on growth regulation leading to precise ultrastructures and structural colors..

eLife assessment

This study presents an important dataset describing the temporal transition from epiblast to amnion using a new in vitro model of human amnion formation. The evidence supporting the authors' claims is overall convincing. Strengths include the efficiency and purity of the cell populations produced, a significant degree of synchrony in the differentiation process, benchmarking with single cell data and immunocytochemistry from primate embryos, and identification of key markers of specific phases of differentiation; weaknesses are the absence of other embryonic tissues in the model, and overinterpretation of certain findings.

eLife assessment

This study describes CLEVER, an improved method for fast and efficient rescue and mutagenesis of SARS-CoV2. While the principle of this method is not new, this work significantly improves upon existing protocols, providing an important advancement in the field of viral infectious clones. Convincing proof-of-concept experiments were performed that demonstrate the utility and efficiency of the method. However, the study would be strengthened by a more direct comparison of the CLEVER approach to other recombinant nucleic acid-based viral infectious clone systems.

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 manuscript is an important contribution toward understanding the mechanisms of transcriptional bursting. The evidence is considered solid, but there are questions regarding the broader advance, details of the analysis, and the models used in the analysis.

eLife assessment

This useful study aims to characterize patterns of demographic aging in naked mole rats by quantifying mortality rates in a captive colony, up to approximately the median age of death. The study system is a fascinating case of unusual longevity and physiology in mammals, but because of limited sampling at older ages and missing analyses, the evidence for the main conclusion – that naked mole rats do not experience actuarial senescence – is incomplete for younger animals and inadequate for older animals. The work nevertheless provides data of interest to biodemographers and biomedical researchers interested in naked mole rats as a model for aging.

eLife assessment

This paper shows that it is possible to optogenetically activate single retinal ganglion cells in vivo in monkeys. This is an important step towards causal tests of the role of specific ganglion cell types in visual perception. Yet the description of many of the details of how this methodological advance was achieved is incomplete in the current version of the paper. The paper would benefit from a more detailed description of the results and limitations of the approach.

eLife assessment

This valuable study focuses on the role of the Gr28 family of insect chemoreceptors. Using the Drosophila larva, the authors show that taste neurons expressing different members of this family of bitter taste receptors trigger opposite behavior - attraction and repulsion. They establish the minimal bitter taste receptor subunit composition needed in these neurons to mediate the repulsion of bitter tastants. The evidence presented is convincing, using well-validated and controlled tools and experiments.

eLife assessment

Using state-of-the-art single-nucleus RNA sequencing, Yao et al. investigate the transcriptomic features of neural stem cells (NSCs) in the human hippocampus to address how they vary across different age groups and stroke conditions. The authors report alterations in NSC subtype proportions and gene expression profiles after stroke and an exemplary gene elevated in NSCs and reactive astrocytes in stroke patients. Although the aim of the study is valuable, the significance is restricted by technical limitations and the incomplete evidence supporting the main conclusions.

eLife assessment

The authors study the growth of two mechanically coupled microtubules using a technically sophisticated, original experimental setup and computer simulations. They provide important new insight into the mechanism of coordinated growth of two microtubules attached to two yeast kinetochores. The study is carefully performed, very clearly presented, and the conclusions are supported by compelling evidence.

eLife assessment

This study provides important, detailed insights into the early stages of angiogenesis and points towards a novel mechanism that could be used to control the density and location of developing blood vessels. Convincing experimental methods, analysis techniques, and mathematical modeling are used to systematically support the findings. This study of the mechanisms by which paracrine and juxtacrine cues control the formation of new blood vessels will be of broad interest to colleagues studying angiogenesis and blood vessel formation.

eLife assessment

This valuable manuscript examines the role of basal forebrain cholinergic (ACh) projection neurons and their inputs to the basolateral amygdala (BLA) and effects on BLA activity during reward seeking. The manuscript provides compelling evidence that ACh may have different effects on network activity in the BLA depending on the state of the network during reward engagement, whereas behavioural data indicating that these ACh neurons/inputs are involved in uncued reward seeking specifically is somewhat less complete. The paper will be of interest to those studying amygdala circuitry, reward processing, and neuromodulation broadly defined.

eLife assessment

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

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment:

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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