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

This valuable study focuses on the impact of growth feedback on the performance of artificial gene circuits capable of achieving adaptive responses, an important problem in synthetic biology. Through solid computational analysis, the authors identify specific failure mechanisms, as well as core topologies associated with robust performance based on systematic analysis of over four hundred circuit topologies. The results will be of interest to those working on engineering gene circuits for diverse applications.

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 is a valuable study of the mechanisms of microtubule organization in pancreatic islet beta cells that enable optimal insulin secretion. Using a combination of live imaging and photo-kinetic assays in an in vitro culture system, the authors solidly demonstrate that kinesin-1-mediated microtubule sliding, which has previously been known from neurons and embryos, is important for establishing the sub-membranous microtubule band in response to glucose levels in beta cells. The inclusion of an animal model or primary cells, as well as data on the physiological relevance of the finding, would have strengthened the study. The work will be of interest to cell biologists studying cytoskeletal dynamics and organelle trafficking and to translational biologists working on diabetes.

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.

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

This study provides a clearly presented and thoughtfully analyzed single cell-resolution dataset of gene expression in wildtype and mutant zebrafish skin. These data are used by the authors to develop and test hypotheses about cell lineage relationships and signaling interactions between cell types in the skin, allowing them to identify roles for several signaling pathways and the hypodermis in scale and pigment cell development. These findings constitute a fundamental contribution to the field, and the rigor of the analyses make this manuscript compelling.

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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