eLife assessment

The authors report the cryo-EM structure of human vesicular monoamine transporter 2 (VMAT2) bound to the noncompetitive inhibitor tetrabenazine (in an occluded state). This important achievement captures the structure of a major facilitator superfamily (MFS) transporter critical for human neurotransmission. The evidence for the structure is solid, but the molecular dynamics aspect of the study is incomplete.

eLife assessment

The authors have made important contributions to our understanding of the pathogenesis of erectile dysfunction (ED) in diabetic patients. They have identified the gene Lbh, expressed in pericytes of the penis and decreased in diabetic animals. Overexpression of Lbh appears to counteract ED in these animals. The authors also confirm Lbh as a potential marker in cavernous tissues in both humans and mice. While solid evidence supports Lbh's functional role as a marker gene, further research is needed to elucidate the specific mechanisms by which it exerts its effects. This work is of interest to those working in the fields of ED and angiogenesis.

eLife assessment

This useful study examines how deletion of a major DNA repair gene in bacteria may facilitate the rise of mutations that confer resistance against a range of different antibiotics. Although the phenotypic evidence is intriguing, the interpretation of the phenotypic data presented and the proposed mechanism by which these mutations are generated are incomplete, relying on untested assumptions and suboptimal methodology. If substantially improved, this work could be of interest to microbiologists studying antibiotic resistance, genome integrity, and evolution, but as yet is of unclear significance.

eLife assessment

This important study advances our understanding of early Cambrian cnidarian paleoecology and suggests that the reconstructed ancestral feeding and respiration mechanisms predate jet-propelled swimming utilized by modern jellyfish. The work combines solid evidence of fluid and structural mechanics modeling, simulating for the first time the feeding and respiratory capacities in a microfossil (Quadrapyrgites), which in turn opens new possibilities using this approach for paleontological research. Assuming that the prior interpretations and assumptions concerning the modeled organism's soft part and skeletal anatomy are correct, the hypotheses that (1) the organism could alternately contract and expand the oral region and (2) such movement increased feeding efficiency seem plausible.

eLife assessment

By assessing what it means to replicate a null finding, and by proposing two methods that can be used to evaluate whether null findings have been replicated (frequentist equivalence testing, and Bayes factors), this article represents an important contribution to work on reproducibility. Through a compelling re-analysis of results from the Reproducibility Project: Cancer Biology, the authors demonstrate that even when 'replication success' is reduced to a single criterion, different methods to assess replication of a null finding can lead to different conclusions.

eLife assessment

In this important study by Theriot et al., the authors utilize an impressive set of innovative approaches to conduct a CRISPRi pooled screen in human cells using large-scale microscopy screen data. They leverage an improved barcoding approach to identify genes targeted in specific cells and examine the effects on cell morphology using high-dimensional phenotypic analysis. The method and data presented are compelling.

eLife assessment

The findings of this study are valuable as they challenge the dogma regarding the link between lowered bacterial metabolism and tolerance to aminoglycosides. The authors propose that the well-known tolerance to AG of mutants such as those of complexes I and II is not due to a decrease in the proton motive force and thus antibiotic uptake. The results presented here are solid but incomplete and the conclusions require additional experimental support.

eLife assessment

This study presents a valuable finding on the possible use of vilazodone in the management of thrombocytopenia through regulating 5-HT1A receptor signaling. The evidence supporting the claims of the authors is solid, with the combined use of computational methods and biochemical assays. The work will be of broad interest to scientists working in the field of thrombocytopenia.

eLife assessment

This manuscript is a valuable contribution to our understanding of foraging behaviors in marine bacteria. The authors present a conceptual model for how a marine bacterial species consumes an abundant polysaccharide. Using experiments in microfluidic devices and through measurements of motility and gene expression, the authors offer solid evidence that the degradation products of polysaccharide digestion can stimulate motility.

eLife assessment

The authors of this study implemented an important toolset for 3D reconstruction and segmentation of dissection photographs, which could serve as an alternative for cadaveric and ex vivo MRIs. The tools were tested on synthetic and real data with compelling performance. This toolset could further contribute to the study of neuroimaging-neuropathological correlations.

eLife assessment

This study presents a valuable investigation of how people approach and avoid uncertainty, with a particular focus on the effects of overall uncertainty. They find that individuals approach uncertainty to a point, but when uncertainty is particularly high, they avoid it. The results are interpreted under a cognitive cost-resource rational framework. The methods are convincing, using appropriate and current methodologies, but more details on analyses and placing the work more fully in the context of the existing literature would make the contribution more significant.

eLife assessment

The work by Hornberger and team presents a novel workflow for the visualisation of myofibrils with high resolution and contrast that will be highly valued by the scientific community. The novel methods include solid validation of both sample preparation and analysis, and have been used to make the fundamental discovery of myofibrillogenesis as the mechanism of mechanical loading-induced growth. However, whether this mechanism is present in other settings of muscle growth (i.e non-loading), other striated tissue (e.g myocardium), or is sex-dependent requires future experiments.

eLife assessment

The work by Hornberger and team presents a novel workflow for the visualisation of myofibrils with high resolution and contrast that will be highly valued by the scientific community. The methods include solid validation of both sample preparation and analysis, and have been used to make the fundamental discovery of myofibrillogenesis as the mechanism of mechanical loading-induced growth. Whether this mechanism is present in other settings of muscle growth (i.e., non-loading), other striated tissue (e.g myocardium), or is sex-dependent, will require future experiments.

eLife assessment

This valuable work performed fMRI experiments in a rodent model of absence seizures. The results provide new information regarding the brain's responsiveness to environmental stimuli during absence seizures. The authors suggest reduced responsiveness occurs during this type of seizure, and the evidence leading to the conclusion is solid, although reviewers had divergent opinions.

eLife assessment

This important study demonstrates that the cells in the behavior of the presomitic mesoderm in zebrafish embryos depends on both an intrinsic program and external information, which provides new insight into the biology underlying embryo axis segmentation. The findings are supported convincingly by a thorough and quantitative single-cell real-time imaging approach, both in vitro and in vivo, which the authors developed.

eLife assessment

This valuable prospective study develops a new tool to accelerate pharmacological studies by using neural networks to emulate the human ventricular cardiomyocyte action potential. The evidence supporting the conclusions is convincing, based on using a large and high-quality dataset to train the neural network emulator. There are nevertheless a few areas in which the article may be improved through validating the neural network emulators against extensive experimental data. In addition, the article may be improved through delineating the exact speed-up achieved and the scope for acceleration. The work will be of broad interest to scientists working in cardiac simulation and quantitative system pharmacology.

eLife assessment

This important study combines experimental infections with laboratory and field Plasmodium falciparum isolates to quantify the force of human malaria parasite transmission. By using compelling methodological approaches, the authors establish clear positive correlations between mosquito infection levels (as determined by oocyst numbers), sporozoite loads in salivary glands, and sporozoites expelled during feeding. The link between heterogenous infection levels in the mosquitoes and malaria transmission would be of interest to vector biologists, parasitologists, immunologists, and mathematical modellers.

eLife assessment

This important study advances our understanding of the biological significance of the DNA sequence adjacent to telomeres. The data presented convincingly demonstrates that subtelomeric repeats are non-essential and have a minimal, if any, role in maintaining telomere integrity of budding yeast. The work will be of interest to telomere community specifically and the genome integrity community more broadly.

eLife assessment

This important work presents an example of how genomic data can be used to improve understanding of an ongoing, long-term bacterial outbreak in a hospital with an application to multi-drug resistant Pseudomonas aeruginosa, and will be of interest to researchers concerned with the spread of drug-resistant bacteria in hospital settings. The convincing genomic analyses highlight the value of routine surveillance of patients and environmental sampling and show how such data can help in dating the origin of the outbreak and in characterising the epidemic lineages. These findings highlight the importance of understanding environmental factors contributing to the transmission of P. aeruginosa for guiding and tailoring infection control efforts; however, epidemiological information was limited and the sampling methodology was inconsistent, complicating interpretation of inferences about exact transmission routes.

eLife assessment

This study presents valuable findings on the role of the sirtuins SIRT1 and SIRT3 during Salmonella Typhimurium infection. Although the work increases our understanding of the mechanisms used by this pathogen to interact with its host and may have implications for other intracellular pathogens, the reviewers found that the evidence to support the claims is incomplete. In particular, the discrepancy between results obtained using cultured cell lines and the animal model of infection stands out.

eLife assessment

This manuscript examines shared and divergent mechanisms of disruptions of five different mTOR pathway genes on embryonic mouse brain neuronal development. The significance of the manuscript is important, because it bridges several different genetic causes of focal malformations of cortical development. The strength of evidence is compelling, relying on both gain and loss of function, demonstrating differential impact on excitatory synaptic activity, conferring gene-specific mechanisms of hyperexcitability. The results have both theoretical and practical implications for the field of developmental neurobiology and clinical epilepsy.

eLife assessment

Little is known about the role of the microbiome alterations in epithelial ovarian cancer. This important and rigorous study carefully examined the microbiome composition of 1001 samples from close to 200 ovarian cancer cases and controls, and presents compelling evidence that the fallopian tube microbiota are perturbed in ovarian cancer patients. These insights are expected to fuel further exploration into translational opportunities stemming from these findings.

eLife assessment

This study presents a valuable finding for the immunotherapy of cancer. The data support the role of PDLIM2 as a tumor suppressor, and more immediately, its relevance for strategies to improve the efficacy of immunotherapy. The evidence supporting the conclusions is compelling and the work will be of interest to biomedical scientists working on cancer immunology.

eLife assessment

This study presents a useful resource for the gene expression profiles of different cell types in the parietal lobe of the cerebral cortex of prenatal macaques. The evidence supporting the claims of the authors is solid, and revision has clarified some of the cell isolation and cell classification issues flagged by reviewers. This dataset will be of interest to developmental neurobiologists and could potentially be used for future comparative studies on early brain development.

eLife assessment

This study presents two useful new mouse models that individually tag proteins from the SMAD family to identify distinct roles during early pregnancy. Solid evidence is provided that SMAD1 and SMAD5 target many of the same genomic regions as each other and the progesterone receptor. Given the broad effect of these signaling pathways in multiple systems, these new tools will most likely interest readers across biological disciplines.

eLife assessment

The authors conduct a valuable GWAS meta-analysis for COVID-19 hospitalization in admixed American populations and prioritized risk variants and genes. The evidence supporting the claims of the authors is incomplete. The work will be of interest to scientists studying the genetic basis of COVID pathogenesis.

eLife assessment

This is an important study on DNA gyrase that provides further evidence for its mode of action via a double-stranded DNA break and against a recently-proposed alternative mechanism. The evidence presented is solid and is derived from state-of-the-art techniques. The work casts new light on the interactions that occur between gyrase molecules and will be of interest to biochemists and cell biologists.

eLife assessment

The important work by Aballay et al. significantly advances our understanding of how G protein-coupled receptors (GPCRs) regulate immunity and pathogen avoidance. The authors provide convincing evidence for the GPCR NPR-15 to mediate immunity by altering the activity of several key transcription factors. This work will be of broad interest to immunologists.

eLife assessment

This study characterized the activity of optogenetically identified dopaminergic and GABAergic neurons in the ventral tegmental area in mice performing a memory-guided T-maze task, and shows that subpopulations of dopaminergic and GABAergic neurons exhibited choice-related activity during the delay period, consistent with some previous studies (e.g. Morris et al., 2006, Parker et al., 2016). The authors demonstrate that these delay-period activities were enhanced when the task requires short-term memory. The results are convincing and this study provides important results regarding the nature of delay-period activity in the task.

eLife assessment

This study used prolonged stimulation of a limb to examine possible plasticity in somatosensory evoked potentials and the role of the blood brain barrier (BBB). The significance is important because thus far BBB modulation of plasticity is mostly in the context of pathology. The revisions greatly improved the paper and the strength of evidence is convincing.

eLife assessment

This important study by Yogesh and Keller provides a set of results describing the response properties of cholinergic input and its functional impacts in the mouse visual cortex. They found that cholinergic inputs are elevated by locomotion in a binary manner regardless of locomotor speeds, and activation of cholinergic input differently modulated the activity of Later 2/3 and Layer 5 visual cortex neurons induced by bottom-up (visual stimuli) and top-down (visuomotor mismatch) inputs. The reviewers found that the experiments are cutting-edge and well executed, and the results to be mostly convincing.

eLife assessment

This important study examined the mechanisms underlying reduced excitability of ventral tegmental area dopamine neurons in mice that underwent a chronic mild unpredictable stress treatment. The authors identify NALCN and TRPC6 channels as key mechanisms that regulate spontaneous firing of ventral tegmental area dopamine neurons and examined their roles in reduced firing in mice that underwent a chronic mild unpredictable stress treatment. The authors' conclusions on neurophysiological data are supported by multiple approaches and convincing, although the relevance of the behavioral results to human depression remains unclear.

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 study is valuable, the significance is restricted by technical limitations and the incomplete evidence supporting the main conclusions.

eLife assessment

This important multicenter study provides convincing evidence that the auditory noise emitted during online transcranial ultrasound stimulation (TUS) protocols can pose a considerable confound and is able to explain corticospinal excitability changes as measured with Motor Evoked Potentials (MEP). The findings lay the ground for future studies optimising protocols and control conditions to leverage TUS as a meaningful experimental and clinical tool. A clear strength of the study is the multitude of control conditions (i.e., control sites, acoustic masking, acoustic stimulation). These findings will be of interest to neuroscience researchers using brain stimulation approaches.

eLife assessment

This important study utilizes a virus-mediated short hairpin RNA (shRNA) approach to investigate in a novel way the role of the wild-type PHOX2B transcription factor in critical chemosensory neurons in the brainstem retrotrapezoid nucleus (RTN) region for maintaining normal CO2 chemoreflex control of breathing in adult rats. The solid results presented show blunted ventilation during elevated inhaled CO2 (hypercapnia) with knockdown of PHOX2B, accompanied by a reduction in expression of Gpr4 and Task2 mRNA for the proposed RTN neuron proton sensor proteins GPR4 and TASK2. These results suggest that maintained expression of wild-type PHOX2B affects respiratory control in adult animals, which complements previous studies showing that PHOX2B-expressing RTN neurons may be critical for chemosensory control throughout the lifespan and with implications for neurological disorders involving the RTN. When some methodological, data interpretation, and prior literature reference issues further highlighting novelty are adequately addressed, this study will be of interest to neuroscientists studying respiratory neurobiology as well as the neurodevelopmental control of motor behavior.

eLife assessment

This study on the effects of fasting on safety learning rests on basic premises and concepts that both reviewers found difficult to follow. If these can be clarified, the findings may well be useful and of some utility for the field of emotional learning as well as experimental clinical psychology. However, the main claims of the study are only partially supported and are therefore incomplete.

eLife assessment

This potentially valuable study uses classic neuroanatomical techniques and synchrotron X-ray tomography to investigate the mapping of the trunk within the brainstem nuclei of the elephant brain. Given its unique specializations, understanding the somatosensory projections from the elephant trunk would be of general interest to evolutionary neurobiologists, comparative neuroscientists, and animal behavior scientists. However, the anatomical analysis is inadequate to support the authors' conclusion that they have identified the elephant trigeminal sensory nuclei rather than a different brain region, specifically the inferior olive.

eLife assessment

This study investigated the role of specific proteins in a mouse model of developmental epilepsy. The significance of the work is important because a new mouse model was used to simulate a type of developmental epilepsy. The work is also significant because the deletion of two proteins together, but not separately, improved the symptoms, and data were convincing.

eLife assessment

The authors used an innovative modified 10X genomic sequencing method to detect cPCDHg is-forms in pyramidal neurons. With solid electrophysiological recordings, they showed that neurons expressing the same sets of cPCDHg isoforms are less likely to form synapses with each other. These valuable findings confirms previous results and extend our understanding of cPCDHg diversity and neuronal connectivity.

eLife assessment

This important study tests the hypothesis that a high autism quotient in neurotypical adults is strongly associated with suboptimal motor planning and visual updating after eye movements, which in turn, is related to a disrupted efference copy mechanism. The implication is that such abnormal behavior would be exaggerated in those with ASD and may contribute to sensory overload - a key symptom in this condition. The evidence presented is convincing, with significant effects in both visual and motor domains, adequate sample sizes, and consideration of alternatives. However, the study would be strengthened with minor but necessary corrections to methods and statistics, as well as a moderation of claims regarding direct application to ASD in the absence of testing such patients.

eLife assessment

This study provides a valuable contribution to understanding the neural mechanisms underlying age-related changes in attention and speech understanding. The large dataset (N=105) provides convincing evidence for how speech recognition behaviour and neural tracking of speech separately evolve in about 2 years. The work would be of interest to psychologists, neuroscientists, and audiologists.

eLife assessment

This paper explores the relationships among evolutionary and epidemiological quantities in influenza, and presents fundamental findings that substantially advance our understanding of the drivers of influenza epidemics. The authors use a rich set of data sources to gather and analyze compelling evidence on the roles of genetic distance, other influenza dynamics and epidemiological indicators in predicting influenza epidemics. The central findings highlight the significant influence of genetic distance on A(H3N2) virus epidemiology and emphasize the role of A(H1N1) virus incidence in shaping A(H3N2) epidemics, suggesting subtype interference as a key factor. This paper also makes relevant data available to the research community.

eLife assessment

In this important study, the authors develop a promising experimental approach to a central question in ecology: What are the contributions of resource use and interactions in the shaping of an ecosystem? For this, they develop a synthetic ecosystem set-up, a variant of SELEX that allows very detailed control over ecological variables. The evidence is convincing, and the work should be of broad interest to the ecology community, leading to further quantitative studies.

eLife assessment

This valuable study describes mice with a knock out of the IQ motif-containing H (IQCH) gene, to model a human loss-of-function mutation in IQCH associated with male sterility. The infertility is reproduced in the mouse, making it a compelling model, but some of the mechanistic experiments provide only indirect and thus incomplete evidence for interaction between IQCH and potential RNA binding proteins. With more rigorous approaches, the paper should be of interest to cell biologists and male reproductive biologists working on the sperm flagellar cytoskeleton and mitochondrial structure.

eLife assessment

This study presents a valuable examination into the role Notch-RBP-J signalling in regulating monocyte subset homeostasis. The data were collected and analysed using solid and validated methodology and can be used as a starting point for exploring the mechanisms involved in RBP-J signalling in non-classical monocytes. The data presented strongly confirm the authors conclusions. However, this paper primarily focuses on providing a description, and additional studies are necessary to fully elucidate the mechanisms through which RBP-J deficiency contributes to the specific increase in Ly6Clo monocyte numbers in both the blood and lungs.

eLife assessment

This study provides an important finding that the local abundance of metabolites impacts the biology of the tumor microenvironment by utilizing kidney tumors from patients and adjacent normal tissues. The evidence supporting the claims of the authors is convincing although certain caveats need to be taken into consideration as the authors acknowledged in the paper. The work will be of interest to the research community working on metabolism and on kidney cancer especially.

eLife assessment

This study is useful as it provides further analysis of previously published data to address which specific genes are part of the masculinizing actions of E2 on female zebra finches, and where these key genes are expressed in the brain. However the data supporting the conclusion of masculinizing the song system are incomplete as the current manuscript is a re-analysis of differential gene expression modulated by E2 treatment between male/female zebra finches without manipulation of gene expression. The conclusions (and title) regarding song learning are not completely supported, with no gene manipulation or song analysis. The use of WGCNA for a question of sex-chromosome expression in species without dosage compensation is considered inadequate. As the experimental design did not include groups to directly test for song learning, and there was also no analysis of song performance, these data were also considered inadequate in that regard.

eLife assessment

This landmark study presents MetaPathPredict, a method that uses a stacked ensemble of neural networks to predict the presence or absence of KEGG modules based on annotated features in the genome. The evidence supporting the conclusions is compelling, with a tool that allows for prediction of KEGG modules in sparse gene sequence datasets.

eLife assessment

In this important study, the authors explore the importance of developmental changes in cortico-DRN innervation in the balance of behavioral control in a foraging task. The authors report somewhat convincing evidence that while juvenile mice and adult mice both perform the task, juveniles exhibit more impulsive behavior due to reduced efficacy of cortico-DRN projections. The authors conclude that the development of cortico-DRN (esp mPFC) projections allows 5HT input to promote perseveration (or exploitation) in the balance of behavioral control. However, reviewers raised issues regarding the strength of the evidence without further experiments.

eLife assessment

Using single-cell sequencing, high-resolution imaging, and inducible genetic deletion of yolk-sac (YS) derived macrophages, the authors present a useful map of fetal liver macrophage subpopulations and provide important data demonstrating that heterogeneous fetal liver macrophages regulate erythrocyte enucleation, interact physically with fetal HSCs, and may regulate neutrophil accumulation in the fetal liver. These novel findings, although yet incomplete, might provide a solid foundation for further investigating the effects of macrophages on HSC function during fetal hematopoiesis and into adulthood and will be useful for the field of macrophage biology and developmental hematopoiesis.

eLife assessment

This manuscript addresses a non-canonical function of the Class 2 ribonuclease III Drosha in the regulation of adult neural stem cell fate, important for understanding how these cells generate neurons or oligodendrocytic cells.<br /> Overall, this manuscript has many strengths. The authors identify 165 proteins, several of them enriched in neural stem cells, and potentially specific for miRNA dependent or independent Drosha macromolecular complexes.<br /> While the authors provide systematic and convincing evidence on the biochemical interactions among the key players in this cascade, the significance of these interactions for neural stem cell fate determination in vivo remains unclear, as the in vitro cellular systems used to document most of the data reported in the paper may not (fully) represent resident neural stem cells in the adult hippocampus. The in vivo function mediated by Drosha/ Safb1 needs to be substantiated by more evidence and/or complementary approaches.

eLife assessment

The authors observed a positive correlation between FSH and fat mass, as well as a negative association with the appendicular lean mass/fat mass ratio. These valuable findings in male subjects within a hypogonadal setting following Degarelix treatment imply that FSH might function as a predictor, similar to observations in women. However, it's important to note that the analysis is incomplete, as other major confounding factors such as testosterone were not included.

eLife assessment

The findings are important and would potentially have theoretical and practical implications outside the field. However the strength of evidence presented was assessed as being incomplete in several respects. Major strengths are (1) genetic factors in facial appearance are of broad interest, and the potential influence of possibly identical factors in a serious congenital disorder (cleft lip/palate) heightens that interest further; (2) proving which single nucleotide variants influence phenotypes, and by what mechanisms, is a major challenge for the field as a whole. The weakness, as assessed, was that in its present form the experimental approach was not sufficiently rigorous to support the conclusions unambiguously.

eLife assessment

This important study presents data suggesting that HFD-induced histone epimutations in sperm may impact the transcriptome of the placenta, thereby contributing to the paternal transmission of paternal metabolic disorders to offspring. Although the hypothesis is interesting and the evidence presented is compelling, more careful statistical analyses and functional validation experiments are needed to further strengthen the conclusion.

eLife assessment

In their short technical report, Verma et al. describe how endogenously-tagged dynein and dynactin molecules localize to growing microtubule plus-ends and move processively along microtubules in cells. The authors present solid evidence that cytoplasmic dynein is a processive motor that takes long excursions prior to dissociating from microtubules. However, there are concerns about the robustness of the imaging and analysis protocols, which should be more clearly defined. This is a useful study that will be of interest to cell biologists and biochemists in the motor protein field.

eLife assessment

The important study uses a new experimental method to provide compelling evidence on how sense- and anti-sense transcription is differentially regulated. The method described here can generally be used to study the alterations in transcription. This paper will be of interest to scientists working in the gene regulation community.

eLife assessment

Benner et al. identify OVO as a transcriptional factor instrumental in promoting the expression of hundreds of genes essential for female germline identity and early embryo development. While they provide the dataset that supports their model, the major evidence for the model proposed in this manuscript comes from a separate manuscript by the same group, making the contribution of this manuscript somewhat unclear - that is, the evidence provided in this paper is incomplete to support the proposal of this paper. Overall, the study provides useful information that will help understand the function of ovo during oogenesis and early embryonic development.

eLife assessment

This study combines molecular genetics and target validation to discover genes involved in obesity and determine their role. It was unanimously agreed that the work is important in terms of significance as it has conceptual and practical implications beyond metabolism, including embryonic and placental development. The strength of evidence is convincing from the use of their forward genetic screen in mice.

eLife assessment

The authors report a previously published method ReplicaDock to improve predictions from AlphaFold-multimer (AFm) for protein docking studies. The level of improvement is modest for cases where AFm is successful; for cases where AFm is not as successful, the improvement is more significant, although the accuracy of prediction is also notably lower. Therefore, the evidence for the ReplicaDock approach being more predictive than AFm is solid for some cases (e.g., the antibody-antigen test case) but incomplete for the more extensive test sets (e.g., those presented in Figure 6). Overall, the study makes a valuable contribution by combining data- and physics-driven approaches.

eLife assessment

This important study provides compelling evidence that the low-cost and open-hardware UC2 microscopy framework can be expanded to enable single-molecule localization microscopy. The authors managed to fit the instrumentation and control thereof in a unit that can be placed in a small stage-top-incubator. Together with providing adapted software for data acquisition and data analysis, the UC.STORM setup can rival the capabilities of comparable commercial instruments at a fraction of the costs.

eLife assessment

This important collection of over 800 new cell type-specific driver lines will be an invaluable resource for researchers studying associative learning in Drosophila. Thoroughly characterized and well documented, this collection will permit researchers to selectively target neurons that deliver information to, or receive it from, the memory center of the fly brain called the Mushroom Body. Given the wealth of new drivers and the genetic access they provide to over 300 cell types, this compelling work will be of interest not only to researchers studying the mechanisms of associative learning but more generally to those dissecting sensorimotor circuits in the fly nervous system.

eLife assessment

This study presents valuable intracranial findings on how two types of natural auditory stimuli – speech and music – are processed in the human brain, and demonstrates that speech and music largely share network-level brain activities, thus challenging the domain-specific processing view. The evidence supporting the claims of the authors is solid but somewhat incomplete: although the data analysis is thorough, the results are robust and the stimuli have ecological validity, considerations such as low-level acoustics control, limitations of experimental design, and in-depth analysis, are lacking. The work will be of broad interest to speech and music researchers as well as cognitive scientists in general.

eLife assessment

In this study, the authors provide compelling evidence for dysgranular insular involvement in top-down and bottom-up interoceptive processing. Its translational application in ADE patients corroborates the assumption that the mid-insula may indeed be a locus of 'interoceptive disruption' in psychiatric disorders, which underscores the study's high relevance for both body-brain as well as clinical research. The authors' findings are fundamental and substantially advance our understanding of the neural basis of interoception and its putative disruption in psychiatric disorders.

eLife assessment

This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. While the strength of the evidence supporting these claims is compelling, the authors do not discuss how their results affect our understanding of insect nest construction or animal-built structures more broadly.

eLife assessment

This valuable study substantially advances our understanding of molecular mechanisms driving the phase separation behavior of HP1 paralogs. The evidence supporting the conclusions is convincing, with rigorous and well-designed computational simulations. The work will be of broad interest to biophysicists and biochemists.

eLife assessment

In this valuable study, the authors aimed to identify and characterize intrinsic factors that govern the aging process of bone marrow mesenchymal stromal cells (BMSCs), which are believed to be related to osteoporosis. The authors conclude that PCBP2 is an intrinsic aging factor, the decrease of its expression during aging results in cell proliferation activity decrease and cell senescence. The study provides convincing evidence in support of its conclusions.

eLife assessment

This valuable study describes an investigation of the properties of two heterologously-expressed Nav1.4 channels, with mutations close to the selectivity filter found in tetrodotoxin(TTX)-resistant snakes. The authors studied these mutants by electrophysiological methods, assessed the muscle properties of two types of snakes bearing these mutations, and built homology models of the channels to hypothesize a molecular explanation of the altered channel properties. The methods employed and the results are generally solid, although some aspects would benefit from additional experiments and a more nuanced discussion.

eLife assessment

The authors provide solid data on a functional investigation of potential nucleoid-associated proteins and the modulation of chromosomal conformation in a model cyanobacterium. While the experiments presented are convincing, the manuscript could benefit from restructuring towards the precise findings; alternatively, additional data buttressing the claims made would significantly enhance the study. These valuable findings will be of interest to the chromosome and microbiology fields.

eLife assessment

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

eLife assessment

The authors examined in detail the epigenetic changes and alterations in the subnuclear arrangement of a unique var gene associated with Plasmodium falciparum placental malaria. Although the observations are mainly confirmatory, the findings are valuable for theoretical considerations and practical applications. Applying the latest methods for the analysis of histone marks, transcriptomics, DNA methylation, and chromosome conformation, the authors provide observations that are convincing, thus making their claims appropriate.

eLife assessment

This important work significantly advances the field of computational modelling of genome organisation through the development of OpenNucleome. The evidence supporting the tool's effectiveness is compelling, as the authors compare their predictions with experimental data. It is anticipated that OpenNucleome will attract significant interest from the biophysics and genomics communities. Providing comprehensive tutorials and documentation is highly encouraged.

eLife assessment

The authors identify a new role for C1ql2 at moss fiber synapses in the hippocampus and find that C1ql2, whose expression is controlled by Bcl11b, controls the recruitment of synaptic vesicles to active zones and is necessary for synaptic plasticity. The data implicating C1ql2 involvement, using numerous viral/genetic rescue approaches, are largely convincing, while the experimental evidence supporting the role of the specific Nrxn3 splice variant is less complete. These data are valuable, building on prior discoveries of how Bcl11b, a disease-relevant molecule, contributes to our understanding of mossy-fiber synaptic development.

eLife assessment

The authors identify a new role for C1ql2 at mossy fiber synapses in the hippocampus and convincingly find that C1ql2, whose expression is controlled by Bcl11b, controls the recruitment of synaptic vesicles to active zones and is necessary for synaptic plasticity. These important results build upon prior discoveries of how Bcl11b, a disease-relevant molecule, contributes to our understanding of mossy-fiber synaptic development.

eLife assessment

This study presents a useful strategy in which the authors devised a simple method to attenuate Candida albicans and deliver a live whole-cell vaccine in a mouse model of systemic candidiasis. While a robust candidiasis vaccine will be critical for the field, the study in its current form is incomplete. The strength of the evidence could be augmented with additional experiments to more fully characterize vaccine efficacy and host immune responses.

eLife assessment

This useful study tackles the well-established overflow metabolism issue by applying a coarse-grained metabolic flux model to predict how individual cells execute various energy strategies, such as respiration versus fermentation. While the model's population average is convincing enough to align with experimental observations on overflow metabolism, the overall assertions to enhance our comprehension of this biological phenomenon are incomplete.

eLife assessment

This study presents a valuable finding on the relationship between neuronal dynamics in the thalamus and brain state modulation. The evidence supporting the claims of the authors is incomplete, as additional analyses and better presentation of the data are needed to support the specific role of the mediodorsal nucleus in this phenomenon. The work will be of interest to systems neuroscientists interested in brain dynamics and behavioural states.

eLife assessment

The manuscript by Agha et al. provides a fundamental understanding regarding the participation of V2a interneurons in generating and patterning the locomotor rhythm. The authors provide convincing and solid evidence regarding the heterogeneity of V2a neurons in their intrinsic and synaptic properties and how these shape their outputs. The manuscript could be much improved by the inclusion of statistical analysis of some of the key data currently presented qualitatively.

eLife assessment

This study presents an important set of results illuminating how movement sequences are planned. Using several different behavioural manipulations and analysis methods, the authors present compelling evidence that multiple future movements are planned simultaneously with execution, and that these future movement plans influence each other. The work will be of great interest to those studying motor control.

eLife assessment

This valuable study, of interest for students of the biology of genomes, uses simulations in combination with published data to examine how many TADs remain after cohesin depletion. The authors suggest that a significant subset of chromosome conformations do not require cohesin, and that knowledge of specific epigenetic states can be used to identify regions of the genome that still interact in the absence of cohesin. The theoretical approaches and quantitative analysis are state-of-the-art, and the data quality and strength of the conclusions are convincing, but it is unfortunately still unclear whether physical boundaries (of domains?) in the model appear to be a consequence of preserved TADs, or whether preserved TADs are caused by the physical boundaries.

eLife assessment

This useful study uses a microfluidic method to evaluate the ability of single human white blood cells to produce combinations of cytokines and the evidence that this takes place is solid. The paper highlights polyfunctionality using data that are similar to a prior dataset from the same group. The authors comment that, in analysis of larger panels, single cells rarely make more than 2 or 3 cytokines so that investigation of 3 cytokines at a time is sufficient to investigate this phenomenon. Coupling this approach to other modes of single cell analysis may provide greater insight into what limits simultaneous production of multiple cytokines.

eLife assessment

This important study indicates a significant role for individual let-7 miRNA clusters in regulating generation of Tc17 CD8 cells and emphysema severity in a mouse model. The authors provide convincing evidence for let-7-mediated repression of the transcription factor RORgt and consequent modulation of IL-17-producing CD8 T cells, with correlated data from human emphysema material, though the most effective let-7 cluster/s is/are yet to be tested for its/their ability to modulate disease. The findings, which substantially advance the understanding of roles that let-7 miRNA clusters play in modulating both T cell responses and emphysematous lung disease, will be of interest to T cell and lung disease researchers.

eLife assessment

In this useful study, the authors analyze droplet size distributions of multiple protein condensates and their fit to a scaling ansatz, highlighting that they exhibit features of first- and second-order phase transitions. The experimental evidence is still incomplete as the measurements were apparently done only at one time point, neglecting the possibility that droplet size distribution can evolve with time. The text would benefit from a connection to and contextualization with the well-understood expectations from the coupling of percolation and phase separation in protein condensates - a phenomenon that is increasingly gaining consensus amongst the community and that emphasizes "liquid-gas" criticality.

eLife assessment

This fundamental study explores the relationship between guanine-quadruplex structures and pathogenicity islands in 89 bacterial strains representing a range of pathogens. Guanine-quadruplex structures were found to be non-randomly distributed within pathogenicity islands and conserved within the same strains. These compelling findings shed light on the molecular mechanisms of Guanine-quadruplex structure-pathogenicity island interactions and will be of interest to all microbiologists.

eLife assessment

This valuable study advances our understanding of spatial-temporal cell dynamics both in vivo and in vitro. The authors provide solid evidence for their innovative deep learning-based apoptosis detection system, ADeS, which utilizes the principle of activity recognition. This work will be of broad interest to cell biologists and neuroscientists.

eLife assessment

This manuscript provides a useful reconstruction of the structure of the sirtuin-class histone deacetylase Sirt6 bound to a nucleosome based on cryo-EM observations, and additional characterization of the flexibility of the histone tails in the complex based on molecular dynamics simulations. While similar structures have recently been published elsewhere, this solid study supports the conclusions of those papers and also includes new insights into the potential dynamics of Sirt6 bound to a nucleosome, insights that help explain its substrate specificity.

eLife assessment

This manuscript presents potentially valuable results indicating a plastic enhancement in the vasomotion response of pial cortical arterioles to external stimulation in awake mice using a wide range of external visual stimulation paradigms. The evidence for this interesting effect, with broad potential applications, is, however, incomplete because it is unclear whether the effect is a modulation of vasomotion rather than stimulus-driven hyperaemia and whether it is reversible. These results are relevant for scientists and clinicians interested in the regulation of blood flow in the brain.

eLife assessment

This valuable study from Zaman et al. demonstrates that the cKit-Kit ligand complex is necessary for the formation and/or maintenance of molecular layer interneuron synapses in cerebellar Purkinje cells. The evidence presented is solid; in particular, the use of cell-type specific knockout of cKit in molecular layer interneurons and knockout of Kit ligand in Purkinje cells provides robust evidence. This work will be of particular relevance to those interested in inhibitory synapse formation or the role of inhibition in Purkinje cell behavior.

eLife assessment

This valuable study from Zaman et al. demonstrates that the cKit-Kit ligand complex is necessary for the formation and/or maintenance of molecular layer interneuron synapses in cerebellar Purkinje cells. The evidence presented is convincing; in particular, the use of cell-type specific knockout of cKit in molecular layer interneurons and knockout of Kit ligand in Purkinje cells provides robust evidence. This work will be of particular relevance to those interested in inhibitory synapse formation or the role of inhibition in Purkinje cell behavior.

eLife assessment

This manuscript presents a generally convincing set of experiments to address the question of whether the lateral parafacial area (pFL) is active in controlling active expiration, which is particularly relevant in patient populations that rely on active exhalation to maintain breathing (eg, COPD, ALS, muscular dystrophy). This study presents a valuable finding by pharmacologically mapping the core medullary region that contributes to active expiration and addresses the question of where these regions lie anatomically. Results from these experiments will be of value to those interested in the neural control of breathing and other neuroscientists as a framework for how to perform pharmacological mapping experiments in the future.

eLife assessment

This study presents important findings for understanding cortical processing of color, binocular disparity, and naturalistic textures in the human visual cortex at the spatial scale of cortical layers and columns using state-of-the-art high-resolution fMRI methods at ultra-high magnetic field strength (7 T). Solid evidence supports an interesting layer-specific informational connectivity analysis to infer information flow across early visual areas for processing disparity and color signals. While the question of how the modularity of representation relates to cortical hierarchical processing is interesting, the findings that texture does not map onto previously established columnar architecture in V2 are suggestive but would benefit from further controls. The successful application of high-resolution fMRI methods to study the functional organization along cortical columns and layers is relevant to a broad readership interested in general neuroscience.

eLife assessment

This manuscript describes a model to estimate what fraction of DNA from specific human tissues becomes cell-free DNA in plasma. This fundamental study, supported by convincing evidence, will be of great interest to the community, as the amount of DNA from a certain tissue (for example, a tumor) that becomes available for detection in the blood has significant implications for disease detection.

eLife assessment

This fundamental study identifies the homeodomain transcription factor Meis2 as a transcriptional regulator of maturation and end-organ innervation of low-threshold mechanoreceptors (LTMRs) in the dorsal root ganglia (DRG) of mice. The authors use histology, behavioral tests, RNA-sequencing, and electrophysiological recordings to provide evidence that conditional deletion of Meis2 in postmitotic DRG neurons causes gene expression changes together with targeting errors and altered sensory neuron responses, ultimately resulting in reduced sensitivity to light touch in mutant animals. The data presented are convincing, the discussion comprehensive, and the conclusions drawn justified.

eLife assessment

This is an important follow-up study to a previous paper in which the authors reconstituted CO2 metabolism (autotrophy) in Escherichia coli. Here, the authors define a set of just 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, and their data suggest possible roles of mutations in two other genes - crp and rpoB. This research will be particularly interesting to synthetic biologists, systems biologists, and metabolic engineers aiming to develop synthetic autotrophic microorganisms.

eLife assessment

Yang et al. investigate whether distinct sources of conflict are represented in a common cognitive space. The study uses an interesting task that mixes different sources of difficulty and reports that the brain appears to represent these sources as a mixture on a continuum in prefrontal areas. While the findings could be valuable to theory in this area, there are some concerns with the design and results, that raise uncertainty regarding the main conclusion of a shared cognitive space. The authors appropriately acknowledge these limitations while also highlighting the valid contributions that the study makes. Thus, while solid evidence is reported here, consistent with the central hypothesis, further experiments are required to support the strictest interpretation.

eLife assessment

SCARF1 is a scavenger membrane-bound receptor that binds modified versions of lipoproteins and has a major role in maintaining lipid homeostasis. This useful study reports the crystal structure of SCARF1 and identifies putative binding sites for modified lipoproteins. While some aspects of the analysis are incomplete, others are solid, and overall, the study advances our knowledge of how scavenger receptors clear modified lipoproteins to maintain lipid homeostasis.

eLife assessment

This important work describes a compelling analysis of DNA damage-induced changes in nascent RNA transcripts, and a genome-wide screening effort to identify the responsible proteins. A significant discovery is the inability of arrested cells to undergo DNA damage-induced gene silencing, which, is attributed to an inability to mediate ATM-induced transcriptional repression. Revisions are suggested that would significantly enhance and support the central claims of the study. This work will be of general interest to the DNA damage, repair, and transcription fields, with a potential impact on the cancer field.

eLife assessment

This study is partly useful as it corroborates what is already known about the elevated proliferation capacity of mid lobular hepatocytes in liver regeneration. Lineage tracing and scRNAseq studies are powerful for the investigation of such heterogeneous hepatocyte proliferation capacity. Nevertheless, based on experimental limitations, incomplete method description and inadequate data analyses the presented data are insufficient to support the proposed conclusions of a mesenchymal-hepatocyte hybrid population in the murine liver.

eLife assessment

This important study identifies a role for triglycerides and lipid droplets in spermatogenesis, with data supporting relevance of this finding across phyla. The work shows with convincing data that a triglyceride lipase is required cell-autonomously for germline differentiation into meiotic stages and haploid spermatids and that an increase in triglycerides is detrimental to spermatogenesis. This paper would be of interest to developmental and cell biologists working on gametogenesis.

eLife assessment

This valuable study investigates likely molecular mechanisms underlying the increasingly common deletions of the hrp2 and hrp3 genes of the human malaria parasite Plasmodium falciparum, that render parasites undetectable by widely used rapid diagnostic tests. The generation of additional long-read data, alongside a new analysis of 19,000 public short-read sequenced genomes, makes this the most detailed investigation currently available on this topic. The authors provide solid evidence for chromosomal breakage with subsequent telomere healing as the mechanism for hrp2 deletion, with more complex patterns for hrp3 deletion, but further methodological details would bolster confidence in the conclusions and enable replication of the results.

eLife assessment

This article provides a review and test of image-analysis methods for bacteria growing in the 'mother-machine' microfluidic device, introduceing also a new graphical user interface for the computational analysis of mother-machine movies based on the 'Napari' environment. The tool allows users to segment cells based on two previously published methods (classical image transformation and thresholding as well as UNet-based analysis), with solid evidence for their robust performance based on comparison with other methods and use of datasets from other labs. While it was difficult to assess the user-friendliness of the new GUI, it appears to be valuable and promising for the field.

eLife assessment

This study provides an important advancement of knowledge by showing neural functional compensation in the brains of healthy older adults completing a fluid-intelligence task. Validated whole-brain voxel-wide analyses and multivariate Bayesian approaches provide compelling evidence that supports the claims of the authors. The work delivers methods for quantifying reserve and compensation in future studies and will be of interest to researchers in the field of the neuroscience of healthy aging.

eLife assessment

This fundamental study addresses the question of how certain zooplankton achieve barotaxis, directed locomotion in response to changes in hydraulic pressure. The authors provide compelling evidence that the response involves ciliary photoreceptors interacting with motoneurons. This work should be of broad interest to scientists working on mechanosensation, cilia, locomotion, and photoreceptors.

eLife assessment

This important study provides a new way to enhance organ preservation. The authors provide solid evidence that an existing drug, SNC80, can rapidly and reversibly slow biochemical and metabolic activities while preserving cell and tissue viability. This study will be of interest to a broad set of readers interested in organ transplantation, tissue engineering, regenerative medicine organoids, and organ-on-a-chip engineering.

eLife assessment

This study provides insights into the developmental origin of endothelial cells found in blood vessels called pial collaterals. The work is important, as collateral capacity can strongly influence the trajectory of outcomes with vascular blockage, and the approaches are novel and overall convincing; however, some mechanistic claims are only partially supported, and collateral characterization is incomplete. Given the clear positive correlation between pial collateral flow and improved stroke outcome, this study will be of interest to vascular biologists and clinicians caring for stroke patients.

This sentence summarizes a growth mindset. They believe that intelligence can be grew and cultivated through hard work and education. They don't believe everyone has uncapped potential, but are more focused on the growth rather then the end goal.

This sentence summarizes a fixed mindset very clearly. It shows that a fixed mindset entails each person having their own set amount of intelligence and its hard set on that

reasons for german conformity - fear of nazi retaliation - maintaining appearances with other germans - pressure to conform - new opportunities in nazi society - disliked nazis but liked german unity - in search of national community - agreed w nazis socially and politically

eLife assessment

The present study offers valuable insights into the emergence of oscillations in neural networks. It underscores the importance of achieving a delicate balance between excitatory and inhibitory links, and deals with the topological conditions for oscillations. The study provides solid evidence in simple networks based on formal mathematical theory and advanced simulations, but the wider implications to biological networks would require a more detailed investigation into delays and nonlinearities.

eLife assessment

This study uses carefully designed experiments to generate a useful behavioural and neuroimaging dataset on visual cognition. The results provide solid evidence for the involvement of higher-order visual cortex in processing visual oddballs and asymmetry. However, the evidence provided for the very strong claims of homogeneity as a novel concept in vision science, separable from existing concepts such as target saliency, is inadequate.

eLife assessment

This study presents useful findings that describe how activity in the corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons) modulates sevoflurane anesthesia, as well as a phenomenon the authors term a "sevoflurane general anesthetic-elicited stress response". The technical approaches are solid, and the data presented is largely clear. However, the primary conclusion, that the PVHCRH neurons are critical for the mechanisms of sevoflurane anesthesia, is incompletely supported by the data.

eLife assessment

This useful study provides incomplete evidence for the functional roles of the human DCP1 paralogs in regulating RNA decay by DCP2. Using a combination of cellular-based assays and in vitro assays, the authors conclude that DCP1a/b plays a role in regulating DCP2 activity. This study makes a number of interesting and potentially relevant observations; however, a number of outstanding questions remain to be addressed. These results will be of interest to the RNA community.

eLife assessment

In their valuable study, Chen et al. aim to define the neuronal role of HMMR, a microtubule-associated protein typically associated with cell division. Their findings suggest that HMMR is necessary for proper neuronal morphology and the generation of polymerizing microtubules within neurites, potentially by promoting the function of TPX2. While the study is recognized as a first step in deciphering the influence of HMMR on microtubule organization in neurons, the reviewers note the current work is incomplete, with significant gaps and it would benefit from further exploration of the mechanism of microtubule stability by HMMR, the link between HMMR-mediated microtubule generation and morphogenesis, and the physiological implications of disrupting HMMR during neuronal morphogenesis.

eLife assessment

This manuscript presents a useful presentation of a new method for assessing the adhesion strength of axons with the use of a laser-induced shock wave. However, the strength of the evidence is incomplete as critical controls for calibration and time course are lacking.

eLife assessment

This useful study explores the phenomenon of glucose-induced mitochondrial repression, known as the Crabtree effect, in cells cultured under high glucose conditions. The study uses a variety of well-designed assays to support the authors' hypothesis, shedding light on inorganic phosphate-mediated metabolic regulation. The analysis and conclusions could benefit from a more rigorous approach, given the limited replication on a single yeast strain background and inadequacies in the normalization methods, leaving the evidence in parts incomplete.

eLife assessment

This important study highlights 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

The solid study addresses the role of extracellular matrix (ECM) in neuronal migration. The authors showed that the interaction between the ternary complex formed by tenascin-C, the chondroitin sulfate proteoglycan neurocan, and hyaluronic acid is important for the multipolar to bipolar transition in the intermediate zone (IZ) of the developing cortex.

eLife assessment

The study presents valuable findings concerning how a highly conserved signal transduction pathway helps budding yeast cells adapt their growth to nitrogen sources of differing qualities. However, the evidence is incomplete for the authors' main claim that the pathway adopts three distinct states depending on the nitrogen source. The presented data, particularly phospho-proteomic datasets, will be of interest to the cell growth signaling community.