Evaluated articles

Evaluation Summary:

This work examines how METTLL18-mediated RPL3 histidine methylation on 245 position regulates translation elongation and protects cells from cellular aggregation of Tyr-rich proteins. The study hints at the existence of a "ribosome code" and how posttranslational modification of ribosomal proteins could affect translation.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

Brodbeck and colleagues make a strong contribution to the field of neurolinguistics by asking whether speech comprehension uses local (e.g., sublexical) or global (e.g., sentences) contextual probabilities. To tackle this, they recorded participants with magnetoencephalography while they listened to a story. The authors assessed which of three possible speech models best explained brain activity using state-of-the-art analyses and information-theoretic measures. The authors report strong and valuable evidence for both local and global contextual analyses supporting the coexistence of both hierarchical and parallel speech processing in the human brain.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

When a cell undergoes rapid shrinking, excess plasma membrane becomes available. The authors show that excess plasma membrane forms very small bleb-like evaginations that disappear after a few minutes. They show a new role for the I-BAR protein IRSp53 and Arp2/3-dependent actin polymerization which surprisingly leads to the flattening of the bud instead of its growth, as it is the case in filopodial protrusions. This manuscript will be of general interest to cell biologists working on membrane-cortex interactions.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This is an innovative and important paper with interest to basic and translational neuroscientists that demonstrates the power of experimental models to advance our understanding of human disease. The authors focus on early-life epilepsy, a devastating and common disorder, and specifically on genetic epilepsies generated via pathological sequence variations in the hyperpolarization-activated nonspecific cation (HCN) channel subtype 1. They delineate the epileptic phenotype and demonstrate some of the potential mechanisms leading to the generation of spontaneous seizures in genetically engineered mice.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

The manuscript by Yanofsky et al. describes the high-resolution structure of the CIII/CIV super-complex from Mycobacterium smegmatis bound to the anti-tuberculosis drug Q203 which is currently in clinical trials. The authors also provide biochemical data for inhibition of purified CIII/CIV and add important new information regarding the mechanism of Q203. This is an important contribution that will be of broad interest to the field of bioenergetic and tuberculosis, as telacebec represents one of few novel drug classes with potential for treatment of tuberculosis and other mycobacterial infections.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

The authors investigate the contribution of a CTCF binding site located 3' of the beta-globin locus to the relative expression of the genes within the cluster. Their results serve to further clarify a longstanding model for how relatively high levels of fetal beta-globin are observed in some individuals harboring a deletion of this region, and contribute to existing models of the function of CTCF binding sites in genome organization.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This paper is of broad interest to virologists, immunologists, and structural biologists as it provides new insights into how the biophysical properties of viruses shape the development of immune responses. Overall, the data presented support key claims of the paper, and the strengths and limitations of the approach are properly acknowledged. However, the working model and its implications could be clarified and extended.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

All-trans retinoic acid (atRA) is a potent regulator of synaptic function known to be critical for certain forms of homeostatic plasticity. Previous work by the Vlachos group established that atRA also modulates synaptic function in human cortex and linked the synaptic effects of atRA to the spine apparatus protein synaptopodin. As a follow up study, the present work investigated the effect of atRA in the hippocampus. The authors found that atRA can play a key role in modulating enduring forms of synaptic plasticity in the dentate gyrus of the hippocampus even when it does not seem to drive overt changes in basal synaptic function, and this "metaplasticity"-related effects also require synaptopodin. Together, these studies establish a critical role of atRA in modulating synaptic transmission and plasticity at multiple regions of the human brain.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors demonstrate that selective inactivation of carnitine acetyltransferase (Crat) – a key metabolic enzyme – in AgRP neurons attenuates the response of AgRP neurons to peanut butter (PB) chips, the release of dopamine in the nucleus accumbens, and the motivation to work for food when mice are fasted. The strength of this study is the demonstration that metabolic sensing by AgRP neurons is somehow linked to dopamine release in the nucleus accumbens, but a weakness is that it is unclear how the lack of Crat in AgRP neurons affects their responsiveness to PB chips or how AgRP neurons regulate dopamine release.

Evaluation Summary:

In mammals the cellular retinaldehyde binding protein, CRALBP, is expressed in the pigment epithelium (RPE) and in Müller glial cells (MGCs) in the retina. Zebrafish has two copies of the gene, each expressed in one of the cell types. By knocking out each gene with CRISPR/Cas9, the authors could show that it is the copy expressed in the RPE that is essential for turnover of retinal and for cone function. Thus, the zebrafish gene duplication suggests that the RPE role of CRALBP is the important one also in humans, implying the RPE as target for future gene therapy in humans with mutations in CRALBP.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript provides a deep characterization of transcriptional regulation and conservation across key stages of complex multicellular development during mushroom formation. The authors present evidence for extensive allele-specific expression that includes many developmentally regulated genes that appear to have evolved recently. These findings help underscore how the tuning of gene expression and gains of new genes, the function of which will need to be unraveled in future, are likely the basis for the evolution of complex morphologies in fungi. This work should be of broad interest to evolutionary biologists, and especially to those studying the evolution of gene regulation.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #4 agreed to share their names with the authors.)

Evaluation Summary:

This technical paper describes a novel strategy for conditional mutagenesis in zebrafish. The method employs the authors' previously reported GeneWeld CRISPR/Cas9 targeted integration strategy to allow target genes to be "turned off" or "turned on" in a tissue-specific manner. Once fully validated, the approach would provide a valuable new addition to the "zebrafish genetic toolkit" that is likely to be widely used for assessing cell- and tissue-specific gene function in this model organism.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript is of considerable interest to neuroendocrinologists and other neuroscientists because it provides important insights into mechanisms controlling the synchronous activity of a specific subpopulation of hypothalamic neurons. Luteinizing hormone is secreted from the pituitary gland in pulses which vary over the estrous cycle. The pulses arise by patterned secretion of a hypothalamic 'releasing factor', the secretion of which is itself governed by a population of hypothalamic neurons that express the neuropeptide kisspeptin. The paper by Voliotis et al. combines novel experimental evidence from transgenic mice with an elegant mathematical model to analyze how the kisspeptin neurons generate the varying pulsatile patterns.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This paper investigates the role of common human genetic variation in explaining the relationship between host genetics, red blood cell physiology, and susceptibility to Plasmodium falciparum (the parasite responsible for malaria). It finds evidence that common variants in a small set of red blood cell proteins predict parasite invasion and growth rates. Contrary to hypotheses about ancestry-associated malaria selection, these variants are not more common in African ancestry populations. The approach used to select host factors that impact parasite fitness is pragmatic especially in the context of a small sample size, but the high predictive accuracy (despite moderate within-subject assay replicability) and the uncertain influence of including closely related family members in the analysis, raises some concerns about generalizability beyond the study sample.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript investigates the plastic properties of synapses impinging on pyramidal neurons in the piriform cortex from the lateral olfactory tract (LOT) and intracortical inputs. Their findings uncover some of the location and pathway-dependent plasticity rules and challenge the notion that LOT inputs (carrying direct odor information from the bulb) become "hardwired" after the critical period. The results provide novel information about how activity and experience alter synaptic communication in the olfactory circuit in a synapse-type specific manner.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This paper will be of interest to the large class of neuroscientists who perform network analyses and are interested in the processing of visual information. It sets a new standard in connectomic analysis because is combines EM data of a whole fly brain with fluorescent labeling of specific neurons. The key claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

The Codetta method developed by Shulgina and Eddy is a powerful approach for inferring codon reassignment by comparative analysis of bacterial and archaeal genomes. Given the rapid advances of genomic and metagenomic sequencing, this will be an important tool for elucidating the genetic codes employed by prokaryotes.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Attempts to produce effective vaccines against HIV have not yet been successful, with the lack of understanding correlates of protection being a significant limitation. This paper analyses gene expression in a number of human and non-human primate vaccine trials and identifies a profile that appears to correlate with protection from infection. This profile is linked primarily to monocytes and the ability of these cells to mediate antibody dependent cellular phagocytosis. The work has implications for ongoing attempts to generate effective vaccines against HIV and perhaps other viral diseases.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study investigates the important question of how vasopressin neurons, which are critical for fluid balance, are rapidly activated or inhibited when mice begin to eat or drink. The study presents useful anatomic data on connectivity between these neurons and other structures and tests a broad range of possible inputs that could mediate these effects. The conclusions are largely supported by the data.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript describes a novel tool for tracking synaptic plasticity at the single synapse resolution with a SEP-tagged GluA1 receptor expressed in a transgenic mouse. The authors rather convincingly demonstrate that this tool does not disturb synaptic physiology or mouse behavior. They also show that this tool can be used to measure the distribution of synaptic weights and its variation during a plasticity protocol in barrel cortex. This tool is useful for more quantitative measurements of synaptic strength in vivo, although some revisions would help making a convincing case of the usefulness of this tool with respect to previous methods. Genetic specificity of the expression of the construct is also a concern.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)