Evaluated articles

Evaluation Summary:

Multiple inherited mutations in the epithelial CFTR anion-permeable channel cause cystic fibrosis through different molecular mechanisms that can be targeted by different types of drugs to treat the disease. Drawing from available structural information and double-mutant cycle analysis of patch-clamp recordings, Simon and Csanády find that one of the most common CFTR disease-causing mutations, R117H, disrupts an interaction between the R117 side-chain and a main-chain carbonyl that selectively stabilizes the open state of the channel. These findings may open new paths of exploration for treating patients carrying this mutation, and provide important mechanistic constraints towards understanding the gating mechanism of CFTR proteins.

(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:

Homeostatic plasticity helps to confine neural network activity within limits. In this study, the authors show that loss of PAR bZIP family of transcription factors leads to overcompensation of excitatory synaptic transmission and average network activity upon sustained activity deprivation. The work identifies an endogenous transcriptional program that constrains upward homeostatic response and whose activity is implicated in preventing aberrant network activity associated with epilepsy and other brain disorders. These are exciting results that address the question of broad importance. While most arguments are supported by data of high quality, further experiments would strengthen the claims about the relative contribution of excitatory and inhibitory mechanisms and clarify the nature of compensation.

(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:

This paper will be of broad interest to many fields, including drug discovery, cancer biology, and structure biology. It makes a significant advance in understanding the mechanism of action of hormone therapies for breast cancer, and how resistance driving mutations alter drug responses. The structural biology data has clear potential for strong impact though some additional analysis might be needed.

(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 manuscript focusses on a little studied, but highly interesting presumptive mechanosensory cell type in cnidarians, the 'hair cell'. The work shows that the POU-IV transcription factor is required for the maturation of this cell type in the sea anemone Nematostella vectensis. Because POU-IV transcription factors also play essential roles in the differentiation of mechanoreceptors in many bilaterian phyla, this suggests an evolutionarily ancient role of POU-IV in regulating mechanosensory identity. This study will hence be of great interest to developmental biologists and evolutionary biologists who are interested in the developmental evolution of neuronal cell types.

(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 name with the authors.)

Evaluation Summary:

Cholesterol has long been known to have significant effects on G protein-coupled receptor (GPCR) ligand binding properties and stability, and cholesterol/GPCR interactions have frequently been observed in high-resolution structures. However, relatively limited biophysical work has been done to investigate the mechanistic basis for cholesterol's effects. This manuscript describes the use of a sensitive 19F NMR probe to monitor conformational equilibria in a prototypical GPCR, the A2a adenosine receptor. These experiments, together with data from other NMR experiments, computational analysis, and G protein assays, show that the subtle effects of cholesterol derive in large part from modulation of membrane biophysical properties, in contrast to conventional allosteric modulators that exert their effects through direct long-lived receptor binding.

(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:

Smith et al. describes the propagation patterns of electrical activity in the brains of human epileptic patients. The authors demonstrate that interictal spikes, commonly observed electrical events in epileptic patients, propagate in a similar manner to seizures. This suggests that interictal spikes could be used in surgical planning, which would be of great interest to neurosurgeons and neurologists treating patients with medication refractory epilepsy.

(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:

This manuscript is of broad interest to developmental biologists and those studying transcriptional/epigenetic regulation of cell-specific and housekeeping gene programs. The work demonstrates that Polycomb complexes coordinate the regulation of distinct groups of genes during early embryogenesis, which offers interesting insights into how very early embryos differentially control housekeeping versus specific developmental gene promoters/enhancers. The data are of high quality, and the conclusions are insightful yet measured.

(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 #3 agreed to share their name with the authors.)

Evaluation Summary:

Kröger et al use 2-photon FLIM tomography to perform correlative imaging on in vitro, ex vivo and in vivo blood and skin cells to determine characteristic NADPH fluorescence lifetimes for M1 and M2 ends of macrophage spectrum. Interestingly, M1 and M2 macrophages, and all other tissue cells, had distinctive lifetime features leading to robust prediction of phenotypes, with ground trust defined by cytokine staining. They generate a decision tree that has ~90% accuracy in identifying M1 and M2 based on FLIM parameters and additional information. The ability to use two photon fluorescence lifetime tomography of NADPH fluorescence to identify macrophages and their inflammatory status in human tissues should open opportunities in experimental medicine and eventually medical diagnosis.

(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:

This paper is of outstanding interest to the broad community of scientists interested in biological energy conversion in general and rotary ATPases in particular. The authors show that the 36{degree sign} power stroke in ATP synthesis is subdivided into two steps of 11{degree sign} and 25{degree sign} in the E. coli enzyme, which serves as a comparatively simple model of the fundamental and universally important process of ATP production in mitochondria and chloroplasts. By combining precise and sophisticated single-molecule studies with directed mutagenesis, this work provides the much-needed functional context for recent high-resolution cryo-EM structures of rotary ATPases.

(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 paper is of interest not only for immunologists studying the inflammation, but also for biomedical researchers studying various biological processes using C57BL/6 mice. The data in this paper indicate that genetic differences between C57BL/6 substrains can affect reproducibility and generalizability in a broad range of biological studies with mouse models reported to date.

(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 work identifies the primary genetic mechanism underlying UV-absorbance variation across the geographic range of sunflower (Helianthus annuus) and provides evidence that suggests that abiotic variables, rather than pollinators, may maintain this variation in H. annuus and perhaps Helianthus broadly. While claims about direct links to fitness in natural population remain untested, the authors synthesize an ambitious amount of work from an impressive breadth of methods (from transgenics to ecology) that will be of high interest to ecologists and evolutionary biologists.

(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:

Kluger and colleagues investigated the influence of respiration on visual sensory perception in a near-threshold task and argue that the detected correlation between respiration phase and detection precision is liked to alpha power, which in turn is modulated by the phase of respiration. The main finding - that the moment-to-moment relationship between excitability and perception is coupled to the body's slower respiratory oscillation - poses a potentially important advance for advancing our understanding of how the brain-body system works as a whole.

(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 #3 agreed to share their name with the authors.)

Evaluation Summary:

Campylobacter jejuni is serious food-borne pathogen and understanding how the various products necessary for pathogenesis are regulated is a key step in preventing its growth and/or treating disease. Here, Sharma and coworkers describe the complex pathway that leads to the maturation of two complementary regulatory RNAs and how one of the RNAs antagonizes the other to relieve repression of a virulence-related gene.

(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 reviewers.)

Evaluation Summary:

In this study, the authors develop a model to understand the simplest form of collective migration represented by a pair of cardiopharyngeal progenitor cells. They propose that the collective migrates as a "supracell", with leader cells assuming a greater protrusive capability and trailer cells assuming greater retractive capability. They meticulously study the effects of leader-trailer and cell-matrix adhesivity, intracellular force distributions and noise on robustness of cell migration. They corroborate their simulation results with experiments. Overall, this study comprehensively demonstrates that migrating as a collective leads to more mechanically efficient and persistent migration than as a single motile cell.

(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 paper will have a high impact for all developmental and cell biologists who are interested in tissue patterning and organogenesis. It provides unexpected insights into the problem of regular spacing of sub-organ structures. The study is based on innovative live imaging technology with state of the art analysis tools.

(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.)

Evaluation Summary:

This manuscript by Jayaram and colleagues uses computational modeling approaches to examine how temporal filtering of an odor signal contributes to navigation success in different odor environments. The manuscript advances the literature in considering how different algorithms may be optimal for different environments. Further evidence is required to more convincingly prove the intriguing trade-off between frequency and "intermittency" sensing described here.

(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:

Mejias and Wang propose here the first large-scale model of the brain that actually performs a cognitive task. Previous models have focused on neural dynamics during the so-called "resting state", in which subjects are not performing any cognitive task - thus, resting. This study is therefore an important improvement in the field of large-scale modelling and will certainly become an influential reference for future modelling efforts.

(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:

The paper is of interest to RNA biologists, especially to those who study small RNAs. The findings deepen our understanding of the rules of DCL3 dicing and explain how 23-nt and 24-nt siRNAs in the RNA-directed DNA methylation pathway are produced. Overall, the data are of high quality and support the paper's conclusions.

(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 #3 agreed to share their name with the authors.)

Evaluation Summary:

This contribution is of interest to molecular phylogeny scientists in particular and to a broad public interested in early evolution in general, as it confirms the long-standing (but recently challenged) assumption that bacteria and archaea are separated by a long branch. It elegantly rebuts a recent study claiming that one of the common markers used for molecular evolution, ribosomal proteins, are actually ill-suited for deep phylogenies and that archaea and bacteria are much closer to each other than previously thought.

(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 show that a widely arborizing inhibitory interneuron AL reduces the variability of olfactory responses in at Drosophila Kenyon postsynapses in the mushroom body calyx, which receive inputs from the projection neurons (PNs) in the antennal lobe. The data support a model in which APL neurons, which also receive inputs from PNs, mediate scaled GABAergic feedback to normalize of postsynaptic responses in the calyx. The conclusions, based on detailed analysis of one odorant are mostly well 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. The reviewers remained anonymous to the authors.)