Evaluated articles

Evaluation Summary:

This paper is of interest for a wide range of readers who study the biology of lipid modifying enzymes, especially as it relates to interfacial reaction kinetics in biological membranes. This study aimed to obtain detailed biochemical insights into the mutual relationship between PI(4,5)P2 lipids and their kinase PIP5K, which engage in an exciting pattern-forming reaction on membranes. The authors find cooperative recruitment of PIP5K to the membrane, oligomerization-enhanced catalytic efficiency and indications of allosteric regulation. Although of very high interest and featuring mostly convincing data, there are concerns about the interpretation of whether the observed phenomenon is dimer specific or related to higher-order oligomerization. In addition, there are inconsistencies in the data presentation.

(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 reported crystal structure of nearly-full-length cGMP-dependent protein kinase β (PGK1β) provides new insights into how the activity of the PKG catalytic domain is held in check by intramolecular interactions between both the upstream regulatory cGMP-binding domains and the autoinhibitory segment and the catalytic domain, and how cGMP binding to the cGMP-binding domains can relieve these inhibitory constraints leading to an increase in catalytic activity. The structure of the activating PKGIα R177Q CNB-A domain mutant, which resembles a cGMP-bound wild type CNB-A domain, provides a nice explanation for how this point mutation activates PKG Iα and leads to the development of the TAAD (Thoracic Aortic Aneurysms and Dissections) syndrome. The work will be of specific interest to the cyclic nucleotide community, and to the broader signaling community in general.

(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 article applies a systems biology approach to understand the mechanism of action of 3-chloropiperidines (a class of anticancer drugs) in cancer cells and evaluate their sensitivity to drugs. It integrates transcriptomic and open-chromatin data and utilizes sound statistical frameworks for building a sensitivity model. The author's methodology can be applied to early-stage drug discovery. This paper will be of interest to the large class of people who tried to understand how omics data will help drug discovery. It sets a new framework to integrate transcriptome and chromatin accessibility data to identify the key mechanisms of action and provide potential disease targets, which will help speed up the early phases of drug discovery.

(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. All three reviewers agreed to share their names with the authors.)

Evaluation Summary:

This study is of interest to the readership interested in the different cell types present in the mouse adult ovary and shows how cellular states change during the four phases of the estrous cycle. This is a valuable resource for the community.

(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 authors first develop a new flexible and robust method to detect deviations from Mendelian inheritance in genomic data from gametes. The authors then apply this method to study deviations from Mendelian inheritance in human sperm data, but find no evidence for it. Even though this is a negative result, and overall the results are expected based on previous studies. the reviewers agreed that the research is rigorous and valuable.

(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:

Bae et al. examine the regulatory role of the PH domain of the AKT Ser/ Thr kinase, finding a key set of interactions that mediate autoinhibitory interactions between PH and kinase domains. The work provides additional mechanistic understanding of the E17K mutation, a common variant in human cancers. This manuscript will be of great interest to scientists focused on protein kinase regulation and molecular mechanisms that control signal transduction.

(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:

Chaudhary and colleagues follow up their preliminary study on mitochondrial genome copy number in AML with this current study by looking if the expression of specific genes encoding mitochondrial components could provide further insight into AML prognosis. Multivariate analysis was used to identify those genes whose expression was prognostic of patient outcome, which led to the identification of three mitochondrial genes whose expression was used to build a multivariate risk model for childhood AML patients. Altogether, the work by Chaudhary and colleagues interestingly builds on their previous work and suggests that mitochondria may influence AML outcomes, and measuring mitochondrial parameters may help assess patient risk. However, the authors will need to identify the novelty of their findings over the previous reports from their own group.

(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 models the evolution of simple multicellular life cycles using evolutionary game theory. The authors discuss natural selection between different life cycles by modeling growth, fragmentation, and interactions between propagules, discovering conditions for selection of a single life cycle or coexistence of multiple ones. Overall, the model is biologically intuitive, the results are rigorous, and the implications for the evolution of multicellularity are interesting.

(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 manuscript is of broad interest to readers in the fields of vitamin D and obesity. It utilises a Mendelian randomization framework to separate the genetically predicted effects of adiposity at two timepoints in the lifecourse, childhood and adulthood. The key claims of the manuscript are well supported by the data. Higher childhood body size had a direct effect on lower vitamin D levels in early life, while in midlife, childhood body size impacted on adult obesity to result in lower vitamin D levels.

(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 focuses on identifying how metabolism can influence the response of cartilage cells to inflammation. This has relevance to the painful disease known as osteoarthritis. Modulation of cell metabolism in the right direction can serve to protect joint cartilage from the negative effects of inflammation which causes onset and disease progression.

(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:

Bouvette et al. describe a new software for fully automated cryo-EM sample screening and data acquisition, making use of deep-learning-based algorithms for the detection of regions and objects of interest. This is the first example of software for fully automated grid screening, which is of great interest to the cryo-EM community, to free skilled researchers and engineers from a serious of tedious tasks, so that they can devote more time to method development or finding answers to interesting biological and medical questions.

(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:

We all have had days where there were multiple distinct memorable experiences that we successfully remember as distinct. This paper for the first time focuses on the important question of whether the resting/sleeping hippocampus maintains a clear distinction between replays of different environments and finds that in fact, replays of different tracks are distinct in the sense that both the right sets of neurons are coactive AND their firing rates in replay reflect their firing rates during experiences.

(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 manuscript by Yue et al describes studies investigating the role of sensory neuron versus arteriole expression of Trpv1 in body temperature control. This is a detail about the contribution of different cells which has significance because of the reported on-target side-effect of hyperthermia by Trpv1-antagonists. The study shows that the effects on body temperature are predominantly produced through sensory neurons. From these studies it is speculated that the actions of Trpv1 might be pharmacologically modified to permit dissociation of the effects on neurogenic inflammation and the undesirable effects on body temperature.

(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. All reviewers agreed to share their names with the authors.)

Evaluation Summary:

This experiment investigated the link between the role of B lymphocytes to neutrophils for the achievement of LPS tolerance. The authors found that B cells can modulate the tissue-damaging properties of neutrophil leukocytes by influencing neutrophil Cxcr4 signaling in a mouse model of bacterial sepsis.

(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 study shows a direct link between inflammation and cholesterol metabolism in endothelial cells. Specifically, the authors show a pathway by which the major inflammatory factor, NF kappa B, activates a gene called STARD10, which, in turn, leads to the activation of the cholesterol biosynthetic pathway. The study, therefore, provides important insights into the inter-relationship between cholesterol metabolism and inflammation at the molecular level.

(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 identifies pH as a common factor that underlies eco-evolutionary dynamics related to priority effects, which play an important role in community assembly. Using multiple lines of evidence, the data support the overall conclusions of the manuscript that pH-mediated priority effects in the nectar microbiome are the drivers of alternative community states. This manuscript will be of broad interest to readers in ecology and evolutionary biology.

(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 manuscript shows that bisphosphonate-related osteonecrosis of the jaw, a rare complication of osteoporosis treatment, was prevented in mice using a novel treatment which works by reversing the associated oral inflammation. The work in this manuscript has the potential to be impactful if limitations are addressed. It will be of interest to investigators in the bone and dental fields who conduct pre-clinical research.

(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:

Using data from a tetraplegic individual, the authors show that the neural representations for attempted single finger movements after multiple years after the injury is still organized in a way that is typical for healthy participants. They also show that the representational structure does not change during task training on a simple finger classification task, and that the representational structure - even without active motor outflow or sensory inflow - switches from a motor representation to a sensory representation during the trial. The results have important implications for the use and training of BCI devices in humans.

(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 present an analysis of SARS-CoV-2 variant of concern movements into and within the Netherlands. The primary finding is that flight bans (in conjunction with other NPIs) were grossly insufficient at stopping the invasion of new variants into The Netherlands over a one-year period. Although consistent with similar analyses of other regions early in the pandemic, this manuscript provides additional evidence of the inadequacy of flight bans at stopping the spread of variants that are already widespread globally, especially (but not only) when importations continue via ground travel. The reviewers have questioned the rigor of the statistical models and the presentation of the main result, including analyses that were included but do not appear to contribute to the main argument.

(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 will be of interest to scientists working to understand Chlamydia trachomatis persistence, and host pathogen interaction in general. The authors report the surprising observation that the mechanism of restriction of bacterial growth is through the inhibition of c-Myc signaling by IFNg as opposed to IDO-dependent depletion of tryptophan levels, as had been previously suggested.

(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.)