Evaluated articles

Evaluation Summary:

The manuscript by Carrasquilla and colleagues applied Mendelian Randomization (MR) techniques to study causal relationship of physical activity and obesity. Their results support the causal effects of physical activity on obesity, and bi-directional causal effects of sedentary time and obesity. One strength of this work is the use of CAUSE, a recently developed MR method that is robust to common violations of MR assumptions. The conclusion reached could potentially have a large impact on an important public health problem.

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

Evaluation Summary:

This addresses an important area of excitation contraction coupling failure of potential clinical translational importance. They report that progressive depolarization of the resting potential upon excitation contraction coupling results in a persistence of action potential generation in the face of a failure of Ca2+ release.

(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:

Nowicka et al., evaluated radiation dose and time dependent changes in the levels of selected serum miRNAs in human patients who received partial or complete myeloablative total body irradiation (TBI) and propose a panel of circulating miRNAs as potential radiation biodoismeters. The team employed next generation sequencing approach for discovery (or rediscovery) and quantification of selected responders by qRT-PCR using non-responsive miRNAs purified from exosomes in serum for evaluation of relative changes. Excellent bioinformatics and bio statistical methods are employed. However, critical biomarkers they propose as radiation biodosimeters have already been identified and published earlier. There is little novelty here and the translational significance of the study is moderate.

(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 article will be of interest to behavioral ecologists studying activity patterns in wild animals. Using accelerometry, rather than polysomnography, opens up exciting opportunities for studying animal sleep under natural conditions for relatively long periods.

(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:

Oligogenic inheritance is likely to be an important mode of disease risk for many male infertility traits, but few validated examples exist. This clear documentation of oligogenic effects on mouse sperm is significant for both the sperm abnormality field and for the broader male infertility 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. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

Circadian disruption is widespread in our modern 24/7 society, leading to an increased prevalence of common diseases including type 2 diabetes. The authors conducted an unbiased screen for small-molecule compounds that can restore the attenuated insulin secretion from pancreatic beta cells caused by a disrupted circadian clock. They identified ivermectin and its clock-controlled target, the P2Y1 receptor, which regulate glucose-stimulated Ca2+ influx and insulin secretion in beta cells.

(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 details the function of the N-Myc downstream regulated gene 1 (NDRG1) during induced hypoxia using the anoxic developing zebrafish as a model system. With some additional support for the central claim of a switch for metabolic suppression, this paper will be of interest to scientists with a focus on kidney development, factors that regulate hypoxic survival, and metabolism in response to stress conditions.

(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 potential interest to investigators in the bone field. The study provides evidence of CypD regulation of osteoblast differentiation and offers new insights into it's transcriptional regulation. Overall, although the findings are compelling and have the potential to advance the field, several conclusions require additional data or clarification and there are some missed opportunities to strengthen the manuscript.

(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 paper will be of interest to the large class of neuroscientists who investigate brain plasticity. It identifies short-term plasticity in a subcortical region, the ventral division of the pulvinar, following monocular deprivation in adult humans. The work is believed to extend our research focus on the topic of ocular dominance plasticity from mainly the cortex to a larger brain network including the subcortical stages of visual processing. This is an intriguing possibility, but further evidence is required to fully support the claims.

(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 is a multifaceted study of the epithelial to mesenchymal transition (EMT) in live cells. EMT is relevant for cancer, development, and wound healing. The authors were able to discern two possible cell transition path categories without multi-color labeling or other advanced experimental approaches, which could be impactful. The study draws on a wide range of experimental, data science, and modelling tools and techniques.

(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:

The overarching goal of this study was to identify eco-evolutionary feedbacks between plant community diversity and global change drivers. The authors aimed to test the hypothesis that a decline in species richness due to various global change drivers selects for traits that will make species more vulnerable to the further effects of these drivers, amplifying thus the initial diversity decline. This research is of prime importance to botanists, plant ecologists and ecosystem ecologists wanting to understand the effects of global change on plant diversity and productivity.

(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:

Nichols et al. developed and characterized the first fluorescent sensors for several nicotinic receptor partial agonists relevant to smoking cessation. It is potentially a major advance for the field. They leveraged crystallography to understand the mechanism by which the ligands enhance fluorescence, then characterized top sensors for sensitivity, selectivity, and kinetics, and their utility in plasma membrane and ER sensing in neurons and cell lines. The tools developed by this team will enable investigators to track nicotinic receptor partial agonists in different subcellular compartments with relatively fast time resolution.

(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 carefully executed study suggests new mechanisms by which Serum Response Factor (Srf) regulates transcription. The manuscript reports the effects that loss of Srf function has on different neural crest lineages in the mouse. The authors conclude that within neural crest, the main function of Srf is in the cardiac neural crest lineage where it regulates cytoskeletal genes.

(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 regulation of cell growth is crucial for our understanding of how cells control their size as well as how they balance cell mass and volume. While recent studies carefully measured single cell mass trajectories during the cell cycle, revealing complex growth patterns, the volume growth patterns of animal cells are poorly understood. In this interesting study, Cadart et al. now present high-precision measurements of 1700 HeLa cell growth trajectories and offering evidence for the mechanisms that regulate volume growth-rate fluctuations. This is an important demonstration of cell autonomous volume 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

This study investigated the role of transient receptor potential vanilloid 4 (TRPV4) in pressure overload-induced cardiac hypertrophy. The expression of TPRV4 is increased in both heart failure and pressure overload-induced cardiac hypertrophy models. The TRPV4 deletion or inhibition ameliorated the hypertrophy cardiac pathology. The authors propose that TRPV4 is a potential therapeutic target for cardiac hypertrophy.

(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 paper will be of broad interest to readers who study anatomical connections of the brain. It demonstrates the efficacy of a cutting-edge viral tracing technique in mapping excitatory projections in macaque monkeys. The work describes the generation of a projectome from the macaque vlPFC cortex across the rest of the brain using AAV2/9-CaMKIIa-Tau-GFP labeling and imaging with high-throughput serial two-photon tomography. The comparison with imaging techniques available in humans (diffusion tractography) will also be of interest to research in human brain anatomy.

(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 will be of interest to researchers interested in the influence of prenatal exposures on infant health. The authors investigate the impact of the season of conception on child DNA methylation levels in two independent cohorts from the Gambia and identify a set of CpGs that are tightly regulated during development. The data support the main conclusions of the manuscript, but some of the analyses could be improved (i.e. possible presence of residual confounding). There is also limited evidence for the functional importance of the observed associations.

(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 interest to cell biologists, biochemists and biophysicists interested in how adhesion and signaling proteins at the cell surface help cells (and especially neurons) interact and perform self/non-self-recognition and self-avoidance. The authors provide the first extensive biophysical dataset examining a large subset of potential trans (across two cells) and cis (on the surface of the same cell) interactions between different isoforms of the ~60 clustered protocadherins (cPcdhs). There data show that all tested trans interactions are strictly homophilic and that not all possible cis interactions are equivalent. These results provide additional layers of complexity and constraints on how this protein family can provide neurons with the ability to perform self-recognition and self-avoidance.

(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 presents evidence that autophagosomes fuse with phagosomes and that this promotes the degradation of phagocytosed cell corpses. The study also resolves controversy in the field about the question why genes involved in autophagy affect cell corpse engulfment and degradation. With some additional data to solidify the main conclusions, the work will be of interest to a broad cell biology audience.

(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 name with the authors.)

Evaluation Summary:

This paper will be of interest to the lipid metabolism and transporter communities. Fatty acids that are too long to be transported into mitochondria are instead transported into peroxisomes for their break down i.e., beta-oxidation. The authors have determined the cryo-EM structure of human ABC transporter ABCD1 (ALDP), which translocates very-long-chain fatty acids (VLCFA) conjugated to coenzyme A across peroxisomal membranes, in complex with its substrate. While the work is well done, it is unclear what new mechanistic insights are gained from the ALDP structure. Also, the proposed conformational differences based on AlphaFold models should be taken with caution.

(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.)