Physiology

eLife assessment

The authors have established new formulas to predict maximum oxygen uptake for cyclists and runners based on submaximal exercise testing and anthropometric characteristics. This is an important study with a large and comprehensive dataset, which may be helpful for many exercise labs. The work is convincing, using appropriate and validated methodology in line with the current state-of-the-art, as shown by references to common exercise books.

eLife assessment

This valuable study provides insights into mechanisms of placental aging and its relationship to labor initiation. The authors provide solid evidence and have thoroughly investigated the molecular characteristics of normal placental aging using in vivo and in vitro model systems and human placental tissue analysis to corroborate their findings. This work contributes to existing work in placental aging and preterm birth and will be of interest to reproductive scientists.

eLife assessment

This important paper provides new insight into the effect of extra-copies of a chromosome, thus aneuploidy, on body metabolisms in mammals. The authors used various solid analyses on the metabolisms and physiology of the transgenic mouse with most of human chromosome 21 and presented convincing results to support the authors' claims. The work would be of interest to researchers who work on the physiology and biochemistry of body metabolisms in mammals.

eLife assessment

This paper reports the fundamental discovery of a new function of neutrophil in specifically clearing apoptotic hepatocytes by penetrating the cells rather than engulfing them without causing inflammation as a part of tissue homeostasis. This solid study transforms the way we think about role of neutrophil in pathogenesis of autoimmune liver disease.

eLife assessment

In this study, the authors made important progress in understanding bone metabolic defects of T2D. They have established a valuable model that could mimic some aspects of T2D in mice. Particularly, the study provided important evidence showing bone turnover and metabolism were in defects, and changes in glycolysis would rescue bone defects in T2D. Overall, the authors provide compelling evidence from dynamic histomorphometry, C13 isotype labeling in vivo, scRNA-seq, and metabolic assays to demonstrate that the defective glucose metabolism causes osteopenia associated with T2D.

eLife assessment

Poison frogs sequester alkaloids to make themselves toxic or unpalatable to predators, but how this sequestration occurs is not well understood. This valuable study identifies an alkaloid-binding protein in the plasma of poison frogs, which may help explain how these animals are able to sequester a diversity of alkaloids with different target sites. The supporting evidence is solid and the study adds to our understanding of how toxic animals resist the effects of their own defenses.

eLife assessment

This important paper advances our understanding of the role of lipid peroxidation in loss of muscle mass and force-generating capacity during aging and hind-limb suspension. The evidence is in general solid, drawing from experiments in vivo and cell culture using multiple types of manipulations of the formation of lipid peroxides although some weaknesses were identified. The results should be of interest to those who study the molecular basis for sarcopenia and disuse atrophy of skeletal muscle.

eLife assessment

This paper provides a valuable systematic analysis of proteomic profiles associated with a particular murine Ryanodine receptor abnormality. Its analysis technique provides a solid and systematic set of data summarising the differences in different muscle types. The work emerges with insights into pathological mechanism of congenital muscle diseases linked to mutations in a range of other genes related to excitation contraction coupling in workers within the skeletal muscle field.

eLife assessment:

Bone marrow stromal cells (BMSCs) can differentiate into a variety of cell types such as osteoblasts, chondrocytes, and adipocytes. The authors of this important study provide compelling and strong evidence that ablating O-GlcNAc transferase (OGT) in BMSCs impairs bone formation but promotes marrow adiposity. The results show that the balance of osteogenic and adipogenic differentiation of BMSCs is controlled by reciprocal O-GlcNAc regulation of lineage-specifying transcription factors, and highlights the importance of an intracellular glycosylation process of specific proteins in bone formation and bone marrow adipocytes.

eLife assessment

This study describes an interesting approach using PEGylated isoprenaline to selectively activate beta-adrenergic receptors in the surface sarcolemma of ventricular myocytes. While the concept is compelling, and the core of an interesting and impactful study is presented, the results are preliminary and incomplete at this stage, and would benefit from more rigorous validation of the approach. The work will be of interest to cardiac cell biologists and pharmacologists.

eLife assessment

This manuscript reports novel and important findings on the mechanisms of regulation of CRAC channels. Collectively, the work represents an important conceptual advancement, showing that stromal interaction molecule-1 is not necessary for Ca2+-dependent inactivation of the Orai1 channel and that Orai1 likely contains a Ca2+ sensor for autoregulatio. The experiments are carefully conducted, and the data is of high quality and support the major conclusions of the authors.

eLife assessment

In this work, the authors provide convincing evidence about the existence of two distinct osteoclast populations with specific expression profiles and properties and show that the probiotic yeast S. boulardii may be useful in managing inflammation-mediated bone loss, including estrogen deprivation-mediated osteoporosis. The reported study aims to bring the concept of heterogeneous osteoclasts into a proof-of-principle therapeutic application, which may mean that the use of probiotics might combat osteoporosis towards a better bone quality than current therapies. The molecular mechanism of how the probiotic yeast S. boulardii treatment acts via the receptors remains obscure since it might act via changes in the gut permeability or by components directly released by the fungus.

eLife assessment

This study presents valuable comprehensive data that underpin the enhanced ventricular arrhythmogenesis in elite trained athletes. The study is logistical challenge and the multiscale approaches used is a strength of the study. The data presented are strong and support most of the authors' claims.

eLife assessment

This study presents a valuable finding of the role of under investigated pathway associated with development of placental oxygenation during pregnancy. The evidence supporting the claims of the authors is incomplete, although inclusion of a larger number of patient samples and an animal model have strengthened the study. The work will be of interest to developmental biologists working on placental function.

eLife assessment

Slusarczyk et al demonstrate that red pulp macrophages (RPM), specialized splenic cells that clear senescent red blood cells through erythrophagocytosis, show diminished function in aging mice. This impairment leads to retention of hemolytic red blood cells and formation of extracellular aggregates which further exacerbate RPM demise. Iron restriction alleviates most of these symptoms in aging RPMs. They propose RPM collapse as an early indicator of aging that could be reversed through iron limitation.

eLife assessment

Masschelin et al. investigate the role of Vitamin B2 (riboflavin), an essential cofactor for FAD and FMN coenzymes involved in the electron transport chain and TCA cycle, in fasting glucose metabolism. This study phenotypes B2-deficient mice liver and provides valuable data on genes and metabolites that are changed with B2 depletion +/- Fenofibrate administration. The work employs solid methodology and will be of interest to liver physiologists interested in fasting in the context of PPAR.

Evaluation Summary:

By the use of liver specific gene knock-out approaches Tang et al have clearly documented an important role for an endoplasmic reticulum sorting receptor, SURF4, in the efficient secretion of PCSK9, a protein in circulation that binds to and enhances the intracellular uptake and degradation of the low density lipoprotein receptor. As a consequence of liver specific knock-outs, adult mice survive well with an exceptionally lower level of circulating cholesterol, triglycerides and various lipoproteins. These compelling results reinforce the prospect for the development of therapeutic approaches in cholesterol and LDL reduction by targeting the intracellular association of PCSK9 and the SURF4 receptor. The work is elegant and complete with the only concern that some of the work and results overlap work published previously by some of these authors.

(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.)

eLife assessment

The complex mechanisms through which diet impact Parkinson's Disease are unclear, limiting the ability to guide patients to an optimal diet. Here, researchers use a mouse model to test the impact of dietary fiber, revealing changes in gut microbes and immune cells in the brain. This study raises intriguing hypotheses about how diet-induced changes in the microbiome could lead to changes in brain function.

Evaluation Summary:

The study provides evidence that specific transcriptional responses may underpin the observation that metabolic rates often scale inversely with body mass. The conclusions are supported by direct measurement of metabolic fluxes in mouse and rat livers, although generalizations to other settings remain to be rigorously tested. The study has broad implications for researching and studying animal metabolism and physiology.

(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 effective approach for targeting select subsets of enteroendocrine cells described here will be important for neuroscientists, endocrinologists, microbiologists, and other scientists studying nutritional biology. The study reveals new detail of how enteroendocrine cells signal through spinal and vagal sensory neurons to control immediate behavior and to guide learning about potential food sources. Overall, the approach is well thought out and the results are interesting and unexpected.

(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.)