Physiology

eLife assessment

This article studies how a human mutation in a specific potassium channel causes altered islet cell function and monogenic diabetes. The work uses CRISPR-engineered mice to show that the gain-of-function mutation causes increased potassium flux, reduced insulin secretion, and impaired glucose tolerance. The convincing data substantially support the conclusions, and the work is important for understanding islet cell function and glucose homeostasis.

eLife assessment

This fundamental study advances our understanding of the cell specific treatment of cone photoreceptor degeneration by Txnip. The evidence supporting the conclusions is convincing with rigorous genetic manipulation of Txnip mutations, however, there are a few areas in which the article may be improved through further analysis and application of the data. The work will be of broad interest to vision researchers, cell biologists and biochemists.

eLife assessment

This important study combines experiments and theory to develop a sex-based in silico model of arterial myocytes. The ionic currents of the model and its sex difference based on experimental data and comparisons of model properties with experimental data at the single cell and tissue scale are convincing. If the rigor used to assess the model (specifically the simplicity of the 1D vessel model) was improved, and there was an addition of quantitative analysis of the data examining similarity between male/female experimental/simulation, the paper would be improved.

eLife assessment

This convincing study demonstrates a potentially important role for the factor Numb in skeletal muscle excitation-contraction coupling. Numb knockout reduced contractile force. The authors thus demonstrate a novel role for Numb in calcium release in skeletal muscle.

eLife assessment

This useful study has the potential to reveal insights into how calcineurin influences C. elegans lifespan through its role in controlling the defecation motor program. Currently, the evidence in support of the conclusions is still incomplete, largely due to concerns about partial gene inactivation by RNAi. The inclusion of experiments using a tax-6 null allele would mitigate these concerns.

eLife assessment

This useful study has the potential to reveal insights into how calcineurin influences C. elegans lifespan through its role in controlling the defecation motor program. Currently, the evidence in support of the conclusions is still incomplete, largely due to concerns about partial gene inactivation by RNAi. The inclusion of experiments using a tax-6 null allele would mitigate these concerns.

eLife assessment

This important study provides a substantial advance with a method by which a protein target resistant to therapeutic approaches can be uniquely modulated by a cellular protein kinase ferried by nanobodies to a precise molecular site of recruitment. Evidence for this major claim is compelling, but evidence for some of the minor claims seems incomplete. The work will be of broad interest to cell biologists, cardiovascular researchers, and drug developers.

eLife assessment

The tool developed and implemented in this study has valuable significance for the combined analysis of large, diverse omics datasets, but some of the methodology is incomplete. Regarding the strength of evidence, there are some more significant concerns regarding potentially inadequate controls for false discovery and multiple testing corrections.

eLife assessment

This valuable study examined the use of dantrolene, a Ryanodine Receptor stabilizer, in slowing pathological progression of pressure-overload heart failure in a guinea pig model and reducing arrhythmias. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for future studies of dantrolene in Ca2+ handling in ROS production and further deterioration of cardiac function in chronic heart failure.

eLife assessment

This is an important paper that links distinctive stinging behavior of two related anemones occupying different ecological niches to varying inactivation properties of voltage-gated calcium channels conferred by auxiliary Cavβ subunits. Further convincing evidence is provided that these differences are mediated by alternative splicing of Cavβ subunit of the calcium channel. The study will be of interest to scientists studying Ca2+ signaling, ion channel biophysicists, and marine biologists.

eLife assessment

The significance of this manuscript is that is provides useful information for the field of hepatology and endocrinology on the regulatory mechanisms of cholesterol homeostasis by melanocortin. The authors provide solid evidence utilizing both in vivo and in vitro molecular, cellular, and biochemical approaches to support their claims.

eLife assessment

This work reports important findings regarding the regulation of ion channels by polyunsaturated fatty acids (PUFAs) through the identification of novel aromatic PUFA analogs with potent effects on the IKs channels, which allow for mechanistic insights into their mode of action. The experiments are solid, combining site-directed mutagenesis, electrophysiological and pharmacological approaches to dissect the different molecular mechanisms and sites involved in the functional interactions. This work will be of broad interest to ion channel biophysicists, physiologists, and medical chemists interested in drug development for LQT syndrome. The study presents some limitations that may need to be addressed or further discussed, in order to strengthen the conclusions reached in the study.

eLife assessment

This important study demonstrates a link between an acute high fat diet, microglial metabolism and improved higher cognitive function. The evidence supporting the proposed model is incomplete at this stage and would benefit from additional experiments probing the link between microglial metabolism and higher cognitive function. Following more mechanistic dissection, this work will be of interest to a broad audience in the field of neuroscience, metabolism, and immunology.

eLife assessment

The authors set out to study the development of high altitude polycythemia, which affects mice in a hypoxia chamber and humans staying at a hypoxic atmosphere at high altitude. The findings are useful both for initiating the discussion of the hypothesis that splenic red pulp macrophages, central to red cell survival, are impacted by hypoxia, and for providing some data that partially supports this hypothesis. However, the current data are inadequate to fully support the authors' conclusions that RPM are inefficient during hypoxia, reducing erythrophagocytosis, and new data provides evidence of the opposite conclusion, given that RBC lifespan is decreased (rather than increased) in response to hypoxia, suggesting that RPM are more efficient at erythrophagocytosis.

eLife assessment

The important work presented here provides findings that substantially advance our understanding of a major research question into how bicarbonate/CO2 signaling regulates cardiac mitochondrial energy supply. The methods, data, and analyses broadly support the claims with only minor weaknesses concerning the exact spatial location of the enzymes involved. The work will be of broad interest to cell biologists and biochemists interested in metabolic control.

eLife assessment:

This study introduces a valuable paradigm in the field of adipose tissue biology: blocking triglyceride storage in adipose tissue does not lead to lipodystrophy and impaired glucose homeostasis but instead improves metabolic health. The evidence supporting these claims is convincing, based on a comprehensive metabolic analysis, although mechanistic studies would strengthen the study and its impact. This study will be of high interest to those in the adipose tissue biology and metabolism fields.

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.