Physiology

Evaluation Summary:

This authors used AAV in mouse retinas to express several candidate genes that they thought might have favorable effects on cone metabolism and therefore make cones more robust to stress caused by genetic deficiencies. Txnip is the most effective at prolonging cones survival and a combo of HK and PFK is the most effective at shortening cone survival. The investigators evaluated effects of specific mutations in Txnip with known biochemical effects. Their general conclusion is that Txnip may be enhancing mitochondrial function and ATP production and it may allow cones to use alternative fuels more effectively. This is an interesting and informative set of findings and it is presented and discussed in the context of what currently is known about retina metabolism and its influences on photoreceptor survival.

(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 is a very interesting, novel and informative study. The effects of the inhibitor on CSF1R inhibition are convincing and provide a compelling explanation for the net effects of the compound on the skeleton. The study opens the way for another possible oral therapeutic for osteoporosis.

(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:

In this manuscript, Dahlen et al. agnostically survey a large transfusion database in Sweden to investigate the association between ABO and RhD blood group and disease occurrence for a large number of clinical phenotypes. The data reported are purely epidemiological associations, with no direct insight into biological mechanism. Nonetheless, these data are a valuable resource for the research community, and offer the potential for a number of important biologic hypotheses and insights for investigation in the future.

(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 combination of Cre and Flp recombinase dependent system is powerful in manipulating specific intersectional neurons and has been successfully used in many systems. However, the system cannot express target genes sufficiently in some neurons, e.g., the LepRb VMH neurons. This paper solved this problem. It is therefore an important technical advance.

(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:

In this work, the authors subjected mice with cardiomyocyte-specific deletion of ion channel TRPM4 to transverse aortic constriction-induced pressure overload, which is a well-validated model for heart failure. The study showed that cell-specific loss of TRPM4 in cardiomyocytes could protect against pathological left ventricular hypertrophy which is associated with an attenuation of pathological changes in the expression several genes that become dysregulated during the development pathological hypertrophy. These findings are likely to contribute to understanding of pressure overload-induced hypertrophy heart disease and the pathophysiology of heart failure.

(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 names with the authors.)

Evaluation Summary:

The association between metrics of malaria transmission based on prevalence of existing infections and the incidence of new infections has epidemiologically important consequences for malaria control and elimination efforts. The association between P. falciparum entomological inoculation rate and parasite prevalence has been previously characterized, and this report evaluates the added-value of spatio-temporal models to such analyses.

(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:

The new work utilizes several elegant genetic mouse models to evaluate the importance of the mitochondrial fusion protein OPA1 in thermogenic brown adipocytes. This well-written and rigorous study sheds insight into the importance of OPA1 in brown adipocytes and also uncovers an unexpected compensatory mechanism that ensures thermoregulation in mice.

(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:

Patients with myotonia congenita (or Becker disease) experience episodes of transient muscle weakness but the reasons underlying this phenomenon are unknown. This study provides the most definitive experimental evidence to date for the mechanistic basis of transient weakness in myotonia congenita and also suggests ranolazine may be beneficial for prophylactic management.

(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. Reviewers #1, #2, and #3 agreed to share their names with the authors.)

Summary: This paper tests the biological embedding model by asking whether and how early maternal loss affects cortisol levels and diurnal cortisol slopes among wild chimpanzees at the Tai Forest, Côte d'Ivoire. The results suggest that maternal loss alters the HPA stress axis in wild chimpanzees, but these effects are not visible later in life. Authors suggest that the lack of a later life association between maternal loss and cortisol levels may be due to selective early mortality of individuals with high cortisol levels but did not provide any survival or behavioural data to show that orphans and non-orphans differ in any fitness-related traits other than cortisol. Furthermore, the association between cortisol and the HPA axis is in the opposite direction to that observed in humans and there seems to be no significant increase in cortisol in orphans compared to non-orphans. Overall, the study is the result of extensive fieldwork, the number of samples collected is impressive and the subject is very interesting.

The analyses will benefit greatly if the authors use effect sizes and confidence intervals for inferences instead of p-values. This may solve the significance threshold issues. Moreover, the reliance on p-values seem to limit the value of the data. For example, authors suggest that results from model 1 should be treated with caution because the full model is not significantly different from the null model, but by relying on it as the key finding of the study without exploring effect sizes, it does not seem that they did exercise sufficient caution.

Summary: Mishra et al. present data characterizing the effect of asprosin neutralizing antibodies on the parameters of metabolic syndrome (weight, glucose, lipids, etc). This group were the initial discoverers and characterized asprosin as a hormone that increases blood sugar and stimulates appetite. In their Nature Medicine 2017 article they also present data on a neutralizing antibody. In this follow-up manuscript the group characterizes the impact of neutralizing monoclonal antibodies on metabolic parameters of three mouse models of obesity (DIO, NASH diet and Leptin receptor knockout). The translational focus of the manuscript is potential use of monoclonal antibodies against aprosin as a treatment of metabolic syndrome.