Evaluated articles

Evaluation Summary:

This work presents a series of enhancements to the PhIP-seq method of autoantibody discovery, with the goal of improving scaling to larger cohorts and increasing disease specificity. The strength of the paper is the validation of the high throughput format, although results from screening patient samples confirm or only modestly extend previous data.

(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:

KdpFABC is a bacterial potassium uptake transporter made up of a channel-like subunit (KdpA) and a P-type ATPase (KdpB). When potassium levels are low (< 2 mM), the transporter actively and selectively uptakes potassium, but must be switched off again to prevent excessive K+ accumulation. Although structures of KdpFABC have been determined before, the structural basis for inhibition by phosphorylation is unknown. Here, the authors have determined the structure of KdpABC in an arrested (off-state) that is in a distinct conformation from previously determined P-type ATPase structures. More detailed structural comparisons are needed to more convincingly show this, however, and the protein required to inhibit KdpABC by phosphorylation remains unknown. This paper will be of interest to researchers in the microbiology and transporter communities.

(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:

Protein-RNA interactions are involved in many diseases and targeting them with drugs can be valuable. Because protein-RNA complexes are considered difficult to target both computationally and experimentally, an integrated computational-experimental approach to solve this limitation is introduced. The approach is demonstrated by targeting the mRNA-binding protein YB-1, which works remarkably well. Inhibitors in the micromolar range are detected, including a previously approved drug. The main strength here is the proof of concept that protein-RNA interactions are targetable. However, additional data are required to support the central claims of the paper.

(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 reports a new tissue clearing procedure that is faster (clearing within 48 hours), uses less hazardous chemicals, and importantly appears to result in less tissue volume change compared to other methods. The simple protocol adds further to the toolbox of tissue clearing methods and is one that is likely to be even more popular than many current methods, although the scope of tissue on which it can be used and rigorous comparisons to existing protocols have not been fully investigated.

(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:

In their study, Gicking et al. study the physical properties of artificial complexes composed of the dynein-dynactin-BicD2 (DDB) complex linked to one of three classes of kinesins (1, 2, or 3) via a DNA scaffold. They find that all three kinesins can move to the plus-end of microtubules when coupled to the DDB complex. This is surprising because motors in the kinesin-2 and kinesin-3 families have been shown to have a higher load sensitivity. However, the authors show that the faster reattachment kinetics of these motors compensate for their faster detachment rates under load. This work is relevant to both the biophysics field for advancing knowledge in fundamental science, and in the neuroscience field since disruption of neuronal transport leads to a variety of neurodegenerative diseases.

(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 paper addresses the toxicity of fluorescent calcium indicators, comparing two series of indicators (GCaMPs and GCaMP-Xs) in mouse neurons. The paper documents GCaMP toxicity during development and following prolonged strong expression, and establishes that GCaMP-X indicators are less toxic. The paper will be of interest primarily to neuroscientists who use fluorescence calcium indicators to monitor calcium dynamics during neuronal development.

(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 is an important study that investigates whether older adults have selective impairments in allocentric navigation (using distal cues to navigate). Using a combination of ecologically inspired real-world navigation, virtual reality, eye tracking, and body-tracking, the study reports, for the first time, that older adults show no difference from younger adults when using geometry to navigate a Y maze. Instead, their deficits appear to relate to perceptual difficulties with processing individual landmarks. This large sample study therefore provides somewhat compelling evidence of age-related difficulties in processing landmarks visually rather than a selective deficit in allocentric navigation.

(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:

There is a debate whether ROS (reactive oxygen species) generated through redox signaling could be a friend or foe. There are several paradoxical studies (both animal and human) wherein exercise health benefits were reported to be accompanied by increases in ROS generation. Utilizing the in-vitro studies as well as mice model work, this manuscript illustrates the different regulatory mechanisms of exercise and antioxidant intervention on redox balance and blood glucose level in diabetes. The manuscript does address some advancements in the area of research specialization.

(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:

A new and interesting operant conditioning paradigm is established for the Drosophila larva. A novel role for serotonergic pathways in the VNC in operant learning points to new circuits and mechanisms for learning and memory. Impressive technology opens doors for new and exciting studies on learned behavior in the small and tractable circuits of the larva.

(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 well-written report provides new insights for neuroscientists studying sleep architecture and stress sensitivity. A particularly important conclusion is that differences in sleep architecture before chronic social defeat stress may serve as a predictive biomarker of stress resilience. Overall the work is very strong, but there are some conceptual and methodological issues that need to be addressed.

(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 neuroscience community studying brain oscillations. It presents a new method to detect sharp-wave ripples in the hippocampus with deep learning techniques, instead of the more traditional signal processing approach. The overall detection performance improves and this technique may help identify and characterize previously undetected physiological events.

(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.)

eLife assessment

This is a potentially important paper that takes advantage of an unusually comprehensive evolutionary genetic dataset to tease apart the relationship between genetic variation and phenotypic divergence over the ~medium term (50 generations). The questions addressed have broad relevance across evolution, conservation, and agricultural fields, and this paper will particularly appeal to evolutionary biologists. Nonetheless, the strength of evidence is incomplete for the major results and conclusions reported.

Evaluation Summary:

Analysis of molecular data from genome sequencing provides crucial information on the diversity of biological and evolutionary processes that shape genetic diversity. However, the models of genetic evolution used to make these inferences sometimes oversimplify important aspects of species biology. This study shows that accounting for high variance in reproductive success in models can better explain the genetic diversity of an extremely fecund marine species, the Atlantic cod. The manuscript is scientifically sound and provides careful statistical analyses of alternative evolutionary models. It concludes that pervasive selection, rather than demographic changes or sweepstakes reproduction, is one of the main drivers of genetic diversity in Atlantic cod.

(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:

The experiments presented in this extensive study by Ronzano et al. are a tour-de-force investigating the spatial organization of premotor interneurons in the mouse spinal cord to re-examine the fundamental question of whether there is spatial segregation of interneurons with monosynaptic connections to motoneurons innervating functionally antagonistic (flexor and extensor) pairs of limb muscles. The authors' premotor circuit mapping experiments, involving four different collaborating laboratories applying an extensive set of complementary rabies virus-based trans-synaptic circuit tracing techniques, convincingly demonstrate complete spatial overlap among flexor and extensor premotor interneurons, contradicting previous mapping results that suggest spatial segregation. The present results revise our understanding of the spatial organization of spinal premotor circuits with fundamental implications for understanding spinal motor circuit function.

(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 describes an interesting phenomenon of long-range transport in self-organized canal structures formed in colonies of the pathogenic bacterium Pseudomonas aeruginosa. The authors measured and analyzed the fluid flows in these open channels, revealing that it is capable of supporting high-speed transport of outer membrane vesicles and bacterial cells over centimeters. This study sheds new light on the potential amplitude of cargo exchange among bacterial communities over long distances.

(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 entitled "Dietary palmitic acid induces innate immune memory via ceramide production that enhances severity of acute septic shock and clearance of infection" Seufert and colleagues have investigated how saturated fatty acids increase susceptibility of the host in a murine model of LPS-mediated septic shock. Pretreatment of macrophages with palmitic acid (PA) was found to reprogram macrophages towards hyper-inflammatory phenotype, which was dependent on ceremide. Importantly, depletion of macrophages intracellular ceremide with oleic acid reversed their hyper-inflammatory phenotype. Interestingly, while PA was harmful in the LPS-acute septic shock model, it was beneficial in clearance of C. albicans in Rag-deficient mice lacking both B and T cells. While this is an exciting study, the presented data don't fully support the central hypothesis and the link with trained immunity is currently weak.

(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 manuscript by Deng et al., is a valuable evaluation of zbtb14 and its role in normal myelopoiesis. The authors provided convincing data supporting the role played by zbtb14 in monocyte and macrophage development and its regulation involving the modulation of PU.1 expression. The finding that a mutation in ZBTB14 exists in AML patients also implies how important this gene product is in normal human myelopoiesis.

(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:

Drs Zhao and Sharpe have highlighted the role of a relatively understudied cell type, the telocyte, in periodontitis, using a mouse model. Periodontitis is a widely occurring inflammatory disease of the gums, that will eventually progress to bone resorption and teeth that are embedded less favorably and will eventually fall out. This disease is linked to many other illnesses, such as rheumatoid arthritis, cardiac disease and even Alzheimer's disease, so more in depth knowledge is needed on cell types that play a role in the progression of the disease.

(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:

Sefton et al. analyze how fibroblast-derived HGF integrates muscle and nerve development during morphogenesis of the mammalian diaphragm. The new findings are based on in-depth analyses of the development of the diaphragm muscle, and the role of Met and HGF in the process. The work is relevant for the understanding of muscle development, and congenital disease (hernia).

(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 Methods paper seeks procedures evaluating the balance between muscle cell quiescence and activation. These could well permit investigations of long-standing questions in key areas of muscle function. The latter include the regulation of adult stem cell pool size and functional heterogeneities in this, as well as regulators of muscle quiescence.

(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.)