Evaluated articles

Evaluation Summary:

This paper is of potential interest to a broad audience of neuroscientists. By concluding that fear conditioning does not occur in a semi-naturalistic experimental setup, the study implies a major adjustment in our current understanding of Pavlovian fear conditioning and associative learning. However, additional controls and data analyses are required to validate the authors' conclusions.

(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:

In this paper the authors study the Rolle of small chain fatty acids receptors FFA2 and FFA3 in the dorsal root ganglia with the goal to define molecularly a gut to brain axis. They identified MOMBA as a compound that binds to FFA2. This paper presents a powerful screening strategy to identify receptor agonists. The main concerns are the specificity of the model, and the functional purpose of this gut to brain axis.

(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 work develops a multistage/component mathematical model to analyze advanced colorectal adenomas and the impact that aspirin therapy has on adenoma formation rates. This study will be interesting to the cancer evolution community and in particular those interested in colorectal cancer incidence. While the model is mainly focused on aspirin chemoprevention, the model could be adapted to test other putative preventative agents, and thus could have a broad impact.

(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:

This paper presents groundbreaking data on the effects of antimicrobial peptides on bacterial cells, obtained by time resolved small angle X-ray and neutron scattering experiments coupled to stopped-flow mixing. Application of this approach to cells is highly innovative and provides ms time resolution, and information on multiple length scales (from conformational changes in the cell, to structural changes in the membranes). This is an important extension of the effort of the scientific community to study model membranes. The main result is that the peptides reach the cytosol in a few seconds, accumulating to high concentrations. The data analysis should be improved, and many conclusions are speculative, in particular on the mechanism of entry of the peptides.

(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 community ecologists working on the impact of predators on prey populations, as well as disease ecologists interested in understanding the potential role of predators on vector traits. The authors uncovered trends in the research that support beneficial impacts of predators on mosquito traits, from the standpoint of vector control.

(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 uses a powerful combination of imaging techniques to provide a thorough view of the structure of the gap junction network connecting rod and cone photoreceptors in the mouse retina. The main conclusion - that rod-cone coupling is much more prevalent than rod-rod or cone-cone coupling - is well supported by the data although some results require qualification. The main concern in review centers around the importance of this result beyond the retina 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 names with the authors.)

Evaluation Summary:

The authors of this study investigate the consequences of acute or chronic disruption of parts of the TCA cycle, and how different interventions can drive different transcriptional responses. Specifically, the authors use both pharmacological and genetic methods to disrupt succinate dehydrogenase or fumarate hydratase, and characterize the effect of each on metabolism. They also find that disruption of these enzymes elicits a transcriptional response through ATF4. This work provides insight into how metabolism is affected by TCA cycle loss, and how how this affects metabolic stress signaling.

(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:

This manuscript features high quality experimental data with a detailed and clear analysis, combined with a neural network model to address the concept of differentiation in cerebellar functioning. This is an intensively debated topic currently and this work has an important, clear message to add to that debate. The data is very exciting, and the analyses and computational modeling very revealing and insightful. This stands on its own as a major contribution. The authors also raise an extremely interesting mechanistic interpretation of these data, which is tantalising but requires further support.

(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:

Baker et al. investigates the molecular evolution in primates of one protein family, the CEACAMs, that are a recurrent target of bacterial surface adhesions at epithelial surfaces. They show that multiple members of this gene family have experienced repeated episodes of positive selection in primates, especially in the N-terminal domains that are associated with protein binding and go on to evaluate the functional consequences of these evolutionary changes.

(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:

This paper is of interest to scientists within the field of motor learning. Converging evidence from several behavioural experiments support key claims of the paper. However, it is unclear to what degree the reported effects can be strongly linked to motor versus cognitive systems, and to what degree they novel demand revision of existing theoretical frameworks.

(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:

In this manuscript, an in vitro Cas1-Cas2 model system is used to study the reaction used to insert foreign DNA elements into a CRISPR array during the adaptive phase of immunity. The authors propose that hydrolysis of one end of the transposon DNA may be the primary mechanism for the insertion of very small DNA elements (which are difficult to bend tightly) that are found for the proto spacer sequences, and that cellular repair pathways are responsible for ligating the CRISPR array back together in vivo. The findings additionally suggest that water-mediated disintegration has an unappreciated role in the generation of CRISPR arrays as part of the bacterial immune response. These hypotheses are intriguing and of potential interest to those in the CRISPR field. However, it is unclear how this in vitro study, which does not monitor the full the reaction (directionality is lost due to the lack of a PAM sequence in the substrate and several required cellular factors are missing), relates to transposition as it occurs in vivo. Overall, this is an interesting study that challenges the current thinking in the field, but it does not present sufficient evidence to establish the physiological significance of the observed effects, thereby limiting its potential broader impact.

(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 will be of interest to readers in the fields of exercise physiology, muscle biology and energy metabolism. The authors provide a proteomic resource where changes in the skeletal muscle proteome and acetyl-proteome have been assessed following the increasingly popular exercise intervention of high intensity interval training (HIIT). The adaptive responses reported provide new insight into the metabolic, contractile and transcriptional changes in muscle, and may represent an excellent resource for stimulating future focussed molecular studies in the field.

(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:

Tworig and colleagues use the mouse retina to explore the motility of Muller glial processes during development and during retinal waves that drive intracellular calcium signals in Muller glia. This is an important topic, because astrocytes in the brain have been suggested to move relative to synapses during neuronal activity. By performing careful and rigorous experiments, the authors find Muller glia processes move during development, but are not driven to move by neuronal activity. This is an important finding that will be of interest to diverse groups of readers.

(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:

Initial insights were provided by yeast genetic experiments into the mechanisms of starvation-induced autophagy. Since malfunctioning of this process is involved in numerous diseases, there is a need for further understanding the role and regulation of autophagy in different physiological settings. This work convincingly shows that a newly identified phosphatase controls basal levels of autophagy via regulation of phospho-acinus levels and reveals how cadmium intoxication triggers a neuroprotective autophagic response in the popular animal model Drosophila.

(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 manuscript by Munoz et al describes the effect of the bisphosphonate zoledronic acid on tissue-resident macrophages. For this, the investigators used both a fluorescent bisphosphonate derivative and an unmodified zoledronic acid, in combination with macrophage populations isolated from different tissues. Based on the pattern of cytokines released by macrophages in the presence of zoledronic acid, the authors conclude that administration of bisphosphonates could, in addition to preventing bone loss, boost immune responses and lessen the consequences of respiratory infections.

(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 paper uses a multi-model virtual reality system to assess which combinations of visual, wind, and olfactory information male silk moths rely on to find a female. The overall conclusion is that for the moths to search effectively, wind direction information is an important input. Vision, on the other hand, while it is used to control angular velocity, does not appear to be important for the moths to search effectively. This paper is of interest to neuroscientists and engineers interested in how multimodal sensory input controls navigational behavior. The experiments and modeling effort provide an advance in our understanding of how odor and wind information are combined in male silkmoths as they search for females.

(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:

Hernandez et al use an elegant mathematical framework to build a novel tool for extracting unusually frequent (or infrequent) patterns in multidimensional biological data when only a small number of measurements are available. This is a common problem in many biological settings, so the tool could potentially be used to answer a wide range of statistically hard questions. As a first demonstration of its use, the authors show that the new tool can be used to reveal novel properties about neural responses in zebra finches during song generation.

(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 work provides valuable new information to those who study enzyme mechanisms, nucleotide metabolism, and the response of cells to stress such as nutrient deprivation. The study focuses on CTP Synthase (CTPS), an important enzyme in nucleotide biosynthesis that has been shown to assemble into foci and filaments in yeast cells undergoing starvation conditions. The authors study the structure of yeast CTPS and its propensity to polymerize in low pH (mimicking starvation conditions), and how CTPS filamentation relates to the cellular assemblies.

(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 research conducted examines how the patterns of human eye-movements recorded during the navigation of complex mazes in immersive virtual reality relates to the computational demands of navigating the mazes. A key result is evidence of sweeps to the goal across the maze and back from the goal towards the current location prior to movement, which may help with understanding computational principles of planning. A key strength is its sophisticated computational measures for characterizing the multiple dimensions of eye movement data and the fact this work is novel with few prior studies investigating this important topic. Its findings and methodology are of interest to many areas within cognitive neuroscience, notably decision making and 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. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study examines a potential mechanosensation mechanism in fly intestinal stem cells and their terminal enteroblast progeny. The manuscript’s data clearly demonstrate a role for vinc in suppressing the proliferation of midgut stem cells and the differentiation of their terminal enteroblast progeny and suggest that this role is exerted specifically through enteroblast vinc. The authors find that similar phenotypes are induced by genetic manipulations of vinc, a-cat, and myosin, and they argue that this similarity implies that vinc activity in enteroblasts is mechanosensitive. These findings are potentially relevant to biologists interested in stem cells, tissue homeostasis, fate decisions, and mechanobiology. Initial studies of vinc null flies failed to reveal any essential functions in development or viability, so the report of an adult-specific phenotype in the intestine is notable. However, the current manuscript falls short of demonstrating a key pillar of its model – that enteroblast vinc is regulated by mechanical tension. In addition, some important experiments using either whole-animal mutants or cell-specific manipulations leave room for alternate interpretations.

(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.)