Evaluated articles

Evaluation Summary:

The authors use an elegant experimental design to study genetic variation in the ubiquitin-proteasome degradation system in yeast. They identify a large number of QTLs for naturally occurring variation, and they elucidate the causal variants and likely functional mechanisms of several of these. The paper illustrates an innovative new approach to high-throughput QTL mapping for specific molecular processes and it will be of interest to colleagues aiming to harness natural variation for understanding a range of biological processes.

(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 described the effects of two different CoronaVac vaccination schedules in a Chilean adult population. They find that a 0 and 28-day two-dose schedule produced superior levels of neutralizing antibodies and antibodies with a great breadth of interaction across variants compared to a 0 and 14-day two-dose schedule. They find no differences in T cell responses or total antibody levels between the two groups. These findings demonstrate that a short two-week two-dose interval should provide sufficient immunity to reduce the likelihood of serious outcomes during a COVID infection.

(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 study bridges the gap between connectomic data from the fly hemibrain and driver lines needed for functional experiments through a new freely available computational tool, NeuronBridge. It demonstrates that this software provides users with the ability to identify the same neurons within different driver lines, and the opportunity to match expression of neurons in a driver line with those in a connectomic database. Overall, this manuscript does a commendable job of describing an important resource for the community, which will hopefully be built upon via collaborative science of many groups as the field develops.

(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 manuscript addresses a long-standing question regarding the highly variable cellular composition and functions as well as immune environments along the epididymis. Using multiple mouse models (bacterial infection and parabiosis between WT and Ccr2 KO) in conjunction with powerful scRNA-seq analyses, the authors provided solid evidence supporting the notion that resident immune cells are strategically positioned along the epididymal duct, potentially providing different immunological environments required for sperm maturations and elimination of pathogens ascending the urogenital tract.

(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:

The manuscript by Noel et al reports parallel neurophysiological responses from the three brain areas MST, 7a and dlPFC of monkeys during a novel behavioural paradigm developed by the same group previously. The continual nature of this paradigm with a closed action-perception loop makes the animal behaviour more naturalistic compared to classical paradigms with artificial breaks between sensory stimulation and action. Findings of neurophysiology under such a paradigm are novel and of broad interest to cognitive and systems neuroscientists. The data presented in the paper support the claim of distributed neural coding in which task-specific sub-networks may form.

(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 and delicately designed study that uses integrated tools to reveal underlying mechanisms of repair of the endometrium at menstruation. It combines single cell sequencing analysis and lineage tracing technologies to strongly prove that repair-specific cells originate from the fibroblast cell clusters and PDGFRα+ endometrial fibroblasts undergo MET and can become incorporated into the luminal epithelium of the post repair tissue.

(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 name with the authors.)

Evaluation Summary:

The manuscript is well organized and clearly written. The discussion provides the required information to easily understand the relevance of each finding. the authors demonstrated using an osteocyte cell model that connexin43 is localized to mitochondria and that this is enhanced in response to oxidative stress. Several lines of evidence were presented showing that mitochondrial connexin43 forms functional hemichannels and that connexin43 is required for optimal mitochondrial respiration and ATP generation. These aspects were major strengths of the study.

(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 #3 agreed to share their name with the authors.)

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.)

Evaluation Summary:

This work provides substantial new insights into how semantic association strength influences the function and relationships across brain regions along a topographical structure of cerebral cortex. A principal gradient with the separation of default mode network from sensory-motor systems represents a hallmark of the retrieval of strong conceptual links. This study will be of interest to cognitive neuroscientists, especially those who are interested in semantic cognition.

(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 #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper uses a new statistical approach called within family Mendelian randomization and asserts that claims of childhood BMI affecting a range of psychiatric traits are unfounded and were mainly caused by confounders that this new approach is able to better identify and control for. They do find a role for maternal BMI on a child's risk for developing depression. The main issue raised is that they do not convincingly show if they do not replicate the old association of childhood BMI with a range of psychiatric traits due to their technique simply having lower power to detect the signal or due to a true lack of this effect.

(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:

The authors investigate how HIV-1 infection affects the immune response in the context of SARS-CoV-2 infection by characterising the circulating B cell response. They conclude that people with HIV-1 infection, who become infected by SARS-CoV-2, produce B cell responses via an extra-follicular pathway to a greater degree than people who do not have HIV-1 infection. These findings imply that in HIV-1 infected individuals, long-term B cell and antibody responses against SARS-CoV-2 might not be as robust and durable compared to those in people without HIV-1 infection. The manuscript will be of interest to infectious disease specialists, virologists, and immunologists.

(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 name with the authors.)

Evaluation Summary:

This paper is of interest to skeletal biologists studying skeletal development and tissue regeneration. The study applies a well-established and elegant axolotl limb regeneration model and transgenic reporter strains to reveal the potential role of osteoclast-mediated resorption in limb regeneration.

(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 important paper uses molecular simulations to explain how actomyosin networks transition from small clusters to the cortex or ring-shaped actin networks. The authors provide compelling evidence that variation in filament turnover rate and myosin concentration triggers a phase transition of these networks. The predictions of this model are consistent with observations made in T cells, where actin ring formation can be induced following their activation by antibodies.

(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:

Knowledge of the protein composition of defined sub-cellular compartments is of key importance for the characterization of protein machines that mediate defined cellular functionalities. The current paper presents a novel mouse line that will serve as a helpful tool in this context - a Cre-inducible APEX2 reporter mouse line for acute ex-vivo proximity biotinylation. The paper documents the successful use of the novel reporter line to assess circuit-specific proteomes and phosphoproteomes in the corticostriatal system during development. The corresponding data largely align with the published record, but potentially new biological insights deduced from bioinformatic analyses of proteomic data were not followed up by experimental validation. In sum, the new APEX2 reporter mouse line will be of substantial interest to researchers in many fields of mammalian biology. The extent of 'new biology' provided is rather limited, but will be of interest to readers in neurodevelopment.

(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 will be of interest to researchers studying control of respiration and also those developing functional magnetic resonance imaging methodology. The work provides insight into the relationship between brain activity (measured directly) and non-invasive functional magnetic resonance imaging measures. The authors find that the respiration signal is associated with the gamma band in the cingulate cortex, and both the gamma signal and respiration signal correlate with distributed neuronal networks across the brain. This contributes to our knowledge of the contribution of respiration on neuro and neuro-vascular signals during resting conditions.

(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 authors developed a set of synthetic proteins, Designed Ankyrin Repeat Proteins (DARPins), that bind gephyrin, the main scaffold protein at inhibitory postsynaptic sites, and characterize them extensively to study gephyrin cluster morphology and biochemistry. In several aspects, DARPins outperform traditional antibodies. This study is clear, well organized and well written, demonstrating that DARPins can be important tools synaptic, cellular and circuit neuroscience fields.

(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:

These studies establish a role for the D2 pseudophosphatase domain of the PTPRK receptor-like phosphotyrosine phosphatase in recruiting Afadin, a cell-cell junction protein that is reported to be a PTPRK substrate, for dephosphorylation by the active D1 phosphatase domain. These findings suggest that the D2 pseudophosphatase domains of RPTPKs might have a general function as platforms to recruit specific phosphotyrosine substrates.

(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 #3 agreed to share their name with the authors.)

Evaluation Summary:

The present manuscript examines cortical representations of basic visual attributes following a manipulation shown to enhance plasticity in the adult brain: binocular dark exposure for several days, followed by light re-introduction. The work has fundamental therapeutic and conceptual implications, and will be of potential interest to a broad readership of vision scientists, neuroscientists, clinicians and modelers. The paper is well-written and based on sophisticated experiments. The evidence provided convincingly supports the authors' contention that dark exposure does not have a negative impact on visual representations in V1. The study uses a generally appropriate study design. However, it would benefit from the addition of some key experimental details, and additional analyses and statistical tests to explore alternative interpretations of results.

(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.)

eLife assessment

This paper, of relevance to a broad range of plant biologists and colleagues in the circandian field, reports important results that demonstrate circadian coordination of characteristic floral development in sunflower. The current manuscript includes convincing observations and possible hypotheses, but the ecological relevance of the temporally-controlled flower development is incompletely shown.

Evaluation Summary:

Bacteria living in stressful and fluctuating environments need to respond to changing conditions. Many species, including Mycobacterium tuberculosis, the causative agent of tuberculosis, use cAMP as a secondary messenger to sense and respond to specific stimuli. What distinguishes M. tuberculosis, is that its genome encodes for at least 15 adenylate cyclases, enzymes that synthesize cAMP from ATP. The authors characterized one specific adenylate cyclase, Rv3645, and demonstrate that it is the most significant contributor to cAMP levels and mediates fatty acid metabolism and antibiotic resistance. This manuscript will be of broad interest to readers in the field of tuberculosis drug discovery and bacterial metabolism.

(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.)