Evaluated articles

Evaluation Summary:

This study will be of broad interest to neuroscientists, immunologists, and gastroenterologists, revealing a novel role of complement C1q in intestinal macrophages and the regulation of gut motility. The manuscript is well written and key datasets are convincing, but the lack of mechanistic details that lead to dysmotility require additional supportive datasets at this time.

(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:

Cryo-electron tomography has been successful at uncovering the details of the eukaryotic cilium/flagellum but there remains a limited number of taxa represented in the studies to date. Pinskey et al. fill this gap with a flagellar structure from choanoflagellates: single-celled organisms that are the closest living relatives of animals. The findings yield many new insights of broad interest to the field, such as the similarity of outer dynein arms and radial spokes to metazoan cilia, the observation of a flagellar vanes, and the presence of mysterious barb structures.

(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 study establishes for the first time that selective auditory attention reduces activity in the auditory cortex, similar to effects produced by engagement in a behavioral task. Moreover the study establishes the diversity of cortical modulations generated by attention.

(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 paper by Dr. Abbas and colleagues uses genomic and epidemiological methods to track SARS-CoV-2 spread in a healthcare facility. It demonstrates that genomic data can be used to track the spread of viruses in healthcare environments and documents that inter-ward transmission is important in healthcare settings. Overall, the conclusions are supported by the data and analysis and the paper demonstrates that genomics may be an important adjunct tool for tracking the nosocomial transmission of respiratory viruses.

(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 names with the authors.)

Evaluation Summary:

This manuscript uses a combination of in vitro and in vivo approaches and uncovers a potential mechanism of autocrine/paracrine signaling in oligodendrocyte maturation, which provides an exciting avenue for future investigation. In particular, the authors examined the role of oligodendroglial exocytosis, and specifically the role of L-type prostaglandin D synthase (LPGDS), in modulating oligodendrocyte differentiation and myelination. This work will be of interest to glial and myelin disease researchers.

(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 names with the authors.)

Evaluation Summary:

Hoye et al. analyzed conditional inactivation of Ddx3x gene in mouse dorsal forebrain, which leads to decreased brain size and widespread apoptosis in females but not males. Interestingly, the authors showed that Ddx3y was transcriptionally upregulated in cKO males, and suggested that Ddx3y compensated for the loss of Ddx3x. These results are attributed to prolonged cell cycle, impaired cell cycle exit, leading to increased progenitor populations. Ribo-Seq analysis showed differentially translated genes, providing potential new insights into Ddx3x function and pathogenic mechanisms. Overall, this study is of great importance and provides novel insights into the pathogenesis of DDX3X syndrome and the crucial role of DDX3X during cortical 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This study investigates the release machinery of synaptic vesicles prior to SNARE-mediated fusion using atomistically detailed molecular dynamics simulations. While the approach provides an unparalleled perspective on a complex process that has eluded direct experimental access, the physiological relevance of the conclusions is not clear yet because of the short duration and necessary molecular approximations and assumptions underlying the simulations. The work will be of interest to all who study vesicle fusions.

(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 puts forward a new approach to generate vascularized brain organoids to copy in vivo structures, which will be of interest to neurobiologists working in both basic and disease-related areas of neuroscience. The novelty of their approach lies in the simultaneous production of vessel-like networks and brain-resident microglia immune cells in a single organoid. The fusion of brain and vessel organoids (fVBOrs) resulted in robust engraftment of vessel-like structures and microglia around ventricular zone (VZ)-like structures, correlating with increased neuronal progenitors. The conclusions are mostly well supported by the data, but a few points need to be clarified and some conclusions would benefit from further experimental 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This work should be of interest to a broad readership in infectious diseases, especially those people interested in modeling of infections. It combines statistical and mechanistic modeling to find assayable correlates of immunity for vaccines. This method could be relevant to many diseases or vaccines, although the particular markers identified here likely will be limited in their generalizability.

(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 Jauch-Speer and colleagues uses a CRISPR/Cas9 screening approach in a myeloid cell line to identify C/EBP-delta as a regulator of the alarmins S100A8 and S100A9, which amplify inflammation. This paper is of great interest to macrophage biologists studying macrophage function in inflammatory diseases. In an elegant series of gene targeting and sequencing studies, the authors also characterized epigenetic mechanisms regulating the expression of these pro-inflammatory mediators. Furthermore, human monocytes from cardiovascular patient cohorts showed correlative changes, indicating possible clinical relevance.

(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 presents a novel EEG-based, real-time feedback approach that enables healthy participants to independently self-regulate excitability of the left versus the right hemisphere. Using this unique approach, the authors demonstrate that their paradigm could have the potential to modulate the neural interplay between both hemispheres which is relevant for the field of neurorehabilitation.

(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 study uses dual intracellular and extracellular recordings in different subfields of the hippocampus in awake mice during immobility to investigate the initiation of sharp wave-ripples, synchronous bursts of hippocampal activity thought to be important for memory formation. It provides unique data obtained in vivo across a diversity of hippocampal cell types. Specifically, these findings lead to a model where inhibition of CA3 pyramidal cells is permissive to ripple 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. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper is of interest for cell biologists studying metabolism and its regulation during the cell cycle, as it demonstrates cross-talk between the CLUH protein, involved in mitochondrial function regulation and metabolism, and astrin, a protein functionally involved in cell division through regulation of centrosome integrity. This physical and functional interaction serves as a hub to integrate the metabolism with cell cycle progression.

(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 article will be of interest to paleobiologists studying the evolution of avian diets and/or prehistoric ecosystem dynamics. The study uses an exceptional new specimen of an early diverging stem bird with a near-complete skull, to reassess diet in the taxon and explore possible early mechanisms for bird-mediated seed dispersal. The claim for frugivory is currently insufficiently supported.

(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 is an interesting paper that uses de novo protein design to probe the effects of oligomerization state on the activity of chimeric antigen receptors (CARS). The successful design of transmembrane domains with specific oligomeric states is an impressive result on its own. The proteins were designed using rotamer-based sequence optimization in Rosetta with an energy function specific for the membrane environment. After experimentally evaluating a couple rounds of designs, the investigators settled on a design protocol that also included screening of the design candidates with docking simulations in alternative oligomerization states to check that the sequences preferred the desired oligomerization state. The designs were experimentally evaluated with gel electrophoresis and X-ray crystallography. In the end, designs that adopted well-defined dimers, trimers, or tetramers were created and carried forward in experiments as CARs.

(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 name with the authors.)

Evaluation Summary:

In this manuscript the authors conditionally knock out the DNA methyltransferase Dnmt3a in developing excitatory cortical neurons to determine the consequences for chromatin regulation, gene expression, and neuron function. As expected they find widespread loss of DNA methylation at CpA dinucleotides but also an increase in histone methylation (H3K27me3) at many similar regions of the genome, which they speculate may be a mechanism of functional compensation. Overall this study offers new insights into the gene regulatory and neuronal cellular functions of an important chromatin regulatory protein.

(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 manuscript the authors carefully describe the activity of individual neurons within the mouse olfactory tubercle, comprised of the two principal cell types, in the context of odor and tone associative learning. The use of 2-photon microscopy to monitor activity of the neurons is a major step forward and unveiled new insights into the dynamics of these neurons. This manuscript will be of interest to a wide range of readers, including those interested in affective circuits, learning, and sensory processing.

(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 paper will be of broad interest to researchers interested in learning, memory, and/or the hippocampus. It offers a neuroanatomically inspired model of the hippocampus that reconciles its well-known role in episodic memory with its more recently appreciated role in category learning and generalization. The computational simulations are well conducted and support the key conclusions regarding complementary roles of distinct hippocampal pathways for different forms of learning. There are concerns with differentiating the current work from prior reports and the apparent discrepancy between the proposed model and well-established findings of place and concept cell recordings in hippocampus, but thought that these issues could be potentially resolved with additional clarification.

(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 authors examine the impacts of the COVID-19 pandemic on excess mortality in the US up to April 30, 2021. The authors separate direct impacts (caused by COVID-19, coded as such or not) of the pandemic from indirect impacts (disruptions), finding that most excess deaths (90%) are due to direct impacts. Importantly, the authors find that the official COVID-19 death tally is an undercount of these deaths. Moreover, the authors also find that excess deaths due to other causes are the main driver of excess mortality among younger populations. The paper is interesting and well written, although we have some concerns, particularly around the estimation of direct vs. indirect impacts.

(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 shows that spontaneous mutations in cancer cells affecting metabolic pathways do not necessarily result in functional defects, as affected cells may be able to be rescued by gap junction-mediated exchange of metabolites. This is verified in three specific examples, although some of the "quantitative" methods of measuring gap junctional coupling are actually only qualitative in nature. In addition, more experiments are needed to address the effect of Cx31 and Cx43 KD. This paper is of potential interest to a broad readership in cancer biology as well as colleagues studying metabolic pathways.

(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.)