Evaluated articles

Evaluation Summary:

This manuscript addresses a significant and timely topic in translational control and will be of interest to researchers studying molecular biology or diseases impacted by the Integrated Stress Response (ISR). The combination of biochemical, structural, and in-cell experiments constitutes a comprehensive study that supports the proposed model for allosteric regulation of the active/inactive states of the eIF2B complex. The findings are relevant to neuropathologies, infectious and inflammatory diseases, diabetes, and metabolic disorders.

(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 assess the role of SMCHD1 provided by the oocyte at fertilization in the regulation of Xist expression in the embryo. They also provide preliminary analysis of the downstream effects of faulty Xist expression, on X chromosome silencing. This work has implications in epigenetics and embryonic development and aims at an audience interested in gene dosage regulation in mammals. Although of potential interest, some further analytical and experimental work is needed to understand how SMHCD1 works on the early stages of X inactivation.

(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:

When the subjects are instructed to produce saccades away from suddenly appearing visual targets under time pressure, early saccades tend to be directed incorrectly to the peripheral target, suggesting that exogenous and endogenous signals that are related to the target position and instruction, respectively, compete to control the motor responses. In this study, the authors provide further evidence for the independence of these two processes by showing that they can account for temporal evolution of correct saccades regardless of the instruction, stimulus luminance or motor bias.

(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 tests the hypothesis that subjective cognitive impairment (SCI) is linked to hyperreactivity to uncertainty. Using an information-gathering task, the authors demonstrate that individuals with subjective cognitive impairment sample more than controls under uncertainty. Despite the clear strengths of the experimental design and the novel insights into SCI, some of the findings rely on problematic between-subject correlation analyses that should be corrected. Furthermore, alternative accounts of the main findings are consistent with the 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:

This paper employs innovative approaches to elegantly tackle the question of how we are able to learn an object category with just a single example, and what features we use to distinguish that category. Through a collection of rigorous experiments and analytical methods, the paper demonstrates people's impressive abilities at rapid category learning and highlights the important role of distinctive features for determining category membership. This paper and its approach will be of interest to those who study learning, memory, and perception, while also contributing to a growing field which uses naturalistic drawing as a window into high-level 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

This paper describes a new structure for a complex between a bifurcating electron transfer flavoprotein (ETF) and its client dehydrogenase. Because electrons are being supplied by the dehydrogenase, the ETF executes confurcation in contrast to all of those elucidated so far, which function in the opposite direction to effect bifurcation. As electron-confurcation and electron-bifurcation have emerged as important paradigms of cellular bioenergetics, the data reported herein pave the way for future exploration of similar electron transfer systems and lay the ground for understanding their structural basis. The work will be of relevance to all who are interested in the mechanisms of enzymes.

(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 authors measure dry mass and its density in growing and proliferating cells at high temporal resolution and with high precision. Using this method to study mitotic cells, the authors show that some cell types lose dry mass early in mitosis by a mechanism involving exocytosis. This work improves upon the authors' method to measure the mass of single cells and its thought-provoking conclusion is that dividing cells 'clean out' their contents to give the daughter cells a clean start.

(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:

Overall, this study explores the differentiation of human pacemaker cells from human iPSCs, demonstrating different subtypes of pacemaker cells, and highlighting the role of Wnt and TGFbeta signaling in the formation of sinoatrial note cardiomyocyte subtypes.

(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 is of interest to cardiovascular and developmental biologists as it describes Dnajb6 as a novel gene linked with Sick Sinus Syndrome. The claims are mostly supported by observations using zebrafish dnajb6b trap line and Dnajb6 heterozygous mouse models. However, the paper would be strengthened be clarification of some experimental aspects and a discussion of the potential connection of DNAJB6 to the Sick Sinus Syndrome in humans.

(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 will be of interest to public health specialists and cancer scientists working in cancer prevention. The work presents valuable data on how the COVID-19 pandemic has impacted breast cancer screening indicators compared with previous years. Overall, the results support the assertion that while many key indicators have not been substantially impacted, the screening participation rate declined and fewer cancers were screen-detected in 2020-21.

(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 an innovative cell-free system to identify antiviral factors that interact with HSV-1 in cells. In addition to cataloging many capsid-interacting factors, the paper probes the antiviral mechanism of one of these, MxB. The data provide strong support for an intriguing model in which MxB "punches" holes in HSV-1 capsids, releasing viral DNA and potentially triggering host DNA sensors. However, the binding of a variety of factors to the capsid appears able to bind to and shield the capsids from MxB attack, suggesting a new perspective on how viruses might evade some host defenses.

(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 will be of interest to readers in the field of infection and cell biology. The authors follow up their previous study to further deepen our understanding of host-pathogen interactions that contribute to transkingdom contact sites. The authors show that the Chlamydia effector protein IncV tethers ER to the bacterial vacuole in a manner dependent on the phosphorylation of its C-terminus by the host kinase CK2. In addition, the authors show that IncV recruits the host kinase CK2 to the bacterial vacuole in manner required for its phosphorylation and ER tethering. Overall, the data justify most of the key claims put forward by the authors. Nonetheless, clarification is required concerning the chain of events and the phosphorylation events required for VAP binding.

(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 paper uses hybrid mouse lines to estimate the heritability of the microbiome and map variants in the mouse genome that are associated with the composition of the microbiome. The findings are of broad interest to microbiome researchers and improve on knowledge in the field, as they focus on mucosa-associated (rather than fecal) microbiome profiles and report a novel correlation between heritability and cospeciation rates. The results are intriguing, but technical and biological confounders are incompletely addressed in the manuscript's present form, potentially leading to surprisingly high estimates of microbiome trait heritability relative to previous work.

(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 report a preregistered study which tests the effects of targeted memory reactivation (TMR), which is typically studied in the context of declarative memory, on motor memory consolidation during sleep. In a nap study, the authors use a standard TMR paradigm. Their results suggest a key role of oscillatory activity for motor memory consolidation, where distinct features of the slow oscillation spindle interaction mediate memory formation. Overall, this is a timely interesting. It is scientifically rigorous and transparently reported. The claims are well supported by the 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 #3 agreed to share their name with the authors.)

Evaluation Summary:

Bao and colleagues present a chemical genetics study to identify novel compounds extending lifespan in C. elegans, and they proceed to investigate the mechanisms of action of their most potent compound. Based on the known target TRPV4 of the screening hit, the authors provide evidence for the involvement of a C. elegans homolog (osm-9) in the observed phenomenon, although this evidence is not completely conclusive. This study will be of interest to researchers working on drug discovery, repurposing and lead optimization in the context of ageing.

(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 is of interest for cancer biologists studying the role microRNAs in tumor growth. The work provides links between over-expression of microRNAs, downregulation of a ubiquitin ligase, inhibition of JNK and reduced tumor growth. Some of the data are properly controlled and analyzed. However, the key claims of the manuscript are not entirely supported by the data, and additional controls are needed.

(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 shows that retinal ganglion cell light responses in awake mice differ substantially from those under two forms for anesthesia and previously attained ex vivo recordings. This difference is central to our understanding of how ganglion cell responses relate to behavior. There are a few technical issues and issues about how the work is presented that could be strengthened.

(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 demonstrates that deletion of MKK6 reduces life span in mice, and leads to cardiac hypertrophy that progresses to cardiac dilatation and fibrosis with age. The authors also demonstrate that the mechanism for this phenomenon is through reduced p38a activation while causing MKK3-p38g/d hyperphosphorylation and increased mTOR signaling. The authors extend previous studies (that demonstrate a role for P38 proteins as downstream effector of MKK6) and identify the isoform of P38 that plays a role in this process. Overall, the studies in this paper are conducted carefully and most of the conclusions are based on the reported 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript uses a micropatterned cell culture system to explore the mechanism of human primordial germ cell-like cell specification from human pluripotent stem cells, and proposes a previously unrecognized role of NODAL signaling operating downstream of BMP signaling. The strength of the manuscript is the development of a simple and efficient in vitro system that is potentially suitable for exploring the mechanism of human primordial germ cell-like cell specification. With a more rigorous validation of the identity of the studied cells and more discussion relating the findings to developmental mechanisms in vivo, this study will be of interest to stem cell and developmental biologists.

(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 is a very elegant study that through cross-species analysis describes the evolution of ubiquitin ligase adaptor protein LZTR1-mediated degradation of RAS-related GTPase RIT1 as a principal regulatory mechanism for RIT1 function and its role in Noonan syndrome, a prominent subgroup of RASopathy disorders. Extensive genetic experiments in Drosophila and mouse suggest that important pathological phenotypes observed in LZTR1-linked RASopathy models are mediated by its ubiquitination target RIT1 and less by the canonical RAS isoforms. While the work further supports the connection between LZTR1 mediated RIT1 level modulation, it does not fully rule out the significance of canonical RAS isoforms in LZTR1-associated RASopathies in humans.

(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.)