Evaluated articles

Evaluation Summary:

The identification of an autoinhibitory mechanism of the dynein intermediate chain provides an important contribution to our understanding of dynein assembly and illustrates the plethora of regulatory mechanisms attainable by intrinsically disordered proteins. This paper provides insight into the autoinhibited inactive state of dynein as well as the activation mechanism. A wide range of biophysical approaches is used, providing a very nice example of how these diverse technologies can be applied in concert and in a synergistic manner to study an important question in the realm of "unstructured biology".

(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 paper describes an interesting, but very abstract extension of normative choice theories. By linking economic and foraging theory, the paper would potentially be of interest to a broad audience in behavioral economics and neuroscience. However, the results in their current form have several important limitations: the lack of a significant validation, such as an account for well-known behavioral or neural effects that would not be explained by alternative theories, a quantitative performance comparison between the proposed EDM and other models in realistic behavioral situations, and a specific link between the actual processes and limitations of real brains and the EDM.

(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 reports candidate causal genes in genome-wide association studies that exhibit a discordant pattern of association, namely a higher waist-hip ratio simultaneously with a lowered risk of type 2 diabetes. Identification of such genes could provide insights into why some individuals with obesity are not developing type 2 diabetes, knowledge that ultimately could shed light on the complex interplay between fat distribution and type 2 diabetes. The work is of relevance to the fields of genetics of diabetes and obesity.

(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:

Advances in the discovery of novel anti-platelet therapeutics remains an unmet need. This manuscript by Chaurasia et al. describes a novel signaling pathway involving Notch1 and its ligand, Delta-like ligand-4 (DLL4) in driving platelet activation and thrombus formation. The authors provide convincing mechanistic studies to show that blockade of this pathway may serve as a new therapeutic approach to prevent/treat thrombosis. The work will be of great interest to individuals in the hematology and thrombosis 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The authors describe new approaches to improve the analysis of single-molecule tracking data to uncover multiple diffusive states of proteins in living cells. This paper will be of interest to researches from the fields of experimental biology, who are interested in tracking of proteins using microscopy, as well as computational scientists who are interested in devising novel methodologies for analysis of multiple-particle tracking data. The paper presents two advanced techniques for estimation of motion parameters (such as diffusion coefficients) and contains rigorous evaluation using simulated and real biological 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:

The shrimp market is growing globally, with 8.12 tons produced in 2020. The market size is thought to reach $55 billion by 2027. Most of the market comes from farms, the white shrimp, Penaeus vannamei, being one of the most commonly farmed species worldwide. The present study provides a single cell transcriptional atlas of the white shrimp, P. vannamei, immune cells in the hemolymph, known as hemocytes. White shrimp single cell RNA sequencing studies uncovered two macrophage-like populations, one of them with markers similar to mammalian macrophages. These findings redefine the current classification of shrimp immune cells which has been done using morphological approaches and via targeted qPCR studies but never using single cell transcriptomics.

(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:

PLK4 is the master regulator of centriole biogenesis, but whether it is also key for centriole amplification during differentiation of multiciliated cells (MCCs) has been questioned based on PLK4 chemical inhibition. Here, using mouse models engineered to lack PLK4 or PLK4 activity, LoMastro et al provide very compelling evidence that PLK4 and its activity are essential for centriole amplification in MCCs. Moreover, they show that centriole amplification in MCCs drives expansion of their apical surface. The findings will be of interest to cell biologists and experts interested in multi-ciliogenesis-related pathologies.

(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:

To precisely diagnose DM2 caused by CCTG repetition in CNBP, the authors established a Cas9-mediated target enrichment system followed by Nanopore sequencing and analysis. The authors are fully aware of the limitations of the current diagnostic tests of DM2 and efficiently presented what novel findings have been revealed by the Cas9 nanopore sequencing. The findings of the current study suggest that Cas9 nanopore sequencing can be very useful for accurate genetic diagnosis of DM2 and understanding the genotype-phenotype correlation of this 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 #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript will be of broad interest to the field of muscle biology, muscle physiology, exercise physiology, metabolism and circadian rhythms. This manuscript identifies a new molecular pathway that connects circadian rhythms to muscle structure and function through titin isoform switching.

(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 identifies an important role for a lytic polysaccharide monooxygenase in allorecognition in the filamentous fungus Neurospora crassa, which is independent of the catalytic activity of this remarkable class of proteins. The study's findings are strongly supported through an interdisciplinary approach, combining microscopy with genetics and biochemistry. The study will be of great interest to fungal biologists and microbiologists, as well as biochemists studying carbohydrate-active 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript reports that Epac2, a downstream effector of cAMP, positively regulates cocaine reward by altering dopamine release properties in the striatum. These results provide insight into Epac2 as a potential presynaptic molecular target through which dopamine signaling and drug taking might be manipulated and is of interest to scientists studying dopamine transmission and substance use 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. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of broad interest to those working on the regulation of gene expression and mycobacteria as it deals with the collaboration of two important transcription regulators. A combination of experiments indicates how a complex of two regulators selectively turns on gene expression of a few genes in intracellular pathogen Mycobacterium tuberculosis.

(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 addresses the important question of how cell types acquire regional identity during embryonic development. The authors study the role of TBXT in the establishment of posterior identity and show unexpected temporally restricted and cell-specific modes of acquisition of posterior identities in neural crest and spinal cord cells. They conclude that Wnt signaling influences posterior identity acquisition in neural crest cells whereas FGF is the main driver for spinal cord axial patterning.

(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 addresses an interesting an important topic bearing on the initiation of labor at the end of pregnancy, invoking interleukin-33 in an alteration of Ca2+ homeostasis in uterine smooth muscle. The study implicated altered IL-33 expression in the third trimester of pregnancy in the endoplasmic reticular stress that might be involved in initiating labor.

(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 provides new insights into one of the most enigmatic brain regions; the posterior cingulate cortex. Using electrophysiological recordings from dorsal and ventral PCC subregions, the authors provide evidence for a dorsal-executive and ventral-episodic functional subdivision. This paper will be of high interest to a broad range of neuroscientists.

(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 paper is of interest to neuroscientists studying the organization of neural activity and of behavior. The authors link the apparently scale-free distributions of behavioral metrics with scale-free distributions of neural activity, and then explore computationally mechanistic models that could account for these observations. While the alternative view set up in the introduction - that scale-free neural activity is "'background activity', not linked to behavior" - is perhaps overly simplistic, the analysis is thorough, and the mechanistic insights garnered from the computational modeling are intriguing.

(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 use a mouse stroke model to address a potential cellular source of functional recovery. Using multiple lineage tracing paradigms, they show that undifferentiated progenitor cells that migrate from the subventricular zone produce trophic factors including VEGF that promote functional and cellular recovery. These findings will be of interest to the neuroscience community, and those who study neural repair.

(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:

In this study, the authors assess the decline of retinal function in a mouse model of slow photoreceptor degeneration. The authors use a linear-nonlinear receptive field model to characterize functional changes across some RGC populations and information theory to assess the fidelity of RGC signaling. They show remarkable preservation of cone-driven ganglion cell light responses in advanced stages of a retinitis pigmentosa model when most rods have died, and cone morphologies are dramatically altered. The results are presented clearly in the text and figures and are scholarly discussed. However, there are several technical and conceptual concerns with the conclusions that can be drawn.

(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:

Meechan et al. present a systematic approach to semi-automate an ultramicrotome operation for targeting a specific plane aided by x-ray tomography measurements. It is a fundamental work of great interest to any users of using electron microscopy (EM), particularly when targeting the imaging of thin sections in a select region of interest by ultramicrotomy, or when targeting volume EM of select sample regions. The manuscript documents with exceptional detail a workflow including both microtome modifications and software adaptations for semi-automated targeting of structures with micrometer precision, resulting in a faster and more accurate orientation of the image acquisition planes for volume electron microscopy, a task that has traditionally been difficult and time-consuming. Therefore, this work will reduce sample preparation labor and, critically, facilitate the comparison of the ultrastructure of multiple samples. The method is based on X-ray imaging acquisition prior to any sectioning and proposes a solution for the two instruments commercially available in the field, and by transparently sharing all the data, hardware, and software, and by describing every detail of the workflow, this fundamental method can be readily adopted by any practitioner, enabling its wide application - it is a key step in the field regarding speed-up, accuracy, and reproducibility in electron microscopy.

(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:

In this manuscript, the authors developed a sensitive single particle tracking method for endogenous AMPA receptors. They found that AMPAR-containing vesicles showed reduced mobility near stimulation sites, likely due to increased F-actin bundling in dendritic shafts. The study found a novel mechanism of AMPAR trafficking using state-of-the-art labeling and analysis techniques, and thus will be of great interest for broad audience. However, their conclusion requires additional 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.)