Evaluated articles

Evaluation Summary:

Budjan et al. describe an organoid protocol to obtain somite-like structures from human iPSCs. Using defined culture media, the authors describe the formation after 5 days in vitro of organoids that express a variety of PSM differentiation markers, such as the segmentation clock gene Hes7 and Pax3. Optimization of their culture conditions and transcription analyses of what they name their "somitoid" system revealed that their culture system recapitulates the time course of expression markers typically observed along PSM and somite early differentiation. Furthermore, somitoid reacted to Shh activation by activating sclerotomal markers Pax1 and 9.

(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 magnetic resonance imaging and responsive imaging probes. In this work, a new imaging probe is designed and applied in proof-of-principle animal models, with future promise for relevance in models that have higher relevance to human 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

In this manuscript, the authors study the discrepancy between the frequency of mutations in Gq alpha subunit (GNAQ and its paralogue GNA11) in uveal vs cutaneous melanoma. They hypothesize that the restriction of GNAQ and GNA11 mutations to non-epithelial melanomas is due to epidermal factors, which convert the impact of GNAQ Q209L mutation from being oncogenic to being inhibitory to melanocyte survival and proliferation, and reduce the maintenance, rather than the establishment of interfollicular epithelial melanocytes. This work provides new insights into the poorly understood difference in mutation frequency in different melanoma types.

(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 tolerance to change in the sequence of telomere repeats, by analyzing a strain expressing mutant TLC1, the RNA component of the telomerase. The authors conclude that Rif2 protects telomere ends in the absence of RAP1 by inhibiting MRX and promoting Rad51-dependent homologous recombination to maintain telomere homeostasis. The study clarifies the role of Rif2 in telomere homeostais and describes how cells can extend telomeres and control senescence in the absence of Rap1 binding to telomeres. The possibility of coping with telomere sequence modification through flexibility and redundancy of capping proteins is of general interest in terms of telomere evolution.

(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 manuscript uses a combination of high-quality in vivo electrophysiology and modelling to demonstrate that Behavioural Time Scale Plasticity (BTSP) is bidirectional, and the amplitude and direction of this plasticity are dictated by the current weight of the inputs and not by the correlated activity of pairs of neurons. These findings challenge our current views on synaptic plasticity, which are primarily based on Hebb's concept. In addition, the network model used in this study demonstrates that this type of plasticity can rapidly reshape population activity to respond to environmental clues. This study will be of interest to the broad neuroscience audience and foster new ideas on biological and artificial learning.

(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:

This manuscript aims to characterize cardiac tissues from patients who developed Covid-19. The authors studied pathological and normal tissues using microtomography scans performed at different resolution scales. Starting on the reconstructed volumes, special automatic analytical procedures were developed to extract some quantitative structural parameters about the samples themselves. This characterization method was used previously in the study of murine heart models. The main outcome of the research is that there are some well defined characteristics found in tissues of COVID patients that are not revealed in other pathological and normal samples.

(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:

There are mixed results from studies of COVID-19 outcomes in patients treated with statins and there are multiple confounders. The authors use two Mendelian randomization methods to explore the association between HMGCoA reductase inhibitors (statins) and other lipid lowering drugs and outcomes and find that increased expression of HMGCoA reductase and HMGCoA reductase mediated LDL cholesterol increase hospitalization risk. This makes it possible but does not prove that statins could improve outcomes which will be of broad interest.

(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:

This work attempts to extract information about protein thermodynamics from X-ray crystallography data, which is a challenging problem. This work presents a comprehensive examination of the structural transitions associated with small molecule binding to proteins. The heterogenous pattern of order parameter changes in response to ligand binding implies that the approach is identifying new information. This work offers insights into ligand binding affinity and specificity mechanisms, suggesting that distal (allosteric) perturbations represent a possible avenue to modulate protein function.

(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:

Truncated splice variants of the androgen receptor (AR) lacking a ligand-binding domain are thought to contribute to therapeutic resistance to antiandrogens in advanced prostate cancer. In this manuscript, the authors show that AR-V7, the most well-studied such truncated variant, displays a different mechanism of nuclear targeting and interaction with chromatin compared to the full-length AR. This work provides new insights into how AR-V7 may contribute to the pathology of Castrate-Resistant Prostate Cancer and will be of interest to researchers trying to improve prostate cancer therapies.

(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 is of interest to a broad audience of cell biologists, pharmacologists and researchers who work in metabolic diseases. The work provides substantial new insights into the mechanism of action for a plant derived pentacyclic triterpene called celastrol elastrol, in effectively reducing the high fat diet induced tissue hypertrophy in mouse liver and adipose. A series of compelling experiments depict the site of covalent inhibition of the ER stress sensor GRP78 as essential for the beneficial effects in-vivo, supporting the main 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 #1 agreed to share their name with the authors.)

Evaluation Summary:

This study examined the effects of social isolation in adolescent and adult male mice, a topic timely and relevant. The work sheds light on oxytocin as a key regulator that modulates the dopaminergic midbrain imparting long-lasting effects on social interaction. A critical open question is whether these results would apply to female subjects. The findings will merit from more thorough interpretations and controls of social behavior data and synaptic plasticity. This paper will be of interest to those interested in social neuroscience and plasticity in general.

(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 performed transcriptomic analyses from compartment-specific, micro-dissected hippocampal region tissue from transgenic mice. One feature that distinguishes this work from previous studies is the use of conditional knock-in tags (GFP or HA) and tissue specific expression of the Cre recombinase to target a population of pyramidal neurons in the CA1 region. The strengths of the paper are the rich data sets and innovative integration of methods that will provide a valuable technical resource for 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

De la Concepcion and colleagues investigated the mode of co-evolution of plant immune receptor pair that functions as a unit to detect pathogen invasion and turn on immunity. The study shows that an allelic mismatch of a receptor paired from rice can cause autoimmunity in the absence of pathogen effectors, and this can be traced to polymorphisms that arose fairly recently. Overall the study provides insights into the co-evolution of paired receptors and supports that the paired receptors have co-evolved to prevent premature inactivation and enable strong activation in response to matching effectors.

(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:

This study is of broad interest to researchers in the field of entomology and physiology. These findings may shed light on at least one mechanism underlying selective advantages conferred to insect species on evolutionary timescales. Though the chemical signal, its source and recipient tissues underlying thermogenesis are elucidated, hypotheses regarding their downstream effects remain to be substantiated.

(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 reports a robust and well-characterized expansion method that achieves 10X expansion with a single expansion step using a simple, easy-to-use protocol. The new protocol leads to an enabling methodology for super-resolution imaging of various sub-cellular structures and organelles and is likely to have a high 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 agreed to share their name with the authors.)

Evaluation Summary:

This paper is of broad interest to readers who are interested in understanding cell migration and the cytoskeleton. It characterizes new behaviors of actin-based stress fibers in vivo during collective cell migration, and provides important observations that contribute to our fundamental understanding of these structures. The use of high-resolution live imaging in combination with Drosophila genetics and pharmacological inhibitors provides compelling data that supports the major claims of the paper.

(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:

This paper addresses the very extremely interesting question of how spontaneous activity in the cochlea prior to hearing onset impacts the development of auditory circuits in the brainstem. The study has many strengths, including the use of complementary in vitro and in vivo recording techniques to characterize both peripheral and central defects resulting from conditional deletion of the gene for the chloride channel TMEM16A. The reviewers identified some concerns over the interpretation of the data and felt that the results could be discussed more in the context of other work, which might require some additional experiments.

(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 will be of high interest to readers in the field of the molecular mechanisms of synaptic operation. The functional demonstration of two different topological states of Munc13 involved in, Ca2+-independent and Ca2+-dependent, synaptic vesicle priming is a remarkable contribution to further understand key mechanisms of neurotransmitter release and its modulation. A multidisciplinary, solid and careful study supported by simulations of molecular dynamics, in vitro assays of membrane fusion and synaptic electrophysiology of mouse hippocampal neurons.

(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:

Aggregates of the protein Tau are a key pathological features of Alzheimer's Disease and several other neurodegenerative disorders (Tauopathies). Hori et al. examined the effects of an acute elevation of Tau levels in synapses, employing high-end paired pre-post-synaptic patch-clamp recordings at the Calyx of Held model synapse. The authors generated a technically very rigorous dataset indicating that increased levels of soluble Tau impair pre-synaptic endocytosis and, consequently, neurotransmission by sequestering Dynamin-1 on microtubules, and propose that this process is part of a synaptic manifestation of Tauopathies. The findings are of major relevance for basic neuronal cell biology and translational neuroscience alike. However, several aspects of the proposed molecular mechanism underlying the synaptic effects of elevated Tau levels remain less clear.

(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 examines model neuron solution sets - combinations of ionic membrane conductance parameters that allow the model to produce functional output properties - and how the extent and shape of these solutions sets depends on ion channel pleiotropy, i.e., that ion channels can influence multiple outputs simultaneously. The work provides an organizing framework for previous experimental and modeling studies related to degeneracy of solutions, ion channel correlations, and homeostatic regulation, and should therefore be of interest to researchers in this area.

(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.)