Evaluated articles

eLife assessment

This important study addresses mechanisms of feedback inhibition between planar cell polarity (PCP) protein complexes during convergent extension movements in Xenopus embryos. The authors propose an interesting model, in which non-canonical Wnt ligand stimulates transition of Dishevelled from its complex with Vangl to Frizzled, with essential roles of Vangl, Prickle and Ror in this process. The main functional observations supporting this model are convincing, but the immunoprecipitation data are incomplete and would benefit from additional clarification. With more rigorous approaches, this work will likely be of broad interest to cell and developmental biologists.

eLife assessment

The manuscript proposes an alternative method by SDS-PAGE calibration of Halo-Myo10 signals to quantify myosin molecules in filopodia and discusses different scenarios regarding myosin 10 working models to explain intracellular diffusion and targeting to filopodia. Overall, the paper is elegantly written and the methodology is valuable in its descriptive potential as these are key numbers to know to ultimately decipher the cellular mechanism of Myo10 action as well as understand the molecular composition of a Myo10-generated filopodium. The evidence for the conclusions is compelling, but there are limitations to this study which should be kept in mind when applying this method to other systems.

eLife assessment

This useful paper reports on two simple methods for improving the efficiency of prime editing, a prominent gene editing technique. In combination with published modifications, the strategies described in this study may lead to significant improvements in editing efficiencies. The data are solid, and the methods will be of broad interest to anyone using gene editing.

eLife assessment

Toll like receptor 2 (TLR2) signaling has traditionally been viewed a surface protein that induces innate immune responses and improves acquired immunity. Here, the authors suggest a different role for TLR2 in the hair cycle. By using a Cre reporter that is largely, but not solely active in hair follicle stem cells, the authors conditionally delete Tlr2 in mice and report that BMP signaling is sustained and hair cycle entry is delayed. Delving further, the authors identify CEP (2-ω-carboxyethyl pyrrole) as an endogenous ligand of TLR2 in hair follicle stem cell regulation. Although a role for TLR2 signaling in hair follicle stem cells is potentially novel and important, the reviewers remain in consensus that evidence presented in two significant areas continues to be incomplete: 1) where TLR2 and CEP are expressed and how specific is their expression to the hair follicle stem cells; 2) whether as the authors suggest, TLR2 functions by regulating BMP signaling in the stem cell niche of the hair follicle.

eLife assessment

This important study advances our understanding of early Cambrian cnidarian paleoecology and suggests that the reconstructed ancestral feeding and respiration mechanisms predate jet-propelled swimming utilized by modern jellyfish. The work combines solid evidence of fluid and structural mechanics modeling, simulating for the first time the feeding and respiratory capacities in a microfossil (Quadrapyrgites), which in turn opens new possibilities using this approach for paleontological research. Assuming that the prior interpretations and assumptions concerning the modeled organism's soft part and skeletal anatomy are correct, the hypotheses that (1) the organism could alternately contract and expand the oral region and (2) such movement increased feeding efficiency seem plausible.

eLife assessment

This important study combines a range of advanced ultrastructural imaging approaches to define the unusual endosomal system of African trypanosomes. Compelling images reveal that, unlike a conventional set of compartments, the endosome in these protists forms a continuous membrane system with functionally distinct subdomains, as defined by canonical markers for early, late, and recycling endosomes. The findings compellingly support that the endocytic system in bloodstream stages has adapted to support remarkably high rates of membrane turnover necessary for immune complex removal and survival in the blood. This research is particularly relevant to those investigating infectious diseases

eLife assessment

This is an important biophysical study combining native mass spectrometry with mutant cycles to estimate the thermodynamic components of lipid A binding to the ABC transporter MsbA. Solid evidence supports the binding energies for lipid-protein interactions to MsbA using this approach, which could be later applied to other membrane proteins in general.

eLife assessment

This important study reports the identification of a new amino acid sequence motif (i.e., "internal beta-signal") on outer membrane proteins, which is recognized by beta-assembly machinery in gram-negative bacteria. The authors carried out rigorous experiments, providing compelling evidence in support of their conclusions. This work significantly advances our understanding of the biogenesis of outer membrane proteins.

eLife assessment

In this manuscript, the authors tested the hypothesis that Aβ42 toxicity arises from its proven affinity for γ-secretases. The authors provide useful findings, showing convincingly that human Abeta42 inhibits gamma-secretase activity. The data will be of interest to all scientists working on neurodegenerative diseases.

eLife assessment

This valuable study examines the role of the interaction between cytoplasmic N- and C-terminal domains in voltage-dependent gating of Kv10.1 channels. The authors suggest that they have identified a hidden open state in Kv10.1 mutant channels, thus providing a window for observing early conformational transitions associated with channel gating. The evidence supporting the major conclusions is solid, but additional work is required to determine the molecular mechanism underlying the observations in this study. Learning the molecular mechanisms could be significant in understanding the gating mechanisms of the KCNH family and will appeal to biophysicists interested in ion channels and physiologists interested in cancer biology.

eLife assessment

The study presented in this manuscript makes important contributions to our understanding of cell fate decisions and the role of noise in gene regulatory networks. Through computational and theoretical analysis, the authors provide solid support for distinguishing distinct driving forces behind fate decisions based on noise profiles and reprogramming trajectories. While acknowledging the potential limitations of small gene regulatory networks in capturing the richness of whole-transcriptome sequencing datasets, this study offers a creative approach for formulating hypotheses about gene regulation during stem cell differentiation using single-cell sequencing data.

eLife assessment

This valuable paper builds on a method, previously conceptualized and validated, of genetic control for insect populations. The method, called pgSIT, uses integrated CRISPR-Cas9 based constructs to generate, in certain combinations of genotypes, mutations that cause both male sterility and female inviability. Release of such genotypes in sufficiently large numbers can lead to an inundation of a local insect population with sterile males and this can lead to localised population suppression, which represents an effective method of control for problematic insect populations. The data are convincing and will be of interest to anyone working on vector control strategies.

eLife assessment

This useful manuscript presents a new therapeutic formulation and these solid findings have potential clinical significance as the efficacy of CK21 is relevant in various pancreatic cancer models.Further validation studies would help to strengthen the findings.

eLife assessment

This fundamental study provides compelling evidence for a new mechanism of host-microbe interaction, with indole, produced by proliferating bacteria in the C. elegans digestive system, signalling through the host via the transcription factor DAF-16 to induce the expression of genes controlling bacterial growth in the gut. The work is relevant to a wide audience as it invites deeper research into this mechanism, while also serving as a template for similar microbiome/host interactions in other systems.

eLife assessment

This important study reports biochemical and structural experiments that were carried out to determine the molecular basis of calcium-sensitive regulation of the guanine exchange factor Ric8A by the neuronal calcium sensor 1 (NCS-1). Structural and biochemical evidence for the NCS-1/Ric8A interface is convincing, but evidence for the full-length interactions is incomplete due to the low resolution of cryo-EM maps. This work will have important implications for scientists interested in G-protein signaling and molecular interactions that contribute to synapse function.

eLife assessment

This paper reports fundamental findings that substantially advance our understanding of a major research question - how hybridization events influence gene regulatory programs and how evolutionary pressures have shaped these programs in response to such events. The methods, data, and analyses are solid and broadly support the claims with only minor weaknesses. This convincing work uses appropriate and validated methodology in line with the current state-of-the-art.

eLife assessment

Purines are native molecules that affect processes in the immune system, among others. The manuscript describes a valuable investigation of the mode of binding of purines, especially their carbohydrate moiety, to human receptors in cell culture and by computer-based modelling. Solid evidence is presented about the way purines interact with and activate two receptors.

eLife assessment

This study presents a valuable finding on an alternative method that combines multiple inhibitors to maximize on-target inhibition and minimize off-target inhibition. The evidence supporting the claims of the authors is solid, although a proper validation of the methodology could strengthen the paper. The work will be of interest to scientists working in the field of drug discovery, particularly in the field of kinase inhibitors.

eLife assessment

This is an important study that investigates the role of astrocytic Gi signaling in the anterior cingulate cortex in the modulation of extracellular L-lactate level and consequently impairment in flavor-place associates (PA) learning. However, whereas some of the behavioral observations and signaling mechanism data are compelling, the conclusions about effects on memory and the role of L-lactate are based on inadequate methods. With the addition of a few key experiments, this work will be of interest to neuroscientists studying learning and memory and the contribution of astrocytes to these processes.

eLife assessment

This important study delineates the molecular changes driving the progression from actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC). Using state-of-the-art single-cell RNA profiling of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, thus covering comprehensive clinical courses of cSCC, the authors provide an invaluable data resource. This study identified several previously unreported and interesting candidate genes involved in different stages of the malignant progression of skin neoplasias, which have been validated in situ, and partially in vitro. Although data analysis needs improvement and comparison to other published data sets to fully support the claims and conclusions, these findings substantially advance our understanding of the molecular changes leading to skin cancer.