Evaluated articles

eLife Assessment

Endothelial cell-specific loss of TGF-beta signaling in mice leads to CNS vascular defects, specifically impairing retinal development and promoting immune cell infiltration. The data are solid, showing that loss of TGF-beta signaling triggers vascular inflammation and attracts immune cells specific to CNS vasculature. These findings are important, highlighting TGF-beta's role in maintaining vascular-immune homeostasis and its therapeutic potential in neurovascular inflammatory diseases.

eLife Assessment

This study presents an important finding linking the bacterial metabolite trimethylamine and its receptor to circadian rhythms and olfaction. The current evidence supporting the claims of the authors is compelling. This work will be of broad interest to researchers interested in nutrition, microbial metabolism, circadian rhythms, and host-microbiome interactions.

eLife Assessment

This valuable study addresses the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau pathology in Caenorhabditis elegans and human cell culture models. The methods are solid and the proposed mechanisms are conceivable. However, the current evidence is incomplete and could be strengthened, due to reliance on imaging data and insufficient biochemical validation. The work will be of broad interest to cell biologists and biologists working on Alzheimer's disease and related proteinopathies.

eLife Assessment

This important series of studies provides converging results from complementary neuroimaging and behavioral experiments to identify human brain regions involved in representing regular geometric shapes and their core features. Geometric shape concepts are present across diverse human cultures and possibly involved in human capabilities such as numerical cognition and mathematical reasoning. Identifying the brain networks involved in geometric shape representation is of broad interest to researchers studying human visual perception, reasoning, and cognition. The evidence supporting the presence of representation of geometric shape regularity in dorsal parietal and prefrontal cortex is solid, but does not directly demonstrate that these circuits overlap with those involved in mathematical reasoning. Furthermore, the links to defining features of geometric objects and with mathematical and symbolic reasoning would benefit from stronger evidence from more fine-tuned experimental tasks varying the stimuli and experience.

eLife Assessment

This fundamental study combines in vitro reconstitution experiments and molecular dynamics simulations to elucidate how membrane lipids are transported from the outer to the inner membrane of mitochondria. The authors provide convincing evidence that a positive membrane curvature is critical for membrane lipid extraction. The work will be of broad interest to cell biologists and biochemists.

eLife Assessment

This study identifies 53BP1 as an interaction partner of GMCL1 (a likely CUL3 substrate receptor). The study proposes a novel mechanism by which cancer cells evade the mitotic surveillance pathway through GMCL1-mediated degradation of 53BP1, leading to reduced p53 activation and paclitaxel resistance. These data are the most useful aspect of the study, but the data supporting the authors' conclusions as to the clinical relevance of the study are inadequate. The authors have not taken relevant data about the clinical mechanism of taxanes into account.

eLife Assessment

This study provides important insights into mural cell dynamics and vascular pathology using a zebrafish model of cerebral small vessel disease. The authors present convincing evidence that partial loss of foxf2 function results in progressive, cell-autonomous defects in pericytes accompanied by endothelial abnormalities across the lifespan. By leveraging advanced in vivo imaging and genetic approaches, the work establishes zebrafish as a powerful and relevant model for dissecting the cellular mechanisms underlying cerebral small vessel disease.

eLife Assessment

The authors present a set of wrappers around previously developed software and machine-learning toolkits, and demonstrate their use in identifying endogenous sterols binding to a GPCR. The resulting pipeline is potentially useful for molecular pharmacology researchers due to its accessibility and ease of use. However, the evidence supporting the GPCR-related findings remains incomplete, as the machine-learning model shows indications of overfitting, and no direct ligand-binding assays are provided for validation.

eLife Assessment

This valuable study expands the inventory of polyadenylated RNAs cleaved by the double-stranded RNA endonuclease Rnt1 in budding yeast, using solid methodology based on high-throughput sequencing. Previous studies had anecdotally discovered mRNA substrates, and this global characterization is comprehensive with multiple complementary controls. This study sets the stage for deeper investigations into the biological function of Rnt1 and substrate cleavage.

eLife Assessment

This important study addresses the role of non-genetic factors in individual differences in phenotype. Using C. elegans, the study finds that non-genetic differences in gene expression, partly influenced by the environment, correlate with individual differences in two reproductive traits. This supports the use of gene expression data as a key intermediate for understanding complex traits. The clever study design makes for compelling evidence.

eLife Assessment

This useful study presents the potentially interesting idea that LRRK2 regulates cellular BMP levels and their release via extracellular vesicles, with GCase activity further modulating this process in mutant LRRK2-expressing cells. However, some of the evidence supporting these conclusions remains incomplete, and additional work is suggested under certain conditions. Overall, the study will be of interest to cell biologists working on Parkinson's disease.

eLife Assessment

This manuscript introduces a useful protein-stability-based fitness model for simulating protein evolution and unifying non-neutral models of molecular evolution with phylogenetic models. The model is applied to five viral proteins that are of structural and functional importance. While the general modelling approach is solid, and effectively preserves folding stability, the evidence for the model's predictive power remains limited, since it shows little improvement over neutral models in predicting protein evolution. The work should be of interest to researchers developing theoretical models of molecular evolution.

eLife Assessment

This study presents a valuable assessment of and solid evidence for increased similarity in visual appearance combined with increased chemical differences between two butterfly species in sympatry compared with differences between three populations of one of the two species in allopatry. The similarity in visual appearance hints to an evolutionary response to shared predators (but alternative explanations are possible). Thus, the difference in chemical signaling likely helps to avoid between-species mating in sympatry.

eLife Assessment

This study presents a valuable advance for the analysis of gene expression variation at the level of individual cells by introducing a novel reference-free framework that can detect splicing, fusion, editing, immune-receptor diversity and repeated elements in sequencing data. The evidence supporting these claims is solid, with rigorous validation on simulated datasets and extensive analysis of full-length single-cell sequencing data demonstrating improved performance over existing methods. This work will be of particular interest to researchers developing methods for high-resolution transcriptome analysis and to those studying cellular heterogeneity in health and disease.

eLife Assessment

This important study investigated whether the nuclear receptor Nur77 is regulated by a non-canonical mechanism of ligand-induced disruption of its interaction with RXRg, similar to the family member Nurr1. The overall evidence is solid, but additional mechanisms that have not been fully explored in this study might contribute as well. This manuscript will be of interest to scientists focusing on mechanisms of transcriptional regulation.

eLife Assessment

This study presents an important finding on the role of GATA4 in aging- and OA-associated cartilage pathology. The conclusions are well supported by compelling in vitro and in vivo evidence. This work will be of broad interest to both cell biologists and orthopedic/skeletal health clinicians.

eLife Assessment

This important study applies an innovative multi-model strategy to implicate the ribosomal protein (RP) encoding genes as candidates causing Hypoplastic Left Heart Syndrome. The evidence from the screen in stem cell-derived cardiomyocytes and whole genome sequencing of human patients, followed by functional analyses of RP genes in fly and fish models, is convincing and supports the authors' claims. This work and methodology applied would be of broad interest to medical biologists working on congenital heart diseases.

eLife Assessment

This study clarifies that stalled RNA pol II is not sufficient for AID targeting, which is important to the field. The authors provide solid experimental evidence that RNA poll II stalling is not the driving mechanism for AID targeting, and even though the results are generally "negative", they are highly relevant to our current understanding of SHM. The authors propose premature transcription termination as a possible mechanism to determine V gene mutability, but the study does not experimentally address such possibilities. This paper makes investigators rethink the model with which AID finds single-strand DNA in the genome.

eLife Assessment

This landmark study describes the structure of the human RAD51 filament with a recombination intermediate called the displacement loop (D-loop). Using cryogenic structural, biochemical, and single-molecule analyses, the authors provide compelling evidence on how the RAD51 filament promotes strand exchange between single-stranded and double-stranded DNAs. The findings are highly relevant to the fields of homologous recombination, DNA repair, and genome stability.

eLife Assessment

This fundamental study demonstrates how a left-right bias in the relationship between numerical magnitude and space depends on brain lateralization. The evidence is compelling and will be of interest to researchers studying numerical cognition, brain lateralization, and cognitive brain development more broadly.