Molecular Biology

eLife assessment

This study provides a valuable survey of SMAD1/5 direct transcriptional events at the time of uterine receptivity to pregnancy in the mouse. The evidence supporting the authors' claims is solid, although functional validation, a more thorough genome-wide bioinformatic analysis, and better provision of methodological details would strengthen the study. The work will be of interest to reproductive biologists.

eLife assessment

In a valuable study that will be of interest to the mechanistic membrane transport community, the authors capture the first cryo-EM structure of the inward facing melbiose transporter MelB, a well-studied model transporter from the major facilitator (MFS) superfamily. Cryo-EM experiments and supporting biophysical experiments provide solid evidence for transporter conformational changes. The supporting evidence is incomplete in that the maps were not provided for review.

eLife assessment

In this valuable study the authors propose a new regulatory role for one the most abundant circRNAs, circHIPK3, mediated by the RNA binding protein IGF2BP2. While the study presents interesting and largely solid evidence, part of the work is incomplete, requiring additional controls to more robustly support the major claims. The work would also benefit from further discussion addressing the apparently contradictory effects of circHIPK3 and STAT3 depletion in cancer progression.

eLife assessment

This manuscript provides important insights into the degradation of a host tRNA modification enzyme TRMT1 by SARS-CoV-2 protease nsp5. The data convincingly support the main conclusions of the paper. These results will be of interest to virologists interested in studying the alterations in tRNA modifications, host methyltransferases, and viral infections.

eLife assessment

This useful article reports the possible roles of the natural product TRPV1 activator Eugenol on muscle performance and remodeling. It provides as yet incomplete evidence for eugenol, through TRPV1, but nevertheless merits future investigation.

eLife assessment

This study presents valuable findings on the presence of 6mA in the Drosophila genome and challenges previous findings regarding the role of TET in 6mA modification. The evidence supporting the claims is solid, and the paper has the potential to stimulate re-evaluations of the significance and regulatory mechanisms of 6mA DNA modifications in Drosophila.

eLife assessment

This important study reports the cryo-electron microscopy structure of a multi-protein complex that recognizes the 5'-end cap of mRNAs and plays a critical role in mRNA export. The structural analyses and biochemical assays in this study provide convincing evidence to support the major claims of the authors, although the inclusion of more functional characterizations in cell-based systems would have strengthened the study. This paper would be of interest to structural biologists and RNA biologists working on mRNA metabolism.

eLife assessment

This valuable study reports comprehensive multi-omic data on the changes induced in young and aged male mouse tail fibroblasts after treatment with chemical reprogramming factors. The authors claim that chemical reprogramming factors induce changes consistent with a reduction of cellular 'biological' age (e.g., correlations with established aging markers in whole tissues). However, the study relies on previously identified aging markers (instead of aging in the tail fibroblast system itself), and thus, at this stage, the evidence in support of the observed molecular changes truly reflecting changes in biological age in the study system is still incomplete.

eLife assessment

This fundamental study offers a compelling molecular model for the organization of rootlets, a critical organelle that links cilia to the basal body, ensuring proper anchoring. While previous research has explored rootlet structure and organization, this study delivers an unprecedented level of resolution, important to the centrosome and cilia field. The model proposed by the authors will serve as a reference for future studies.

eLife assessment

This paper is of interest to cell biologists studying the mechanisms of protein posttranslational modifications. The study investigates Cullin-RING ubiquitin E3 ligases (CRLs) that regulate cyclin D1 protein stability in cells by utilizing siRNA screening and ectopic expression approaches. By screening a siRNA library containing different E3 ligases, the authors identified a previously uncharacterized combination of Cullin 1-7 and associated E3 ligases (Keap1-CUL3, DDB2-CUL4A/4B, WSB2-CUL2/5, and RBX1-CUL1-7) that are important for cyclin D1 ubiquitination and proteasome-mediated degradation.

eLife assessment

This valuable study draws attention to the importance of a previously overlooked structural motif in kinase regulation. While the data presented are intriguing, the analysis is incomplete. Additional experiments are needed to support the authors' hypothesis. The work will be of interest to protein biochemists and enzymologists with an interest in kinases and allostery.

eLife assessment:

This important study combines molecular genetics and target validation to discover genes involved in obesity and determine their role. The reviewers unanimously agree that the work is important in terms of significance: it has conceptual and practical implications beyond metabolism, including embryonic and placental development. They also considered that the strength of evidence is convincing from the use of their forward genetic screen in mice. In some instances, reviewers considered that the work was not more than solid because although the methods, data, and analyses broadly support the claims, minor weaknesses emerge on which they suggest improvements for you to consider and selectively address.

eLife assessment

This paper presents valuable insights into the implication of PI3Ka in heterotopic ossification (HO), and illustrates a potential therapeutic efficacy of BYL719 in suppressing HO within a murine model of Fibrodysplasia Ossificans Progressiva. While certain data are novel and compelling, others exhibit redundancies with prior publications and are inadequate in terms of methodology and presentation. Additionally, elucidating the precise molecular mechanisms of BYL719's action is imperative for a comprehensive understanding.

eLife assessment

Antibodies are some of the most critical tools in biomedical research. However, their quality and specificity vary significantly. This fundamental study provides guidelines for how the quality of an antibody should be assessed and recorded and provides compelling data on the selected antibodies. This paper will be of interest to researchers working in experimental cell biology.

eLife assessment

This study combines CLIP, RNA-seq, and splicing assays with manipulation of RBMX and its homologs RBMY and RBMXL2 to show that the RBMX family suppresses the recognition of cryptic splicing within long exons. The study is important in that it puts forward the intriguing claim that the RBMX family is responsible for the cryptic splice site repression in ultra-long exons. The methods, data, and analyses supporting the claims are solid, broadly supporting the claims, with some weaknesses. The generalization of the findings is somewhat overstated but could be strengthened by deeper statistical integration of the RNA-seq and CLIP datasets.

eLife assessment

This manuscript describes a deep mutational scanning study of the kinase domain of the MET receptor tyrosine kinase. The study yields a valuable catalog of essentially all possible deleterious mutations in this portion of the receptor., with convincing evidence. The manuscript will be of interest to researchers working in the field of receptor tyrosine kinases.

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 important study advances our knowledge of Drosophila Bonus, the sole ortholog of the mammalian transcriptional regulator Tif1. Solid evidence, both in vivo and in vitro, shows how SUMOylation controls the function of the Bonus protein and what the impact of SUMOylation on the function of Bonus protein in the ovary is.

eLife assessment

This manuscript presents a useful method for a comprehensive numerical simulation to systematically characterise the effect of heterogeneity in either the initial conditions or the biophysical parameters on the dynamic behaviour of protein signalling networks. Nevertheless, the presentation and detail of their model appear incomplete to fully support the main claims of the manuscript.

eLife assessment

This work presents convincing evidence for the presence of wooly mammoth/rhinoceros ancient environmental DNA (aeDNA) far from the time likely to host living individuals: what is effectively a genetic version of a geological inclusion. These are important findings that will have ramifications for the interpretation and conclusions extracted from aeDNA more generally.