Molecular Biology

eLife assessment

In this valuable study, the authors investigate the transcriptional landscape of tuberculous meningitis. They reveal potentially significant molecular differences contributed by HIV co-infection, and derive a prognostic model to predict mortality combining a gene expression signature with clinical parameters. Whilst some of the evidence presented is compelling, the bioinformatics analysis remains limited and cannot be used to make causal inferences and conclusions about immunopathogenesis for tuberculous meningitis. The work will be of broad interest to the infectious disease community however, further validation of the findings is critical for future utility.

eLife assessment

This study presents valuable insights into the potential role of a general transcription factor in MYCN-dependent regulation of transcription. The study presents solid evidence that TFIIIC and MYCN interact to control transcription. The methods, data, and analyses broadly support the claims with minor weaknesses, yet the logic can be improved, and several specific issues should be addressed. The paper would be of interest to molecular biologists working on MYCN-dependent regulation of gene expression.

eLife assessment

This study offers valuable insights into the remarkable resistance of tardigrades to ionizing radiation by showing that radiation treatment induces a suite of DNA repair proteins. They identify a strongly induced tardigrade-specific DNA-binding protein that can reduce the number of double-strand breaks in human cancer-derived cells. The evidence of upregulation of repair proteins is compelling and the case for a role of the newly identified protein in repair can be strengthened as genetic tools for tardigrades become better developed. The results will be of interest the fields of DNA repair and radiobiology as well as tardigrade biologists.

eLife assessment

The study elucidates a detailed molecular mechanism of the initial stages of transport in a medically relevant GABA neurotransmitter transporter GAT1 and thus generates useful new insights for this protein family. In particular, it presents convincing evidence for the presence of a "staging binding site" that locally concentrates Na+ ions to increase transport activity, whilst solid evidence for how Na+ binding affects the larger scale dynamics.

eLife assessment

This study presents evidence that suggests that the coalescence of sister chromatids induced by global double-strand DNA breaks (DSBs) during late mitosis is mediated by cohesin SMC3. These findings are valuable for studying the mechanism of eukaryotic cells to repair DNA during late mitosis. Although the discrete DSB induction system in budding yeast is sound, the strength of evidence is incomplete and could be buttressed to better support the major claims and to represent a clear advance with respect to the authors' previous contributions to this field.

eLife assessment

This is a potentially important study that deals with the toxic effects of an intermediary in lipid degradation [trans-2-hexadecenal (t-2-hex)] in yeast through modification of mitochondrial protein import via the TOM complex. However, in the current version, the claims are incompletely supported by the data. Lacking is evidence that Tom40 is a direct target of the lipid derivative or causally implicated in the described consequences. Were such evidence forthcoming, the paper would be interesting to a broad audience of molecular and cell biologists.

eLife assessment

This valuable study applies voltage clamp fluorometry to provide new information about the function of serotonin-gated ion channels 5-HT3AR. The authors convincingly investigate structural changes inside and outside the orthosteric site elicited by agonists, partial agonists, and antagonists, helping to annotate existing cryo-EM structures. This work confirms that the activation of 5-HT3 receptors is similar to other members of this well-studied receptor superfamily. The work will be of interest to scientists working on channel biophysics but also drug development targeting ligand-gated ion channels.

eLife assessment

The OpuA Type I ABC importer uses two substrate binding domains to capture extracellular glycine betaine and present the substrate to the transmembrane domain for subsequent transport and correction of internal dehydration. This study presents valuable findings addressing the question of whether the two substrate binding domains of OpuA dock and physically interact in a salt-dependent manner. The single-molecule fluorescence resonance energy transfer and cryogenic electron microscopy data that are presented provide convincing support for the existence of a transient interaction between the substrate binding domains that depends on ionic strength, laying a foundation for future studies exploring how this interaction is involved in the overall transport mechanism.

eLife assessment

This study shows that the yeast transcription factor Sfp1 binds to a subset of its target gene mRNAs, increases their half-lives, and affects RNA polymerase II backtracking. These, and other related findings, provide important new insights into mechanisms by which a transcription factor can affect post-transcriptional steps in gene regulation. The main claims are partially backed by the evidence presented. However, the evidence remains incomplete as the methods used to estimate RNA degradation rates and the biochemistry of Sfp1-RNA complexes require further validation.

eLife assessment

The manuscript provides interesting evidence that miR-199b-5p regulates osteoarthritis and as such it may be considered as a potential therapeutic target. This finding may be useful to further advance the field. Although the study is considered potentially clinically relevant, the evidence provided was deemed insufficient and incomplete to support the conclusions drawn by the authors.

eLife assessment

Based on the observation of an increase in miR-182-5p in diabetic patients, the authors propose that miR-182-5p and its target gene LRP6 may play a role in dysregulated glucose tolerance and fatty acid metabolism in obese type 2 diabetics. The use of human livers complemented by supporting data in mice and cells are strengths, but the evidence presented remains incomplete. Nonetheless, the findings provide valuable insights into the role of miRNAs in the regulation of liver metabolism and insulin sensitivity in individuals with diabetes and fatty liver disease.

eLife assessment

This study presents two valuable new mouse models that individually tag proteins from the SMAD family to identify distinct roles during early pregnancy. Convincing evidence is provided that SMAD1 and SMAD5 target many of the same genomic regions as each other and the progesterone receptor. Given the broad effect of these signaling pathways in multiple systems, these new tools will most likely interest readers across biological disciplines.

eLife assessment

In an important 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.

eLife assessment

This study explores the role of one the most abundant circRNAs, circHIPK3, in bladder cancer cells, providing convincing data that circHIPK3 depletion affects thousands of genes and that those downregulated (including STAT3) share an 11-mer motif with circHIPK3, corresponding to a binding site for IGF2BP2. The experiments demonstrate that circHIPK3 can compete with the downregulated mRNAs targets for IGF2BP2 binding and that IGF2BP2 depletion antagonizes the effect of circHIPK3 depletion by upregulating the genes containing the 11-mer motif. These valuable findings contribute to the growing recognition of the complexity of cancer signaling regulation and highlight the intricate interplay between circRNAs and protein-coding genes in tumorigenesis.

eLife assessment

This manuscript provides important insights into the degradation of the host tRNA modification enzyme TRMT1 by the SARS-CoV-2 protease Nsp5 (nonstructural protein 5 or MPro). The data convincingly support the main conclusions of the paper. These results will be of interest to virologists 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 investigates the presence of DNA adenine methylation (6mA) and the associated function of TET enzyme, a DNA methylation mark eraser, in Drosophila. The study presents valuable findings on the scarcity 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 important study reports comprehensive multi-omics data on the changes induced in young and aged male mouse tail fibroblasts after treatment with chemical reprogramming factors. The authors provide solid evidence to support their 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).

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.