Evaluated articles

eLife Assessment

This manuscript presents an important contribution to the field of single-cell transcriptomic analysis in cancer by introducing a novel computational framework-SCellBOW-which applies embedding techniques from natural language processing to model phenotypic heterogeneity in tumors. The revised version includes new validation experiments and significant clarifications that provide convincing evidence for the method's utility. The authors have benchmarked SCellBOW across diverse datasets, including glioblastoma, breast, and metastatic prostate cancer, and have demonstrated its superior performance compared to existing state-of-the-art methods.

eLife Assessment

The authors studied cognitive control signals in the anterior cingulate cortex (ACC) while rats selected between small immediate and larger delayed rewards. The description of behavioral strategies related to value-tracking signals in ACC is potentially useful. The evidence in support of this finding is incomplete due to issues with the task design, analyses, and modeling.

eLife Assessment

Working with a diverse panel of rice accessions grown in field conditions, this valuable study measures changes in transcript abundance, tests for patterns of selection on gene expression, and maps the genetic basic of variation in gene expression in normal and elevated salinity treatments. The manuscript provides solid evidence that mean gene expression levels are further from the optimum abundance for more genes under the elevated salinity treatment compared to normal treatment, and that a relatively small number of genes are hotspots that harbor genetic variants which affect broader genome-wide patterns of natural variation in gene expression under high salinity conditions. However, the design, clarity, and interpretation of several statistical analyses can be improved, some opportunities for integration among datasets and analyses could yet be realized, and genetic manipulation is required to confirm functional involvement of any specific genes in regulatory networks or organismal traits that confer adaptation to higher salinity conditions. The manuscript will be of interest to evolutionary biologists studying the genetics of complex traits and a resource for plant biologists studying mechanisms of abiotic stress tolerance.

eLife assessment

This study provides a valuable characterization of individual sarcomere's contractility and synchrony in spontaneously beating cardiomyocytes as a function of substrate stiffness. The authors, however, provide an incomplete explanation for the observed heterogeneous and stochastic dynamics, so that the work remains mainly descriptive. The work will be of interest to scientists working on muscle biophysics, nonlinear dynamics, and synchronization phenomena in biological systems.

eLife Assessment

This study demonstrates a novel role for SIRT4; a mitochondrial deacetylase, shown to translocate into nuclei where it regulates RNA alternative splicing by modulating U2AF2 and the gene expression of CCN2 in tubular cells in response to TGF-β. This fundamental work substantially advances our understanding of kidney fibrosis development and offers a potential therapeutic approach. The evidence supporting the conclusions of a SIRT4-U2AF2-CCN2 axis activated by TGF-β is compelling and adds a new layer of complexity to the pathogenesis of chronic kidney disease.

eLife assessment

Zhao et al. report valuable adverse effects on cell proliferation, differentiation and gene expression, possibly linked to reduced binding activity of the transcription factor GTF2IRD1 to the transthyretin (TTR) promoter, in a human forebrain organoid model of Williams Syndrome (WS). The authors provide incomplete evidence of the effects of GTF2IRD1, a mutated gene in WS, on altering MAPK/ERK pathway activity, a well-recognized target in cell proliferation.

eLife Assessment

This study provides new insights into the expression profile of ILCs that demonstrate a history of RAG expression. It examines in part the potential intrinsic regulation of RAG expression and seeks to understand how the epigenetic state of ILCs is established, although a full understanding of intrinsic factors is only partially supported. The work provides a convincing and important molecular dataset, and strengthens our understanding of intrinsic regulation, and would be of interest more broadly to cell biologists seeking to understand immune cell development.

eLife Assessment

This study presents data on sex differences in gene expression across organs of four mice taxa. The authors have generated a unique and convincing dataset that fills a gap left by previous studies. They claim that sex-biased expression in the soma can overlap between genetic males and females, and that the relevant patterns both turn over quickly over short evolutionary times and do so faster in somatic than gonadal tissues. These conclusions could largely have been predicted by extrapolating from previous findings in the field, but nevertheless demonstrating them directly is a fundamental advance.

[Editorial note: The work was originally assessed by colleagues who are active in the field of evolution of sex differences or in areas adjacent to this field (see initial assessment at https://doi.org/10.7554/eLife.99602.2). The appeals process involved consultation with experts working in other areas of evolutionary biology. The above assessment synthesises the opinions of both sets of reviewers.]

eLife assessment

This paper provides valuable findings related to the impact and timing of exogenous interleukin 2 on the balance of exhausted (Tex) versus effector (Teff) that differentiate from precursors T cells (Tpex) during chronic viral infection. While the data appear solid, the overall claims that IL-2 suppresses Tpex are only partially supported, with the rationale for the timing of IL-2 treatment and its underlying mechanisms remaining unclear.

eLife Assessment

This important study elucidates the molecular function of the SARS-CoV-2 helicase NSP13, which inhibits the transcriptional activity of the YAP/TEAD complex in vitro and in vivo. The evidence supporting the authors' claims is compelling, based on cell biological assays and multi-omic studies. This work contributes to the understanding of the new regulatory mechanism of YAP/TEAD after SARS-CoV-2 infection and will be of interest to researchers investigating COVID-19 infection and the Hippo-YAP signaling pathway.

eLife assessment

This is a useful manuscript describing the competitive binding between Parkin domains to define the importance of dimerization in the mechanism of Parkin regulation and catalytic activity. The evidence supporting the importance of Parkin dimerization for an 'in trans' model of Parkin activity described in this manuscript is solid, but lacks more stringent and biochemical characterization of competitive binding that could provide more direct evidence to support the author's conclusions. This work will be of interest to those focused on defining the molecular mechanisms involved in ubiquitin ligase interactions, PINK-Parkin-mediated mitophagy, and mitochondrial organellar quality control.

eLife assessment

This study provides compelling data that defines the structure of the S. cerevisiae APC/C. The structure reveals overall conservation of its mechanism of action compared to the human APC/C but some important differences that indicate that activation by co-activator binding and phosphorylation are not identical to the human APC/C. Thus this study will be of considerable value to the field.

eLife Assessment

This important study highlights the essential role of AARS2 in safeguarding cardiomyocytes against ischemic stress by modulating energy metabolism towards glycolysis via PKM2. This mechanism unveils a promising new therapeutic target for treating myocardial infarction. Convincing findings are underpinned by a comprehensive dataset, including cardiomyocyte-specific genetic modifications, functional assays, and ribosome profiling, all collectively providing strong evidence for the critical involvement of the AARS2-PKM2 signalling pathway in cardiac protection.

eLife assessment

This valuable study investigates how the human brain flexibly adjusts its representations of the world as the environment continually changes. It utilizes a unique dataset in which participants view thousands of natural scenes across many fMRI sessions over multiple months. The evidence supporting the claims of the authors is incomplete, with statistical inference not always warranted. The study would interest a broad readership in cognitive neuroscience.

eLife Assessment

Cav2 voltage-gated calcium channels play key roles in regulating synaptic strength and plasticity. In contrast to mammals, invertebrates like Drosophila encode a single Cav2 channel, raising questions on how diversity in Cav2 is achieved from a single gene. Here, the authors present solid evidence that two alternatively spliced Cac isoforms enable important changes in Cav2 expression, localization, and function in synaptic transmission and plasticity at the Drosophila neuromuscular junction. How the isoforms affect synaptic calcium channel levels remains less clear. This study provides insights into the roles of voltage-gated calcium channel splice isoforms in synaptic transmission.

eLife Assessment

This study describes the impact of mycobacterial genetic diversity on host-infection phenotypes by assessing the effect of different M. tuberculosis lineages on granulomatous inflammation using a 3D in vitro granuloma model. Despite being descriptive and showing mostly correlative relationships, the findings are useful and provide some solid support regarding the functional impact of M. tuberculosis's natural diversity on host-pathogen interactions. The study will interest researchers working on mycobacteria and motivate future studies to understand how genetic diversity influences virulence and immunity outcomes.

eLife Assessment

The study is a valuable contribution to the question of evolutionary shifts in neuronal proliferation patterns and the timing of developmental progressions. The authors present convincing data which confirm the presence of type-II NB lineages in beetle with the same molecular characteristics as the Drosophila counterparts but differing in lineage size and number. The data lay the foundation for future analysis of the role and molecular characteristics of individual lineages and of whether differences in the identity, proliferation pattern and timing of developmental progression can be linked to differences in the development of functionality of the central complex.

eLife Assessment

This important manuscript describes a creative approach using dual-component gRNAs to create a new class of molecular proximity sensors for genome editing. The authors demonstrate that this tool can be coupled with several different gene editing effectors, showing convincingly that the tool functions as intended. This study not only introduces a first-of-its kind approach, but through careful measurements also enables future further development of the technology.

eLife Assessment

This is an important study providing compelling evidence that the Mediator kinase module mediates an elevated inflammatory response, manifested by heightened cytokine levels, associated with Downs syndrome (DS) via transcriptional changes impacting cell signaling and metabolism that involve mobilization of nuclear receptors by altered lipid metabolites, which has significance for the treatment of DS and other chronic inflammatory conditions. Particular strengths of the study include the combined experimental approaches of transcriptomics, untargeted metabolomics and cytokine screens and the use of sibling matched cell lines (trisomy 21 vs disomy 21) from various donors. Evidence is also provided implicating the Mediator kinase module in controlling mRNA splicing and mitochondrial function that should stimulate new research to elucidate the mechanistic bases for these novel functions.