Evaluated articles

eLife Assessment

This work introduces FunC-ESMs, a proteome-scale framework to classify loss-of-function missense variants into distinct mechanistic groups by combining two complementary state-of-the-art machine learning models. The strength of evidence is convincing, supported by solid benchmarking, integration with experimental datasets, and careful methodological design. The significance of the findings is valuable, providing a resource of clear interest to researchers and diagnostic laboratories working on variant interpretation.

eLife Assessment

This study offers a valuable methodological advance by introducing a gene panel selection approach that captures combinatorial specificity to define cell identity. The findings address key limitations of current single-gene marker methods. The evidence is compelling, but would be strengthened by further validation of rare cell states and unexpected marker categories.

eLife Assessment

This study addresses an important question in liver biology: how zonal hepatocytes balance survival and proliferation following injury; using spatial transcriptomics, mechanistic perturbations, and functional assays, the authors propose that a mid-zone Atf4-Chop axis to Btg2 program temporarily suppresses proliferation to promote survival during APAP-induced hepatotoxicity. The idea that distinct intrahepatic zones mount tailored stress responses is conceptually significant and has implications for regeneration and toxicology. The dataset is rich and the methodology modern, but several conclusions rely on assumptions about zonation under injury, limited injury models, and incomplete functional validation of the Atf4-Chop-Btg2 axis. With targeted revisions and additional experiments, the work has the potential to provide strong mechanistic insights into liver zonation and injury responses.

eLife Assessment

This study presents an important finding by identifying OPG as a novel stromal checkpoint influencing T-cell anti-tumor responses, thereby shedding new light on the complex interplay between the tumor microenvironment and immune regulation. The data are robust and the experimental approaches are sound, providing solid support for the study's conclusions; however, there are a number of additional questions raised by the data. Of particular note are the questions raised on the mechanistic effects of TRAIL versus RANKL. In addition, it would broaden the interest in this study to include more translational human data to complement the work presented.

eLife Assessment

This work reveals metabolic pathways and molecular events mechanistically linked to B cell activation. Using an unbiased, comprehensive proteome profiling method and various functional validation approaches, this study generated convincing evidence suggesting a role for amino acid uptake, cholesterol accumulation, and protein prenylation in the proliferation, survival, and biogenesis of B cells stimulated with LPS and other activating stimuli. The significance of the findings is considered to be fundamental, in that they will advance our understanding of cell metabolism during B cell activation.

eLife assessment

This is a valuable study that combines a wide range of approaches to provide a biophysical and evolutionary mechanism that could explain why some particular mutations in the SARS-CoV-2 protein N arose during the COVID-19 pandemic. The evidence is solid and relies on multiple experimental approaches. However, some of the results were dependent on extremely high protein concentrations, which may affect certain conclusions.

eLife Assessment

The study reports a potential pathway for isoleucine biosynthesis mediated by the underground activity of AHASII, which converts glyoxylate and pyruvate to 2-ketobutyrate. While the findings are valuable in revealing a possible alternative route for isoleucine production, the evidence presented remains incomplete. More comprehensive biochemical experiments are required to substantiate the physiological feasibility of this pathway.

eLife Assessment

The reviewers have found that this manuscript is a valuable contribution, and the evidence in support of its conclusions is mostly solid. It provides novel insights and raises interesting possibilities about the functions of an understudied histone modification within the nucleosome core; however, the data are mostly descriptive and correlative, and although this has value, it is not totally persuasive. Short of additional non-genomic experiments, a more detailed analysis of the genomic data and perhaps additional data would strengthen the conclusions. The manuscript crucially needs further antibody validation to raise confidence in the data.

eLife Assessment

This important manuscript evaluates how sample size and demographic balance of reference cohorts affect the reliability of normative models. The evidence supporting the conclusions is convincing, although some additional analysis and clarifications could improve the generalisability of the conclusions. This work will be of interest to clinicians and scientists working with normative models.

eLife Assessment

This valuable study compares auditory cortex responses to sounds and cochlear implant stimulation measured with surface electrode grids in rats. Beyond the reduced frequency resolution of cochlear implants observed previously, this study suggests key discrepancies between neuronal representations of cochlear stimulations and natural sounds. However, the evidence for this potentially interesting result is incomplete because there is a lack of evidence for the effectiveness of the comparison method. This study is of interest to researchers in the auditory neuroscience field and clinicians implementing treatments with cochlear implants.

eLife Assessment

This important study shows that visual search for upright and rotated objects is affected by rotating participants in a VR and gravitational reference frame. However, the evidence supporting this conclusion is incomplete, given the authors' use of normalized response time and the assumption that object recognition across rotations requires mental rotation.

eLife Assessment

This important study uses simultaneous EEG and fMRI recordings to shed light on the relationship between alpha and gamma oscillations and specific cortical layers. The sophisticated methodology provides solid evidence for correlations between oscillatory power and the strength and contents of fMRI signals in different cortical layers, though some caveats remain. This paper will be of interest to neuroscientists studying the role and mechanisms of alpha and gamma oscillations.

eLife Assessment

This paper presents a valuable theory and analysis of the role of neurogenesis and inhibitory plasticity in the drift of neural representations in the olfactory system. For one of the findings, regarding the impact of neurogenesis on the drift, the evidence remains incomplete. The reason lies in the differences in variability/drift of the mitral/tufted cell responses observed in the model compared to experimental observations, where these responses remain stable over extended time scales.

eLife Assessment

This study provides important results with regard to the ongoing debate of the relationship between internalizing psychopathology and learning under uncertainty. The methods and analyses are solid, and the results are backed by a large sample size, yet the study could still benefit from a more detailed discussion about the difference in experimental design and analysis compared to previous studies. If these concerns are addressed, this study would be of interest to researchers in clinical and computational psychiatry for the behavioral markers of psychopathological symptoms.

eLife Assessment

This important study uses innovative microfluidics-based single-cell imaging to monitor replicative lifespan, protein localization, and intracellular iron levels in aging yeast cells. The evidence for the proposed role of Ssd1 and reduced nutrients for lifespan through limiting iron uptake is convincing, even though some mechanistic details remain unclear. This work will be of interest to cell biologists working on aging and iron metabolism.

eLife Assessment

The authors describe an interesting approach to studying the dynamics and function of membrane proteins in different lipid environments. The important findings have theoretical and practical implications beyond the study of EGFR to all membrane signalling proteins. The evidence supporting the conclusions is convincing, based on the use of a nanodisk system to study membrane proteins in vitro, combined with state-of-the-art single-molecule FRET. The work will be of broad interest to cell biologists and biochemists.

eLife Assessment

This interesting study adapts machine learning tools to analyze movements of a chromatin locus in living cells in response to serum starvation. The machine learning approach developed is useful, the experiments are well controlled, and the data are solid. The study would be greatly strengthened by testing key predictions made using perturbation experiments. This work will be of interest to those studying chromosome biology and gene expression patterns.

eLife Assessment

Ruppert et al. investigated how activation of thermogenesis by cold exposure (CE) and methionine restriction (MetR) impacts health and leads to weight loss in mice. The authors provided valuable datasets showing that the responses to MR and CE are tissue-specific, while MR and CE affect beige adipose similarly. Although the study is descriptive, the data analyses are solid, with well-supported conclusions drawn from the findings.

eLife Assessment

This useful study investigates how intrinsically disordered domains can interact to dictate the sub-cellular localization of a major innate immune sensor termed cGAS. The data from various cellular and biochemical assays are mostly solid, but the main conclusions from these experiments need to be validated further. This paper is relevant to immunologists, especially those interested in cytosolic DNA-sensing pathways.

eLife Assessment

In this valuable study, through carefully executed and rigorously controlled experiments, the authors challenged a previously reported role of the Death Receptor 6 (DR6/Tnfrsf21) in Wallerian degeneration (WD). Using two DR6 knockout mouse lines and multiple WD assays, both in vitro and in vivo, the authors provided convincing evidence that loss of DR6 in mice does not protect peripheral axons from WD after injury. Questions remain about whether this conclusion is generalizable to CNS axonal degeneration in disease models such as ALS, AD, and prion diseases. In addition, the authors need to provide information about the sex, age, and genetic background of their animal studies to allow readers to better assess the basis for inconsistencies from previous reports on the protective effects of DR6.