Evaluated articles

eLife assessment

Semenova et al. have studied a large cross-sectional cohort of people living with HIV on suppressive antiretroviral therapy and performed high dimensional flow-cytometry for analysis with data science/machine learning approaches to investigate associations of immunological and clinical parameters and intact/total HIV DNA levels (and categorizations). The study is useful in introducing these new methods and large data set and appears mostly solid, though some of the claims were incompletely supported by the modeling results. The authors have revised the text to fairly reflect their results, yet open questions remain about utility, particularly as to the value of categorical classification (vs continuous measurement) of reservoir size.

eLife assessment

This useful study aimed to quantify associations between regular use of proton-pump inhibitors (PPI) with the occurrence of respiratory infections, such as influenza, pneumonia, COVID-19, and others over a period of several years. PPI use was associated with increased risks of influenza, pneumonia, but not of COVID-19, although severity and mortality of COVID-19 infections were higher in PPI users. There are inevitable weaknesses of the study design used, such as the fact that PPI use was only measured at one time-point whereas infections were assessed over a long time period, but these are appropriately highlighted in the discussion. Weaknesses are highlighted in the discussion and the study presents convincing evidence for the conclusions overall.

eLife assessment

In this important study, the authors found, with the use of statistical methods, that compound heterozygous rare deletion variants affecting the kinase-domain of non-receptor tyrosine kinase TNK2/ACK1 and PTK6/BRK are associated with human systemic lupus erythematosus (SLE). The authors use a convincing mouse experimental model and human-induced pluripotent stem cell (hiPSC)-derived macrophages to clarify cause-effect relationships and the cellular basis of nephritis. With the identification of new SLE-related genes, this manuscript improves our understanding of human SLE pathogenesis.

eLife assessment

This paper provides important insights into the role of rice OsNF-YB7, an ortholog of Arabidopsis LEC1, in chlorophyll biosynthesis, uncovering the genetic and molecular basis for negative regulation of chlorophyll production in the rice embryo. Mutational analysis, gene expression profiles and protein interaction combine for convincing evidence that OsNF-YB7 represses chlorophyll biosynthesis.

eLife assessment

This important study uses single-cell RNA-seq to obtain a more granular understanding of cell subsets within allergic contact dermatitis in a model system with DNFB. The convincing data revela unique subpopulations of dermal fibroblasts as key responders to interferon gamma and likely as mediators of dermatitis. This study has many novel aspects and provides a unique resource as well.

eLife Assessment

This important study describes mRNA shortening during cellular stress and interestingly observes that this shortening is dependent on localization in stress granules. Surprisingly, this mRNA shortening does not appear to require the shortening of poly A tails. These are novel, paradigm-shifting findings, using cutting-edge technologies and convincing data, that should be of broad interest to the RNA community and beyond.

eLife assessment

This important study combines fMRI and electrophysiology in sedated and awake rats to show that LFPs strongly explain spatial correlations in resting-state fMRI but only weakly explain temporal variability. The authors propose that other, electrophysiology-invisible mechanisms contribute to the fMRI signal. The evidence supporting the separation of spatial and temporal correlations is convincing, and the authors consider alternative potential factors that could account for the differences in spatial and temporal correlation that were observed. This work will be of interest to researchers who study the mechanisms behind resting-state fMRI.

eLife Assessment

This fundamental study illuminates the dynamics of BRAF in its monomeric and dimeric forms, both in the absence and presence of inhibitors, through a convincing combination of traditional experiments and sophisticated computational analyses. By revealing novel insights into the selectivity and cooperative processes of BRAF inhibitors, it holds significant promise for the development of future therapeutics, particularly against mutant isoforms in cancer. Overall, these findings will be of great interest to structural biologists, medicinal chemists, and pharmacologists.

eLife assessment

This valuable manuscript shows that the optogenetic stimulation of direct and indirect pathway spiny projection neurons (SPNs) in the dorsomedial versus the dorsolateral striatum has different consequences for locomotor activity, real-time place preference, and action selection, in a contextually mediated manner. The evidence in support of this conclusion is solid but would be further strengthened through deeper analysis of the effect and specificity of optogenetic manipulations on SPN activity. These findings will be of interest to neuroscientists, particularly behavioral neuroscientists.

eLife Assessment

This well-designed study provides important findings concerning the way the brain encodes prediction about self-generated sensory inputs. The authors report that neurons in auditory cortex respond to mismatches in locomotion-driven auditory feedback and that those responses can be enhanced by concurrent mismatches in visual inputs. While there remain alternative explanations for some of the data, these findings provide convincing support for the role of predictive processing in cortical function by indicating that sensorimotor prediction errors in one modality influence the computation of prediction errors in another modality.

eLife assessment

This important manuscript provides compelling experimental evidence of extended motivational signals encoded in the mouse anterior cingulate cortex (ACC) that are implemented by orbitofrontal cortex (OFC)-to-ACC signaling during learning. The experimental methods used were state-of-the-art. These results will be of interest to those interested in cortical function, learning, and/or motivation.

eLife Assessment

This important work compares the strain properties of a-synuclein fibrils isolated from LBD and MSA patient samples with the resulting amplified fibrils following SAA. Using orthogonal biochemical and structural approaches to strengthen their analyses, the authors provide solid evidence that the SAA-amplified fibrils do not recapitulate the disease-relevant strains present in the patient samples. CryoEM would further strengthen this data but it is outside the scope of the work. This work should be considered in the widespread applications of SAA in synucleopathies and its potential limitations.

eLife Assessment

This study presents important methodologies for repeated brain ultrasound localization microscopy (ULM) in awake mice and a set of results indicating that wakefulness reduces vascularity and blood flow velocity. The data supporting these findings are solid. This study is relevant for scientists investigating vascular physiology in the brain.

eLife Assessment

This useful study describes expression profiling by scRNA-seq of thousands of cells of recombinant yeast genotypes from a system that models natural genetic variation. The rigorous new method presented here shows promise for improving the efficiency of genotype-to-phenotype mapping in yeast, providing convincing evidence for its efficacy. This manuscript focuses on overcoming technical challenges with this approach and identifies several new biological insights that build upon the field of genotype-to-phenotype mapping, a central question of interest to geneticists and evolutionary biologists.

eLife assessment

This important study presents a new quantitative imaging pipeline that describes with high temporal precision and throughput the movements of late-stage Drosophila embryos, a critical moment when motion first appears. A new approach is used to explore the role of miRNAs in motion onset and presents solid evidence that shows a role for miR-2b-1 and its target Motor in embryonic motion. The data are well supported even if the mechanistic insight into the emergence of movement remains to be explored.

eLife assessment

This study provides valuable insights into the role of actin dynamics in regulating the transition of fusion models during homotypic fusion between late endosomes. The evidence supporting the authors' claims is convincing. However, while the observations are significant, the study could benefit from further exploration of the mechanistic details and physiological relevance.

eLife Assessment

This paper investigates the Achilles' heel of an aggressive pediatric bone cancer known as Ewing sarcoma. The authors aimed to better understand how its previously undruggable drivers mediate oncogenic mechanisms using several omics approaches. Transcriptomic changes aligned with their findings provide convincing evidence for the role of a short alpha helix in the DNA binding domain of FLI1 in modulating binding to GGAA microsatellites and promoting enhancer activity. The study provides valuable new insights into the underlying oncogenic mechanisms in Ewing sarcoma.

eLife assessment

In this interesting study, Drożdżyk and colleagues analyze the ability of placental CALHM orthologs to form stable complexes, identifying that CALHM2 and CALHM4 form heterooligomeric channels. The authors then determine cryo-EM structures of heterooligomeric CALHM2 and CALHM4 that reveal a distinct arrangement in which the two orthologs can interact, but preferentially segregate in the channel. This is an important study; the data provide compelling support for the interpretations and overall, the work is clearly described.

eLife Assessment

This manuscript presents solid evidence suggesting that the loss of ZNRF3 and RNF43, two E3 ubiquitin ligases, leads to dysregulation of EGFR signaling in cancer. The authors propose that EGFR is a direct substrate of ZNRF3/RNF43. While the authors provide immunoprecipitation data showing increased detection of ubiquitinated species, this evidence does not definitively establish that EGFR itself is ubiquitinated by RNF43/ZNRF3. The absence of direct evidence for EGFR ubiquitination is a major limitation, although the findings are useful as they may provide novel insights into the mechanisms underlying EGFR-driven cancers and open new therapeutic avenues.