Evaluated articles

eLife Assessment

The authors performed extensive coarse-grained molecular dynamics simulations of 140 different prion-like domain variants to interrogate how specific amino acid substitutions determine the driving forces for phase separation. The analyses are solid, and the derived predictive scaling laws can aid in identifying potential phase-separating regions in uncharacterized proteins. Overall, this is a valuable contribution to the field of biomolecular condensates. It exemplifies how data-driven methodologies can uncover new insights into complex biological phenomena.

eLife Assessment

This study highlights an important discovery: a bacterial pathogen's effector influences plant responses that in turn affect how the leafhopper insect vector for the bacteria is attracted to the plants in a sex-dependent manner. The research is backed by convincing physiological and transcriptome analyses. This study unveils a complex interdependence between the pathogen effector, male leafhoppers, and a plant transcription factor in modulating female attraction to the plant, shedding light on previously unexplored aspects of plant-bacteria-insect interactions.

eLife assessment

This valuable study provides new insights into the neural circuits involved in post-mating responses in Drosophila females. It presents convincing evidence that the circuits for mating receptivity and egg-laying are distinct. A more thorough discussion regarding the integration of the new findings into the current understanding of post-mating behavior as well as clarification of some experimental details would further improve the manuscript.

eLife Assessment

These important findings detail the role of Pim1 and Pim2 in controlling the behaviour and activity of 'killer' T cells; a vital cell within of our immune system. The authors capitalized on high resolution quantitative analysis of the proteomes and transcriptomes of Pim1/Pim2-deficient CD8 T cells to provide compelling evidence for how the PIM1/2 kinases control TCR-driven activation and IL-2/IL-15-driven proliferation and differentiation into effector T cells. It's also noteworthy that Pim1/Pim2 impact is better revealed through quantitative proteomics than transcriptomics.

eLife Assessment

This important body of work uses state-of-the-art quantitative methods to characterize and compare behaviors across five different fish species to understand which features are conserved and which ones are differentiated. The convincing results from this study will be of interest to ethologists and also have potential utility in understanding the neural mechanisms leading to these behaviors.

eLife assessment

This fundamental study provides a near-comprehensive anatomical description and annotation of neurons in a male Drosophila ventral nerve cord, based on large-scale circuit reconstruction from electron microscopy. This connectome resource will be of substantial interest to neuroscientists interested in sensorimotor control, neural development, and analysis of brain connectivity. However, although the evidence is extensive and compelling, the presentation of results in this very large manuscript lacks clarity and concision.

eLife assessment

This paper describes an important advance in an in vitro neural culture system to generate mature, functional, diverse, and geometrically consistent cultures, in a 384-well format with defined dimensions and the absence of the necrotic core, which persists for up to 300 days. The well-based format and conserved geometry make it a promising tool for arrayed screening studies. Some of the evidence is incomplete and could benefit from a more direct head-to-head comparison with more standard culture methods and standardization of cell seeding density as well as further data on reproducibility in each well and for each cell line.

eLife assessment

This important study describes the crystallographic screening of a number of small molecules against a viral enzyme critical for the 5' capping of SARS-CoV-2 RNA and viral replication. While the high-quality crystal structures and complementary biophysical assays in this study provide solid evidence to support the major claims regarding how these small molecule compounds bind to the viral enzyme, the mismatch between the antiviral activity and binding to the viral enzyme of several small molecule compounds could have been more thoroughly investigated or discussed. This paper would be of interest to the fields of coronavirus biology, structural biology, and drug discovery.

eLife Assessment

This landmark study elucidates the intricate structural mechanisms by which both covalent and non-covalent synthetic ligands can co-occupy the binding pocket of the nuclear receptor transcription factor PPARγ. Through a compelling integration of structural, biochemical, and biophysical evidence, the authors challenge the reliability of two commonly used covalent inhibitors. These findings have far-reaching implications for the broader field of nuclear receptor research. This work will be of high interest to structural biologists and biochemists exploring ligand interactions within the nuclear receptor superfamily.

eLife Assessment

This study uses state-of-the-art methods to label endogenous dopamine receptors in a subset of Drosophila mushroom body neuronal types. The authors report that Dop1R1 and Dop2R receptors, which have opposing effects on intracellular cAMP, are present in axons termini of Kenyon cells, as well as those of two classes of dopaminergic neurons that innervate the mushroom body indicative of autocrine modulation by dopaminergic neurons. Additional experiments showing opposing effects of starvation on Dop1R1 and Dop2R levels in mushroom body neurons are consistent with a role for dopamine receptor levels increasing the efficiency of learned food-odour associations in starved flies. Supported by solid data, this is an important contribution to the field.

eLife Assessment

This is an important study demonstrating that anosmia in Parkinson's disease patients is due to dysfunction in cholinergic neurons. This study provides compelling evidence, using scRNA sequencing, that cholinergic olfactory projection neurons (OPN) are consistently affected in five different fruit fly models of Parkinson's disease, exhibiting synaptic dysfunction before the onset of motor deficits. Comparisons with scRNA sequencing of patients' human brain samples reveals similar synaptic gene deregulation in cholinergic neurons of patients. This study points the possibility that targeting cholinergic neurons could be a potential avenue for early diagnosis and intervention in PD.

eLife assessment

This study presents a valuable finding that PRMT inhibitors may exert synergistic effects with PARP inhibitors to eliminate ovarian and triple-negative cancer cells in vitro and in vivo using preclinical mouse models. The evidence supporting the claims of the authors is solid, although the inclusion of novelty justification would have strengthened the study. The work will be of interest to scientists working on breast cancer and ovarian cancer.

eLife assessment

This important work, leveraging state-of-the-art whole-night sleep EEG-fMRI methods, advances our understanding of the brain states underlying sleep and wakefulness. Despite a small sample size, the authors present convincing evidence for substates within N2 and REM sleep stages, with reliable transition structure, supporting the perspective that there are more than the five canonical sleep/wake states.

eLife assessment

This useful study shows the representations that emerge in a recurrent neural network trained on a navigation task by requiring path integration and decodability. The network modeling was solid, but interpretation of neural data and mechanisms was incomplete.

eLife Assessment

This valuable study uses fluorescence lifetime imaging and steady-state and time-resolved transition metal ion FRET to characterize conformational transitions in the isolated cyclic nucleotide binding domain of a bacterial CNG channel. The data are compelling and support the authors' conclusions. The results advance the understanding of allosteric mechanisms in CNBD channels and have theoretical and practical implications for other studies of protein allostery. A limitation is that only the cytosolic fragments of the channel were studied.

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

It is known from model organisms that genes' effects on traits are often modulated by environmental variables, but similar gene-by-environment (GxE) interactions have been difficult to detect using statistical analyses of genomic data, e.g., in humans. This study introduces a new framework to estimate gene-by-environment effects, treating it as a bias-variance tradeoff problem. The authors convincingly show that greater statistical power can be achieved in detecting GxE if an underlying model of polygenic GxE is assumed. This polygenic amplification model is a truly novel view with fundamental promise for the detection of GxE in genomic datasets, especially with continued development to detect more complex signals of amplification.

eLife assessment

This valuable study explores T cell receptor activation during autoreactive T cell development and how the strength of T cell receptor engagement in naïve cells can predispose T cells to develop into effector/memory T cells. Solid evidence confirms published data that naïve T cells with higher CD5 expression were poised for activation and more pathogenic in the mouse model of autoimmune diabetes. However, the evidence regarding the regulation of differentiation of these cells during development is still incomplete.

eLife Assessment

This study provides valuable information on the single nucleus RNA sequencing transcriptome, pathways, and cell types in pig skeletal muscle in response to conjugated linoleic acid (CLA) supplementation. Based on the comprehensive data analyses, the data are considered compelling and provide new insight into the mechanisms underlying intramuscular fat deposition and muscle fiber remodeling. The study contributes significantly to the understanding of nutritional strategies for fat infiltration in pig muscle.

eLife Assessment

This study offers valuable insights into the conformational dynamics of the nucleic acid recognition lobe of GeoCas9, a thermophilic Cas9 from Geobacillus stearothermophilus. The authors investigate the influence of local dynamics and allosteric regulation on guide RNA binding affinity and DNA cleavage specificity through molecular dynamics simulations, advanced NMR techniques, RNA binding studies, and mutagenesis. While the mutations studied do not lead to significant changes in GeoCas9 cleavage activity, the study provides convincing evidence for the role of allosteric mechanisms and interdomain communication in Cas9 enzymes, and will be of great interest to biochemists and biophysicists exploring these complex systems.