Evaluated articles

eLife assessment

This valuable manuscript presents resources for genome-wide genetic perturbation in the fruitfly, Drosophila. The evidence for the usefulness is solid, with the authors demonstrating that they can identify novel genes that affect an important pathway, the mTOR pathway, which plays key roles in cell proliferation and cell death. The genetic resources are significant for their availability to colleagues in the Drosophila community seeking to to identify genes with important cellular functions.

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Descovich et al examine the important decision between proliferative (planar) and differentiation (perpendicular) divisions in the basal layers of the skin and find a key promoter of perpendicular divisions is inhibited by its paralog to specify planar divisions. The authors use sophisticated mouse genetics and imaging and discover that LGN and its paralog AGS3 function antagonistically in determining perpendicular vs. planar divisions. Some statements need to be tamed or further backed up, but overall this study provides a significant advance in the field.

eLife assessment

This is an important study on the role of a bacterial cell wall component, D-alanylated lipoteichoic acid, as a bacteria cue in Drosophila melanogaster-microbiome interactions. Overall, the evidence supporting the conclusions is compelling, with a solid approach combining crystallography with biochemical and cellular assays, that take advantage of both fly and bacterial mutants, to demonstrate a physiological role in juvenile growth promotion. The work will be of broad interest to those studying host-microbe interactions, especially as it is related to immunology and metabolism mediated by the microbiome.

eLife assessment

The manuscript describes a fundamental study of the atypical MAPK, ERK3, in the activation of RhoGTPase Cdc42 and the formation of actin-rich protrusions and cell migration. The results show that ERK3 is required for the motility of tumor cells in vivo, providing a new target for fighting metastasis.

eLife assessment

These are important findings that show that pupil size is not only governed by the locus coeruleus but also by other neuromodulatory subcortical systems. Furthermore, the authors demonstrate that using a standard hemodynamic response kernel is not appropriate for capturing the activity of these systems, at least at rest. Thus, this paper presents compelling evidence against two prevalent working assumptions among researchers in the field.

eLife assessment

This important work utilizes a model organism, zebrafish, to explore changes to the proteome and the role of KLHL40, a component of the ubiquitin-proteasome system, in the development of skeletal muscle disease. Using mass spectrometry, the authors demonstrate a major and selective role for proteome remodeling in development. They identify a specific role for KLHL40 deletion in regulating the expression of Sar1 - a key component of biosynthetic secretion, where the resulting elevated levels of Sar1 expression potentially lead to collagen secretion defects in the disease state. The findings are incomplete as further experimental characterization of the overall morphological changes and secretion defects, in particular ones derived from the deregulation of Sar1 levels, is required.

eLife assessment

In this useful study, a GWAS-type analysis is applied to clinical Mycobacterium tuberculosis isolates to discover genetic polymorphisms linked to poor tuberculosis outcomes. The evidence for the detected associations is still incomplete, as the corresponding polymorphisms are not adequate to power a prediction model for infection outcome, although key host factors - including patient age, sex, and duration of diagnostic delay (which have stronger predictive value) - appear to enhance predictive capacity.

eLife Assessment:

The manuscript by Godoy and colleagues is an important contribution to the understanding of how lung endothelial regeneration progresses following endothelial ablation. The novelty and elegance of this study are rooted in the regional and specific ablation of lung endothelial cells using diphtheria toxin without the massive inflammatory activation that is seen with lung injury induced by bacterial infections, viral infections, or lipopolysaccharide. The data convincingly demonstrate that there is an emergence of a highly proliferative lung endothelial subpopulation that drives endothelial regeneration. The translational implications of the study include the identification of potential therapeutic targets to augment endothelial regeneration as a treatment for ALI/ARDS. This study will be of interest to vascular biologists, lung biologists, and researchers studying adult tissue regeneration.

eLife assessment

This is an important contribution to colorectal cancer research to understand how we can predict high-risk patients for recurrence. The strength of the evidence is solid and looks at a novel approach but an approach that still has opportunities to improve.

eLife assessment

This study provides an important demonstration that loneliness is associated with smaller hippocampal volume, reduced cortical thickness, and worse cognition in healthy older adults. This has theoretical or practical implications beyond a single subfield. The strength of evidence is solid given the cross-sectional and longitudinal design with a few weaknesses. With the analytical and interpretational part strengthened, this paper would be of interest to gerontologists, and dementia/cognitive aging researchers.

eLife assessment

This paper provides strong evidence for the important point that microtubule function is required for the proper localization of Glut4 glucose transporters in an insulin responsive compartment. This membrane localization is required in turn for effective translocation of Glut4 to the muscle cell surface in response to the hormone.

eLife assessment

This paper deals with an important unsolved problem in developmental biology of how cells execute their dynamics at the right time. The study combines compelling quantitative single cell and single transcript experiments with genetic perturbations and computational modelling and provides important insights into how the timing of transcription is regulated. The work would be strengthened by better integration of modeling and data.

eLife assessment

This important study uses two well-established colorectal cancer models to estimate the potential impact of disruptions in screening caused by the COVID-19 pandemic. By dividing the population into separate cohorts based on age and pre-pandemic screening status, the authors provide convincing evidence for the adverse impact of delays in screening, switching regimens, and screening discontinuation. The finding that discontinuation has a much greater impact on screening-associated gains in life expectancy than shorter-term delays or switching of regimens suggests that access-related barriers to screening resumption may lead to the worsening of current disparities.

eLife assessment

This is an interesting study investigating the propagation dynamics of ripples recorded from the dorsal hippocampus of mice using an open-access dataset. Findings may have theoretical and practical implications for the study and manipulation of sharp-wave ripples, a main oscillatory event underlying memory consolidation. While the strength of evidence is solid and claims broadly supported, there are some points requiring additional analysis to clarify issues regarding the anatomical axes involved and to reinforce mechanistic insights.

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This study presents valuable findings on how the ectopic expression of the Lck protein tyrosine kinase in Chronic Lymphocytic Leukemias (CLL) contributes to malignant transformation. The evidence supporting the claims of the authors is solid, although the use of gene editing to directly explore the functions unique to LCK in a CLL model would increase the appeal of the work.

eLife assessment

This study provides valuable insight into the diversity within the NRAMP superfamily of transporters. Evidence of divalent metal ion transport and the structure (obtained without added metal ions) are convincing. However, molecular insight into Al3+ recognition and transport is incomplete, and the work would be strengthened by the determination of a metal-bound structure or additional experiments (such as molecular dynamics simulations or quantitative Al3+ binding/transport assays) to support the proposed Al3+ binding site. The work will be of interest to structural biologists and biophysicists studying NRAMP transporters.

eLife assessment

The authors use data from 3 cross-sectional age-stratified serosurveys on Enterovirus D68 from England between 2006 and 2017 to examine the transmission dynamics of this pathogen in this setting. Understanding these dynamics, including how it changes over time, may help uncover potential changes in the transmissibility of the virus. While the topic is relevant, interpretation of the results challenging largely due to the great uncertainty around how to interpret the serological (serostatus) data, and the impact this has on the inferences made. We ask the authors to perform some additional analyses and to provide more intuition to understand some of the key findings of this analysis.

eLife assessment

In this manuscript, a method to test a large number of drug combinations in a single cell culture sample is presented. The strength of the evidence lies in their multiple experiments with different combinations of agents. The paper suggests that results from this application are feasible and the methodology could be applied in other laboratories to use drug combinations for defined outcomes.

eLife assessment

The authors' finding that Btk kinase activation relies on specific interactions with the Grb2 scaffold protein, including for recruitment into signaling clusters on membranes, is an unexpected finding that will potentially be of broad interest. The authors make a case for reinterpretation of the "Saraste dimer" of Btk as a signaling entity and assign roles to the component domains in the Src module in Btk activation, but the data provided are not yet fully convincing for this scenario.

eLife assessment

This is a very interesting and important study that convincingly demonstrates a descending pathway for the control of nociception in non-mammalian organisms.