Evaluated articles

eLife assessment

This paper directly estimates the fitness cost of loss-of-function mutations in almost every gene in the human genome, providing an interpretable measure of the severity of mutations. The authors then compare datasets of presumably healthy individuals and individuals affected by severe complex disorders or genetic disorders, finding enrichment of de novo loss-of-function mutations in highly constrained genes among probands alongside other illuminating results. This important study will be useful to researchers interested in interpreting and prioritizing disease-causing mutations and in the process of human evolution. Overall, the approach is elegant and the results are of high quality and compelling.

eLife assessment

In this manuscript, the authors address the variable results and data regarding the role of the FAAH variant (C385A at the nucleotide level and P129T at the protein level) in the control of feeding. The authors hypothesize that the variable results might be due to the environmental context, specifically stress related conditions. They designed studies to address the role of glucocorticoids in regulating feeding and metabolism.

eLife assessment

In this study the authors show that neural tuning for object orientation in IT is unaffected by whole-body tilt, suggesting that neurons are encoding objects relative to the gravitational vertical. However, these observations could also be because IT neurons may encode object orientation relative to cues and not due to gravity, or due to dynamic, compensatory torsional eye movements made by the animals. With these concerns adequately addressed, this would be an important study showing that IT neurons may play a role not only in object recognition but more broadly in physical scene understanding.

eLife Assessment

In this manuscript, Sell et al., investigate the role of the long non-coding RNA H19 in regulating cellular senescence. Using several cell models they identify upstream and downstream effectors of H19 including let-7 and EZH2. The advances in this work include the identification of a specific cascade of factors connecting H19, senescence and the actions of rapamycin.

eLife assessment

This study presents a valuable finding that adds to a growing body of evidence reporting heritable cell states that can guide fate choices in single cells, in this case the fate of early IFN-I response. The evidence supporting the claims of the authors is solid, although testing the generalizability of the result to other cell types or contexts and strengthening the link to epigenetic regulation would have strengthened the study. Overall, this work will be of interest to a wide set of scientists, including cell biologists, immunologists, and systems biologists.

eLife assessment

This important study reports cryo-EM structures of human ferroportin (FPN), a protein essential for iron transport in humans. This manuscript will be of interest to researchers studying membrane transport mechanisms as well as to those interested in drug design. The structures detail interactions between FPN and the small-molecule inhibitor vamifeport, which is currently in clinical trials for sickle cell disease, and ta new (occluded) protein conformation that is stabilized by a sybody (a nanobody selected from a synthetic library) is identified. Evidence for the mechanism of inhibition by vamifeport is convincing, but evidence for the physiological relevance of the occluded conformation is still incomplete.

eLife assessment

This fundamental work reveals a novel direct projection from the lateral entorhinal cortex to the medial entorhinal cortex. Using multiple techniques, the authors provide compelling evidence that fan cells from the lateral entorhinal cortex project to superficial neurons in the medial entorhinal cortex. This newly identified connection may support the combination of spatial inputs with sensory or high-order signals, providing novel insight into potentially how the 'what' (lateral entorhinal cortex) and 'where' (medial entorhinal cortex) features of memory are incorporated.

eLife assessment

This paper will be of interest to those studying DNA replication in the context of chromatin and development. This important study uncovers a new interaction partner for the chromatin protein SuUR and tries to understand how this complex (SUMM4) functions to control under-replication in polytene chromosomes. While the experiments are of high quality and carefully controlled, the data currently do not fully support all the conclusions, particularly as they relate to conclusions about DNA replication timing.

eLife assessment

This manuscript is extremely useful for describing an R package that provides a valuable pattern and overlay framework for producing colorblind-friendly scatter plots for the field. The utility of this tool for making plots more accessible was demonstrated compellingly. This work will be of broad interest to many biomedical scientists, especially to viewers with color-vision deficiency.

eLife assessment

The authors investigate the cost and benefits of maintaining seemingly redundant multiple copies of the translation machinery components. The authors demonstrate that while redundant multiple copies are beneficial in a nutrient-rich environment, maintaining these extra copies is costly and deleterious in a nutrient-poor environment. This explains why copy numbers of translation machinery genes are under selection according to the environmental niche an organism occupies. The work is very important and the findings exciting and supported by compelling evidence. In particular, the fitness gain upon deletion of translation genes in poor conditions is an insightful observation.

eLife assessment

Giesberg and colleagues provide evidence both in yeast and human cells that fast elongation speeds of RNA polymerases result in a "downstream-shifted" poly(A) profile while the opposite is true for slower speeds of elongating polymerases. GC content of sequences downstream of poly(A) clusters influences the cluster profiles by affecting elongation and thus allowing more time for the 3'-cleavage complex to find the poly(A) site and form the transcript terminus. Although the findings presented in this manuscript are not surprising, they are new and contribute a missing piece to our knowledge of how the transcription machinery determines which poly(A) site to utilize at the end of genes.

eLife assessment

As shown by the authors, the focal adhesion protein, kindlin-2, plays an essential role in liver development in that its genetic inactivation leads to severe fibrosis and death in young mice. This lethality is attributed to increased liver inflammation and cell death. This work will be of interest to readers studying mechanisms of liver development and pathological fibrosis.

eLife assessment

The authors use a clever experimental design and approach to tackle an important set of questions in the field of decision-making. From this work, the authors have a number of intriguing results. However, questions remain regarding the extent to which a number of alternative models and interpretations, not considered in the paper, could account for the observed effects.

eLife assessment

The authors report that, in the murine liver, intermittent fasting alters the homeostatic regenerative programme. This has fundamental implications for the use of murine models to study liver regeneration and cancer and highlights through a series of solid mechanistic studies the role of FGF/Wnt signalling interactions in modulating fasted associated regeneration. It opens up further questions as to why this occurs, how this is beneficial to adapting to a fasting state, and the potential for translation.

eLife assessment

This study, supported by reasonably solid evidence, will be of interest to breast cancer researchers. The finding that EHD2 promotes tumor growth and impacts store-operated calcium entry (SOCE) adds to our understanding of breast cancer cell physiology. If supported by further research, the study provides a rationale for using SOCE inhibitors in a subset of breast cancers, with high expression of EHD2 serving as a potential predictive biomarker for using SOCE inhibitors.

eLife assessment

The paper will be of interest to cognitive neuroscientists in the field of spatial navigation as well as to systems neuroscientists interested in neural representations. Using simultaneous electrophysiological recordings in the anterior thalamus and the retrosplenial cortex, the study investigates the coordination of neurons coding for the head direction in this thalamocortical network. Environmental manipulations led to a near-synchronous update of the head direction signal encoded by the two populations. Further data analysis is needed to support the main claim of the study.

eLife assessment

This paper, which provides useful information on the assembly of volume-regulated anions channels formed by LRRC8 proteins, will be of interest scientists in the field of ion channels. The authors report the structure of a LRRC8C-LRRC8A chimera with native functional properties as a heptameric complex with a lipid-filled pore. This is very interesting and well-presented work, but the evidence supporting the physiological relevance of the heptameric assembly and the hypothesized role of lipids is still incomplete.

eLife assessment

This is an important study that resolves a controversy about a proposed molecular linkage between the fields of mechanobiology and RNA signaling. While prior research had claimed that a specific mechanosensitive ion channel in the gut responds to a specific fecal RNA, this study provides compelling evidence that the mechanosensitive ion channel does not respond to the RNA.

eLife assessment

This paper will interest neuroscientists working in the field(s) of basal ganglia, amygdala, and fear learning. Overall this is an important study that examines the contribution of an understudied brain region to fear conditioning in male subjects. Some conclusions will benefit from additional verification and evaluation of the specificity of the findings to the amygdala-striatal transition zone relative to adjacent regions.

eLife assessment

The fluorescently tagged SYT-1 mouse line will be useful for the field. Importantly, the authors used a comprehensive set of immunohistochemical and physiological experiments to demonstrate that the fluorescence tagging did not alter the function of SYT-1. These are important control experiments that will make the strain useful for physiological experiments in the future. However, the advance of this manuscript is less clear.