Evaluated articles

eLife assessment

Tilk and colleagues present a computational analysis of tumor transcriptomes to investigate the hypothesis that the large number of somatic mutations in some tumors is detrimental such that these detrimental effects are mitigated by an up-regulation by pathways and mechanisms that prevent protein misfolding. The authors address this question by fitting a model that explains the log expression of a gene as a linear function of the log number of mutations in the tumor and show that specific categories of genes (proteasome, chaperones, ...) tend to be upregulated in tumors with a large number of somatic mutations. Some of the associations presented could arise through confounding, but overall the authors present solid evidence that mutational load is associated with higher expression of genes involved in mitigation of protein misfolding – an important finding with general implications for our understanding of cancer evolution.

eLife assessment

This useful study reports that a week or more of hypoxia exposure in mice increases erythropoiesis and decreases the number of iron-recycling macrophages in the spleen, compromising their capacity for red blood cell phagocytosis – reflected by increased mature erythrocyte retention in the spleen. Compared to an earlier version, the study has been strengthened with mouse experiments under hypobaric hypoxia and complemented by extensive ex vivo analyses. Unfortunately, while some of the evidence is solid, the work as it currently stands only incompletely supports the authors' hypotheses. While the study would benefit from additional experiments that more directly buttress the central claims, it should be of interest to the fields of hemopoiesis and bone marrow biology and possibly also blood cancer.

eLife assessment

This manuscript reports important data on the cellular response to a single site-specific replication fork block in human MCF7 cells. Compelling evidence shows the efficacy of the bacterial Tus-Ter system to stall replication forks in human cells. Fork stalling let to lasting ATR-dependent phosphorylation of histone H2AX but not of ATR itself and its downstream targets RPA and CHK1.

eLife assessment

The manuscript represents an important study on the pathogenesis of rubella virus tropism and neuropathology in human microglia-containing human stem cell derived organoids and human fetal brain slices. The strength of evidence is compelling, employing two different human-relevant models. The findings will be of broad interest to virologists and infectious disease experts, as well as neurodevelopmental biologists. The findings could also be of interest to pediatrics and obstetrics clinical colleagues.

eLife assessment

This valuable study uses multiple large neuroimaging data sets acquired at different points through the lifespan to provide solid evidence that birthweight (BW) is associated with robust and persistent variations in cortical anatomy, but less-substantial influences on cortical change over time. These findings, supported by robust statistical methods, illustrate the long temporal reach of early developmental influences and carry relevance for how we conceptualize, study, and potentially modify such influences more generally. The paper will be of interest to people interested in brain development and aging.

eLife assessment

This valuable study revisits the effects of substitution model selection on phylogenetics by comparing reversible and non-reversible DNA substitution models. The authors provide evidence that 1) non time-reversible models sometimes perform better than general time-reversible models when inferring phylogenetic trees out of simulated viral genome sequence data sets, and that 2) non time-reversible models can fit the real data better than the reversible substitution models commonly used in phylogenetics, a finding consistent with previous work. However, the methods are incomplete in supporting the main conclusion of the manuscript, that is that non time-reversible models should be incorporated in the model selection process for these data sets.

eLife assessment

This important study provides novel strategies to overcome certain limitations when investigating the metabolism of hematopoietic stem cells, mainly due to their low abundance. The study provides compelling evidence suggesting that proliferative hematopoietic stem cells mainly use glycolysis (rather than mitochondrial OXPHOS or TCA cycle) as their primary energy source during emergency hematopoiesis. The article provides direct links between metabolic features and cell proliferation and explores alternative energy sources, and is of great interest to stem cell biologists.

eLife assessment

This important study uses CRISPRi to silence multiple effectors in the pathogen, Legionella pneumophila. It provides a technique that will allow researchers to address functional redundancy amongst effectors, a problem that has persisted even after decades of study. The methodology used is convincing, and further improvement (such as using multiple guides per gene) can lead to the identification of novel virulence factors.

eLife assessment

This useful study provides a systematic mutational analysis to elucidate mechanisms involved in transcriptional activation by the murine DUX protein, DUX is a master transcription factor regulating mammalian early embryonic gene activation and its human homolog DUX4 is also involved in a muscular disease, fascioscapulohumeral dystrophy (FSHD). The data are solid and the interpretations of the findings are reasonable. The work will be of interest to colleagues studying early embryonic development or FSHD.

eLife assessment

This important paper exploits new cryo-EM tomography tools to examine the state of chromatin in situ. The experimental work is meticulously performed, with a vast amount of data collected, with convincing interpretation of possible nucleosomal structures in yeast. The majority of these nucleosomes appear not to possess stable octameric configurations. Although it cannot be excluded that there could be an unknown bias in class detection, we agree that the authors have gone as far as is possible, given constraints in current technology and analysis, to support their model. Despite the provocative nature of this report, it is our hope that such work will spark debate, and further the development of exciting new tools that can interrogate the dynamic nature of the nucleosome, and its associated functions in situ.

eLife assessment

This fundamental study describes the mechanisms for regulation of the phosphate starvation response in baker's yeast, clarifies the interpretations of prior data, and suggests a unifying mechanism across eukaryotes. The study provides compelling data, based on biochemical analyses, protein localization by fluorescence, and genetic approaches that 1,5-InsP8 is the phosphate nutrient messenger in yeast.

eLife assessment

FKBP35 is the only FK506-binding protein present in the malaria-causing parasite Plasmodium falciparum, and has been considered a promising drug target due to its high affinity to the macrolide compound FK506, an immunosuppressant with antiplasmodial activity. This study demonstrates the essentiality of FKBP35 in parasite growth, based on compelling genetic evidence. The data also suggest that FK506 may exert its antimalarial activity through FKBP35-independent mechanisms that have not yet been characterised. This important study will be of interest to scientists working on the parasite biology and antimalarial drug development.

eLife assessment

The current manuscript investigates the energy landscape of the mammalian sugar porter GLUT5 using enhanced molecular dynamics simulations and biochemical assays. The approach generates important insights into the mechanism of GLUT5 conformational change, and into mechanistic diversity among the GLUT sugar porters more generally. The overall strategy is solid, but without an additional error analysis, the computational components remain incomplete. These findings will be of interest to the transporter and membrane biology communities.

eLife assessment

This useful study adapts methods from causal inference to develop analytical tools for determining the causal influence of single cells on downstream neurons. The simulation evidence is solid, suggesting that these causal methods produce better estimates under biologically-relevant confounds given enough data, although the practical application of the method and the biophysics it relies on is unclear. Nonetheless, this application of causal methods developed in econometrics and other fields could suggest new ways to think about largely observational datasets in neuroscience.

eLife assessment

Hyperpolarised-activated and Cyclic Nucleotide-gated (HCN) channels are the only mammalian channels to open under hyperpolarisation, being important for their roles in cardiac and neuronal cells. The authors of this study use atomistic simulations to enforce changing interaction distances that have been identified from a cryoEM structure and a homology model based on the hERG channel. The simulations suggest state-dependent interactions involving pore and voltage sensor helices, as well as with lipids, leading the authors to propose a domino-like mechanism of activation. These findings will be of considerable interest to the ion channel community.

eLife assessment

This is a comprehensive approach to understanding the genetic requirements of the VEGF family in the generation of brain capillary structure in zebrafish. The manuscript combines vascular brain/meningeal anatomy revealed with a variety of reporter lines, with mutants for Wnt/β-catenin signaling and angiogenic cues. In particular revealing genetic redundancy in VEGF receptor family in an essential function in vasculature development.

This paper is significant because it provides compelling evidence that features methods, data, and analyses more rigorous than the current state-of-the-art in analysis of brain vasculature development. The data derived from the reporter lines are convincing, and the germline mutations allow for solid visualization and quantification of results.

eLife assessment

This study provides continuous maps of human brain gene expression and explores their relationship with a large variety of microscopic and macroscopic aspects of brain organisation. The authors provide convincing evidence for a relationship between gene expression maps with various aspects of the anatomy of adult brains, during development, and in the case of mental disorders. The data and methods introduced can be an important tool for neuroimaging research.

eLife assessment

These important findings will be of interest for the study of dystroglycanopathies and in the general area of axon migration and synapse formation. This work provides convincing conclusions about how a range of dystroglycan mutations alter CCK interneuron axonal targeting and synaptic connectivity in the forebrain, and seizure susceptibility.

eLife assessment

This study provides valuable new insights on how a prevailing model of hippocampal sequence formation can account for recent data, including forward and backward sweeps, as well as constant cycling of sweeps across different arms of a T-maze. The convincing evidence presented in support of this work relies on classical analytical and computational techniques about continuous attractor networks.

eLife assessment

The study expands our understanding of the neural circuitry downstream of the cerebellum by describing pathways between the deep cerebellar nuclei and the nucleus accumbens. The authors use a combination of in vivo electrophysiology, electrical and optogenetic stimulation, and both anterograde and retrograde tracing to demonstrate two functional neural pathways. The experiments convincingly support the claims. The finding extends previous investigations about the connections between these two brain areas, and are important for elucidating the role of the cerebellum in influencing functions supported by the nucleus accumbens, such as motivation and reward.