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Subcellular mRNA localization is prevalent but with poorly understood physiological roles. Here, the authors show that Net1 mRNA targeting to the basement membrane controls epithelial tissue organization and keratinocyte-stromal connections.

This study identifies transcription factor 7-like 2 (TCF7L2) as a key regulator of hepatic metabolic zonation, and demonstrates that disruption to the transcriptional activity of TCF7L2 exacerbates the development of dietary-induced hepatic fibrosis.

Tools to determine the spatial distribution of components and their networks inside cells are not well developed. Here, authors provide the open-source 3D-cell-image analysis platform Cell Detection and Analysis of Intensity Lounge (CellDetail) for quantitative distribution analyses.

Here, Fry and colleagues examine the impact of antigen experience on subsequent CD8⁺ CAR T cell activity during the antileukemia response and show that RUNX2 overexpression enhances antitumor activity of these cells.

Analysis of more than 95% of each diploid human genome of a four-generation, twenty-eight-member family using five complementary short-read and long-read sequencing technologies provides a truth set to understand the most fundamental processes underlying human genetic variation.

Fetal haematopoietic stem cells (HSCs) display higher self-renewal potential than their adult counterparts. Eaves and colleagues show that adult HSCs express lower levels of Lin28b and higher levels of let-7 miRNA. They demonstrate that Lin28 overexpression, as well as that of Hmga2 (a target of let-7), induces fetal properties in adult HSCs. Conversely, HMGA2 loss in fetal HSCs results in premature induction of adult HSC self-renewal properties.

DNA:RNA hybrids are linked to genetic instability in several pathological situations. Here, the authors report that various types of DNA lesions can trigger hybrid formation in yeast and humans, calling for a re-examination of the causality between these structures and genetic instability.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Mesoscale connectomic mapping of the cortico–basal ganglia–thalamic network reveals key architectural and information processing features.

Melanocortin receptor accessory protein 2 (MRAP2) is an adaptor protein that contributes to melanocortin-4 receptor and prokineticin receptor 1 signalling. Here the authors show that MRAP2 also regulates ghrelin receptor signalling in the hypothalamus and starvation sensing in mice.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Singer and colleagues show that the developmental fate of autoreactive CD4⁺ thymocytes is determined by the timing and duration of agonist signaling. Early agonist signaling induces clonal deletion, whereas late agonist signaling induces differentiation into Foxp3⁺ T_reg cells or IL-2⁺ T_eff cells depending on whether TGF-β disrupts TCR signaling.

Eukaryotic Arf family proteins involved in endomembrane organelle dynamics arose from the Asgard archaeal ArfR GTPases, indicating this capability likely originated in the archaeal ancestor of eukaryotes.

The development of neutralizing antibodies can limit the therapeutic effectiveness of systemically administered oncolytic viruses (OV). Here, to enable repeated intravenous administration, the authors report the development of synthetic RNA viruses formulated within lipid nanoparticles, showing anti-tumor efficacy even in the presence of OV neutralizing antibodies.

Sherman and colleagues show that ATX suppresses the accumulation of eosinophils in the tumor microenvironment of pancreatic cancer via suppression of CCL11 expression and find that ATX inhibition increases eosinophil influx, promoting tumor cell death.

Studies with patient derived xenografts are hampered by factors such as genetic variability and sample availability. Here, the authors generate a leukemia mouse model by lentiviral transduction of normal human cord blood and show an oncogenic role of HOXB genes.

Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence.

Now that genetic engineering of mice is so easy, centralized repositories are essential, argue Kent Lloyd and colleagues.

Translational research for rare genetic diseases often suffers from a lack of funding. Advocacy groups that support individuals who are affected by such conditions are well placed to motivate and coordinate research that is aimed squarely at generating translational advances.

Gouldian finches have a head colour polymorphism that is also associated with physiological and behavioural differentiation. Here, the authors map this colour polymorphism to a putative regulatory region for follistatin on the Z chromosome and suggest it is maintained by balancing selection.

A novel drug, ribocil, is shown to mimic the binding of a natural ligand to a bacterial riboflavin riboswitch (a non-coding stretch of messenger RNA whose structure is affected by a ligand—usually one related to the function of the protein encoded by the messenger RNA) to cause inhibition of bacterial growth; the ability to target an RNA structural element with a synthetic small molecule may expand our view of the target space susceptible to therapeutic intervention.

Understanding how SARS-CoV-2 gains initial entry into the human body is a key step towards the development of prophylaxes and therapeutics for COVID-19. Here, the authors show that ACE2, the receptor for SARS-CoV-2, is abundantly expressed in the motile cilia of the human nasal and respiratory tract and is not affected by the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

Mouse skeletal muscle can be regenerated using a small-molecule cocktail that activates resident satellite cells in situ and by myogenic stem cells selectively induced and expanded from dermal or skeletal muscle when the cocktail is used in vitro.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Zihni et al. discover a role for Cdc42–MRCK signalling in establishing contractility at the apical pole, which in turn controls epithelial polarity in mammalian cells and Drosophila photoreceptors.

Wu and colleagues identify gene networks and transcription factors that control the differentiation of stem-like CD8+ CAR T cells into effector or exhausted CD8⁺ CAR T cells.

To determine how T cell lineage fates are determined in the thymus, Singer and colleagues generated ‘FlipFlop’ mice with a functionally reversed T cell immune system that distinguishes TCR signal strength versus TCR signal duration.

Hexokinase 2 expression is markedly induced in cancer cells and contributes to cancer cell metabolism. Here, the authors show that hexokinase 2 can contribute to the metastatic spread of cancer cells independently of its glycolytic function via inhibiting the activity of GSK3β, which in turn elevates the protein levels of the EMT transcription factor SNAIL.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

Genome-wide association meta-analysis across individuals of diverse ancestries identifies risk loci for nonalcoholic fatty liver disease. The associated variants implicate plausible biological pathways and improve estimates of disease risk.

The molecular mechanisms that regulate intestinal Clu+ revival stem cells (revSCs) and their niche to enable regeneration in response to injury are unclear. Here, the authors show that mice without the phospholipid transport protein, TNFAIP8, causes less revSCs to be induced following injury.

The post-translational modification O-GlcNAc on amyloid-forming proteins can inhibit their aggregation. Now, it has been shown that O-GlcNAc modification of small heat shock proteins HSP27, αA- and αB-crystallin can increase their anti-amyloid activity and block the amyloid formation of both α-synuclein and Aβ(1–42). A mechanism for this protective effect based on decreased physical interactions is also proposed.