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The cyanobacterium Synechococcus elongatus is a model organism for the study of circadian rhythms, and is naturally competent for transformation. Here, Taton et al. identify genes required for natural transformation in this organism, and show that the coincidence of circadian dusk and darkness regulates the competence state in different day lengths.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Concurrent chemoradiation and durvalumab is standard of care for stage III non-small cell lung cancer, however, efficacy is variable. Here, the authors show PD-L1 tumor proportion score expression and increased tumor mutational burden are predictive of response and that early-onset pneumonitis leading to durvalumab discontinuation is associated with poor survival.

Improved base editing libraries enable high-throughput functional analysis of single-nucleotide variants in cancer.

Na et al. identify KMT2C deficiency as a driver of small cell lung cancer metastasis and demonstrate that it leads to epigenetic reprogramming through histone and DNA hypomethylation by upregulating DNMT3A.

A population of β-cell-specific autoimmune stem-like CD8 T cells initiates and sustains β-cell destruction and disease in a mouse model of type 1 diabetes.

Defensins are a class of host defence peptides that contribute to the immune system of eukaryotes. Here, the authors report the structure of saltwater crocodile defensin CpoBD13 and the mechanism of pH-dependent antifungal activity.

Rectal cancer organoids retain the pathological features of matched patient tumors and recapitulate clinical responses to chemoradiation.

Composite mutations, of two or more nonsynonymous somatic mutations in the same cancer-associated gene, are present in nearly one in four human tumours.

Epigenomic data on chromatin accessibility and transcription factor occupancy can reveal enhancer landscapes in cancer. Here, the authors develop a computational strategy called PSIONIC (patient-specific inference of networks informed by chromatin) to model the impact of enhancers on transcriptional programs in gynecologic and basal breast cancers.

Orienting cancer drug discovery to the patient requires relating the genetic features of tumors to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

A study of more than one million 23andMe research participants identifies genetic and nongenetic associations with COVID-19 susceptibility and severity.

TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.

Acquired drug resistance is common during chemotherapy. Here, the authors describe the structural basis and molecular mechanism by which allosteric and clinically approved, ATP-competitive inhibitors of EGFR synergize to overcome resistance in lung cancer.

Genome-wide association analyses of DNA methylation in peripheral blood from 3,799 Europeans and 3,195 South Asians identify unique SNP–CpG associations (meQTL), providing insights into molecular mechanisms and the potential links to phenotypic variation.

Finley et al. show that Brd4 is dispensable for self-renewal and pluripotency in murine embryonic stem cells (ESCs). In metastable ESCs, Brd4 independence can be achieved by increasing the expression of the pluripotency transcription factors Oct4, Sox2 and Nanog as long as Tet1/2 are present.

Receptor tyrosine kinases are key mediators of cell proliferation that have been implicated in several disease states for which they represent promising drug targets. Here the authors determine the thermodynamic basis for the low propensity of FGFR1 to access the DFG-Phe-out conformation required to bind type-II inhibitors.

Cathy Laurie and colleagues detect mosaicism for large chromosomal abnormalities in peripheral blood in a subset of healthy individuals. They show that the frequency of such events increases with age and is associated with elevated risk of developing a subsequent hematological cancer.

IL-33, released by epithelial cells in response to stress, is a potent activator of inflammation. Here Cohenet al. show that secreted IL-33 is rapidly inactivated by disulfide bond formation that prevents binding to its receptor, and that IL-33-related cytokines are susceptible to similar oxidation.

Aerial and underwater survey data combined with satellite-derived measurements of sea surface temperature over the past two decades show that multiple mass-bleaching events have expanded to encompass virtually all of the Great Barrier Reef.

In this Perspective article, Brian Grone and Scott Baraban examine some of the numerous nonhuman animal models of epilepsy. The authors outline how traditional animal models have advanced our understanding of seizure initiation and epileptogenesis and also describe how the use of more 'non-traditional' model systems may further improve insight into both disease mechanisms as well as potential therapeutic avenues.

Stable RNA interference by shRNA provides a means to study multiple facets of gene function. Fellman and Lowe explore the rules of implementation of this silencing method in the vertebrate system for achieving maximal knockdown with minimal off-target effects.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them.

The phosphoribosyl pyrophosphate synthase PRPS2 catalyses the first step ofde novo purine nucleotide biosynthesis, and has recently been shown to couple protein and nucleotide metabolism. Zhang et al. demonstrate that PRPS2 activity is regulated by tRNA-dependent post-translational addition of arginine.

Normal cells can respond to expression of activated oncogenes by initiating cellular senescence, a permanent state of proliferative arrest. But whether this process reflects a relevant anticancer mechanism has been debated. Several studies now show that oncogene-induced senescence can occur in vivo and provides a bona fide barrier to tumorigenesis.

Genome-wide analysis of self-reported dyslexia identifies 42 associated loci, including 27 not previously associated with cognitive traits. Dyslexia shows genetic correlation with ambidexterity but not neuroanatomical measures of language-related circuitry.

Experiments at the Joint European Torus tokamak show improved thermal ion confinement in the presence of highly energetic ions and Alfvénic instabilities in the plasma.

Five studies show that disabling p53, an essential tumour-suppressor protein, improves the efficiency of stem-cell production. Are these results a 'heads up' that cancer cells and stem cells are disturbingly similar?

The finding that genes encoding enzymes that modify histone proteins are among the targets of certain mutant forms of the p53 protein sheds light on how these mutations cause cancer beyond p53 inactivation. See Article p.206

Whereas p73 is closely related to the tumour-suppressor protein p53, its contribution to tumour suppression and the spatial and temporal regulation of its isoforms is unclear. It has now been established that p73 is a transcriptional target of E2F1. Its ability to induce apoptosis in TP53^−/− cells indicates a tumour-control mechanism that runs parallel to but independent of that mediated by p53. The new results illustrate a complex cross-talk between p53, E2F1 and p73.

RNA interference screens were used to identify chromatin-associated factors that impede reprogramming of somatic cells into iPS cells; suppression of the chromatin assembly factor CAF-1 enhances the generation of iPS cells by rendering chromatin more accessible to pluripotency transcription factors.

Molecular simulations reveal the self-assembly of small molecules into nanoparticle drug carriers. Targeting of colon and liver cancer cells by the nanoparticles via kinase inhibitors is employed in anti-tumour therapy in vivo.

Skamagki et al. show that pluripotency factor ZSCAN10 is poorly expressed in iPSCs derived from aged donors, and its addition during reprogramming restores the DNA damage response and genomic stability through normalization of ROS–glutathione levels.

Multi-ancestry genome-wide association analyses for birth weight in 153,781 individuals identified 60 genomic loci in which birth weight and fetal genotype were associated and found an inverse genetic correlation between birth weight and cardiometabolic risk.

Recent advances in understanding the biology of senescent cells, especially the secretory phenotypes and the role of immune cell clearance of senescent cells, has revealed more about the role of senescence induction in tumorigenesis and tumour progression. This includes the surprising findings that senescence may promote tumour growth in some contexts.

Analyses of the relationships between temperature, moisture and seven key plant functional traits across the tundra and over time show that community height increased with warming across all sites, whereas other traits lagged behind predicted rates of change.

The use of ATP competitive kinase inhibitors against the pseudokinase Her3 has been largely unsuccessful. Hydrophobic tagging of a covalent kinase inhibitor promotes Her3 degradation and prevents productive dimerization and signaling.

Restoring the function of p53 in a mouse model of pancreatic ductal adenocarcinoma leads to the accumulation of α-ketoglutarate, which increases levels of the 5-hydroxymethylcytosine chromatin modification and results in reduced tumour-cell fitness.

The measurement of the total cross-section of proton–proton collisions is of fundamental importance for particle physics. Here, the first measurement of the inelastic cross-section is presented for proton–proton collisions at an energy of 7 teraelectronvolts using the ATLAS detector at the Large Hadron Collider.