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Aspergillus fumigatus is an opportunistic human pathogen in immunocompromised individuals and is associated with severe asthma and sinusitis, and has only been known to reproduce asexually. This paper now shows that it can reproduce sexually, for which isolates of complementary mating type are required.

MDM2 and BET inhibitors have shown efficacy in AML treatment. Here, the authors show that the two compounds can synergize through both p53 protein stabilization and inhibition of BRD4-mediated repression of p53 target genes.

In many regions, a warming climate may lead to large decreases in annual snowfall while having a much weaker effect on the intensities of the heaviest snowfall events — those that can be most disruptive to urban infrastructure.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

Here, the authors present mtDNA and chronological data for sediments from excavations in the South Chamber of Denisova Cave, from which they construct a timeline of hominin and faunal occupation that fills stratigraphic gaps in other parts of the cave.

Acute myeloid leukaemia (AML) affects people of all ages. Here, the authors model AML in vivo and demonstrate that the age of the cell of origin impacts leukaemia development and the genetic signature where adult cells of origin give rise exclusively to AML and young cells of origin give rise to myeloid, lymphoid or mixed phenotype acute leukaemia.

Glioblastoma multiform (GBM) is a common and aggressive type of primary brain cancer that currently has no effective therapy. Here, the authors show, using a mouse GBM model and EGFRvIII-targeting chimeric antigen receptor (CAR)-T cells, that Intratumoral injection of interleukin-12 helps condition the microenvironment and promote anti-tumor immunity.

The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.

The function of macrophages in myeloid leukaemia can be difficult to assess because of lack of differentiation between transformed and non-transformed cells. Here the authors use a chimeric mouse model to characterise the effect of myeloid leukaemia on bystander macrophages noting altered functional properties of these cells.

The SARS-CoV-2 main protease is an important target for the development of COVID-19 therapeutics. Here, the authors combine X-ray crystallography and mass spectrometry and performed a large scale fragment screening campaign, which yielded 96 liganded structures of this essential viral protein that are of interest for further drug development efforts.

The persistence of leukemic stem cells (LSCs) is known to limit the success of imatinib in patients with chronic myeloid leukaemia (CML). Here, the authors identify a reliance of these persisting LSCs on pyruvate carboxylase mediated pyruvate anaplerosis for survival after imatinib and demonstrate the therapeutic efficacy of targeting this using an inhibitor of mitochondrial pyruvate carrier.

Precipitation extremes increase in intensity over many regions of the globe in simulations of a warming climate, but not always consistently. Observational constraints, together with a close relationship between model responses to interannual variability and climate change, suggest a high sensitivity of tropical extreme precipitation to warming.

Extreme precipitation over land has increased over the wettest and driest regions and is likely to keep intensifying over the twenty-first century. This has key implications for dry regions, which may be unprepared for the potential related flooding.

The transcripts generated by frameshifts and indels in cancer are frequently degraded by nonsense mediated decay. Here, the authors show that some of these transcripts can escape this degradation mechanism and their prevalence correlates with tumour response to immunotherapy.

Aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ, reduces soluble and insoluble Aβ in the brain, an action accompanied by a dose-dependent slowing of clinical decline in treated patients.

It is hoped that quantum computers may be faster than classical ones at solving optimization problems. Here the authors implement a quantum optimization algorithm over 23 qubits but find more limited performance when an optimization problem structure does not match the underlying hardware.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Human activity is changing Earth's climate. Now that this has been acknowledged and accepted in international negotiations, climate research needs to define its next frontiers.

Machine learning has been used to represent small-scale processes, such as clouds, in atmospheric models but this can lead to instability in simulations of climate. Here, the authors demonstrate a use of machine learning in an atmospheric model that leads to stable simulations of climate at a range of grid spacings.

CDC25 phosphatases are attractive anticancer drug targets that regulate CDK activity. Here, the authors present the cryo-EM structure of the CDK2-cyclin A-CDC25A complex at 2.7 Å resolution, detailing key protein-protein interactions.

Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.

Triggering and sustaining fusion reactions — with the goal of overall energy production — in a tokamak plasma requires efficient heating. Radio-frequency heating of a three-ion plasma is now experimentally shown to be a potentially viable technique.

Eukaryotic genomes fold into topologically associated domains (TAD). Here the authors characterise a TAD regulatory architecture underlying lineage-specific gene regulation, finding that stripe TADs are associated with poised and active chromatin landscapes and linked to the cells functional state.

The dynamics of fibroadipogenic progenitors (FAPs) after muscle injury are crucial to ensure efficient regeneration. Here the authors show that a pool of FAPs originates from adipose tissue and are necessary for effective muscle regeneration.

TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers.

HOXA9 plays an important role in acute myeloid leukaemia (AML), but its relevance for other blood malignancies is unclear. Here, the authors show that HOXA9 has a binary switch function that can clinically stratify AML patients, and model how the interactions with JAK2, TET2 and NOTCH impact myeloproliferative neoplasms.

The ability to maintain blood stem cells (HSCs) in vitro would allow us to provide better therapies for blood diseases. Here, the authors report that polymer-organised extracellular proteins, coupled to soft environments mimicking bone marrow stiffness, allow stromal cells to maintain HSCs in vitro.

Leukaemic stem cells (LSCs) are responsible for BCR–ABL-driven chronic myeloid leukaemia relapse; here, p53 and MYC signalling networks are shown to regulate LSCs concurrently, and targeting both these pathways has a synergistic effect in managing the disease.

An analysis of blood samples from longitudinal cohorts reveals insights on the dynamics of clonal hematopoiesis of indeterminate potential and proposes a model that could be used for individualized clone monitoring over time.

TGF-β signalling suppresses tumorigenesis in breast cancer cells but its effects on breast cancer initiating cells have not been reported. Using cells in culture, Brunaet al. show that TGF-β increases breast cancer initiating cell numbers in cells that have low levels of the tight junction protein claudin.

The inability of tyrosine kinase inhibitors to eliminate quiescent leukaemic stem cells (LSC) in chromic myeloid leukaemia (CML) results in recurrence. Here, the authors identify a reliance of CML LSCs on low P53 expression for self-renewal and therapeutically target this by combining an MDM2 inhibitor with TKI in preclinical models of CML.

Haematopoietic stem cells emerge from the haemogenic endothelium via an endothelial-to-haematopoietic transition. Here, the authors show using single cell functional and transcriptional analyses that haemogenic endothelial cells begin to lose their endothelial potential while still located within the haemogenic endothelium.

The tumour microenvironment (TME) may change in response to cancer treatments such as KRAS G12C inhibition, with potential implications for combination therapies. Here, the authors provide an antibody panel and workflow for analysing the TME with imaging mass cytometry in pre-clinical mouse models.

Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

Single-cell technologies allow quantification of cell-types in human tissues, yet detecting if their abundance changes in aging or disease is challenging. By using cell-attribute aware clustering, this work presents a differential abundance testing algorithm with increased power.

Cancer cells frequently harbour genetic aberrations that protect them from programmed cell death. Here, the authors show in non-small cell lung cancer that the anti-apoptotic gene MCL-1 is subject to copy number gains and that deletion of MCL-1 reduces tumour formation.

FUS/EWS/TAF15 (FET) fusion oncoproteins contain low complexity domain which forms biomolecular condensates that recruit RNA polymerase II. Here the authors develop a single-molecule assay to visualize this phenomenon providing in vitro evidence to support causative relationship between the formation of condensates on DNA and gene transcription. Furthermore, they also determine a threshold number of fusion-binding DNA satellite elements required for the formation of FET protein condensates.

Smoking-associated DNA methylation changes in whole blood have been reported by many EWAS. Here, the authors use a cell-type deconvolution algorithm to identify cell-type specific DNA methylation signals in seven EWAS, identifying lineage-specific smoking-associated DNA methylation changes.

Robust quantification of the differentiation potential of single cells is a task of great importance. Here the authors integrate single-cell RNA-Seq profiles with a cellular interaction network to compute the signaling entropy, and show that it can identify normal and cancer stem-cell phenotypes.

PI 3-kinase is a major regulator of inflammatory responses. In this study, the authors show that inhibition of the delta isoform of PI 3-kinase attenuates the release of tumour necrosis factor from microglia as well as the signs and symptoms associated with cerebral stroke in an in vivomouse model.

CellDMC finds cell type–specific differential methylation in mixtures of cells, including epithelial tissues, and scenarios in which methylation changes in opposite directions in different cell types.