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The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

Alterations in oncogenes and tumor suppressor genes are a hallmark of cancer, yet how they interact remains poorly understood. Here, the authors describe a quantitative functional cancer genomics platform in genetically engineered mice, and uncover complex interactions between tumor suppressors and KRAS, BRAF, and EGFR oncogenes across more than 100 different lung tumor genotypes.

Astrocytes can encode an expected reward location in familiar spatial contexts.

The functions of small nucleolar RNAs (snoRNAs) in cancer remain to be studied. Here the authors show that the snoRNA Snord67 promotes lymph node metastasis of breast cancer cells through guiding modifications of the spliceosome and regulating the splicing landscape.

Telomere shortening as a result of cell proliferation has been implicated in human ageing. Here, Daniali and colleagues show that telomere length and the rate of age-dependent shortening vary between adults but are similar within tissues of the same individual.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Here, the authors investigate chromatin-based gene regulation in the closest relative of animal, choanoflagellates. They uncover a putative dual role for the histone modification H3K27me3 in regulating of protein-coding genes during differentiation and transposable elements.

This study investigates how homeostatic mechanisms endow sensory representations in the auditory cortex with resilience against neuron loss. The map of sounds has the ability to recover after microablation by recruiting previously unresponsive neurons.

Klein and colleagues characterize 04_A06, a new V_H1-2-encoded broadly neutralizing antibody that has marked breadth and potency against extended multiclade HIV-1 pseudovirus panels and can maintain full viral suppression in HIV-1-infected humanized mice.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

In bat CA1, the authors found contextual time cells encoding spatial context and time, another population purely encoding elapsed time and social time cells encoding sequences aligned to another bat’s landing in a social imitation task.

Ataxia-telangiectasia mutated protein (ATM) phosphorylates CD98HC to promote neutral amino acid antiporter trafficking. Here the authors show that ATM loss impairs glutamate, cystine, and arginine transport, driving metabolic stress and ataxia telangiectasia–like phenotypes.

Simultaneous recordings from hundreds of grid cells in rats, combined with topological data analysis, show that network activity in grid cells resides on a toroidal manifold that is invariant across environments and brain states.

A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.

Low level of pyruvate kinase M2 (PKM2) activity in cancer cells is essential for the dependence on aerobic glycolysis. Here the authors show that PKM2 sulfhydration by hydrogen sulfide destabilizes the PKM2 tetramer, leading to reduced PKM2 enzyme activity and enhanced proliferation of breast cancer cells.

Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Deep brain stimulation of the basal ganglia restores cognitive flexibility and rebalances exploration disrupted by NMDA receptor antagonism in nonhuman primates, offering insights into the neural basis of psychosis and a potential treatment for schizophrenia.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

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.

Recordings from the brains of freely flying bats show that grid cells that represent 3D space have multiple firing fields and are organized with local rather than global order.

How traits specific to modern humans have evolved is difficult to study. Here, Gokhman et al. compare measured and reconstructed DNA methylation maps of present-day humans, archaic humans and chimpanzees and find that genes that affect vocal tract and facial anatomy show methylation changes between archaic and modern humans.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Serological tests are important diagnostic and disease surveillance tools for addressing the COVID-19 pandemic. Here, the authors present a tri-part Nanoluciferase based assay to detect antibodies against SARS-CoV-2.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Weakening of the Tibetan Plateau’s annual temperature cycle has been observed in recent decades, yet the long-term context remains unknown. Here, the authors reconstruct a 300-year temperature record from tree-ring width and maximum latewood density, which indicates the onset of weakening as early as the 1870s.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Hippocampal place cells encode the animal’s position within the environment. Using flying bats navigating either by vision or echolocation, the authors found that hippocampal spatial maps changed completely between vision and echolocation. This suggests the hippocampus does not contain a single abstract map for a given environment, but rather multiple maps for different sensory modalities.

A comprehensive cell atlas of the aged prefrontal cortex identifies two distinct cellular trajectories of ageing driven by specific glial and neuronal subpopulations, some of which are associated with clinicopathologic traits that define Alzheimer’s disease.

Breed et al. identify a subset of thymic SIRPα⁺ cDC2 dendritic cells that express CD301b, induced by type II cytokines, and high amounts of MHC-II. They find that the deletion of these cells can alter thymic CD4-single-positive repertoires, suggesting that they contribute to thymic tolerance.

Loke and colleagues show that vitamin A is required for the conversion of interleukin 4 (IL-4)-activated monocyte-derived macrophages into macrophages with a tissue-resident phenotype in the peritoneal cavity and in S. mansoni–induced liver granulomas in mice.

Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1, a gene involved in endothelial-mesenchymal transition.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

The endolysosomal pathway plays an important role in regulating protein and lipid sorting and degradation. Here, the authors show that TMEM16K, an endoplasmic reticulum lipid scramblase, forms ER-endosome contact sites where it regulates endosomal sorting.

Cerebellar climbing fibers provide predictive, context-specific instructional signals that do not rely exclusively on motor errors to support learning of arbitrary sensorimotor associations.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Zhang et al. show that in mice, an adipocyte population with high expression of the transcription factor JunB in the brown adipose tissue shows reduced thermogenic capacity. Depletion of JunB increases the fraction of adipocytes with high thermogenic capacity and ameliorates diet-induced insulin resistance.

Endocrinologists have traditionally focused on studying one hormone or organ system at a time. Here the authors use transcriptomic data from the mouse lemur to globally characterize primate hormonal signaling, describing hormone sources and targets, identifying conserved and primate specific regulation, and elucidating principles of the network.

In this study, the authors use electronic health record data from the US to characterise post-acute sequelae of SARS-CoV-2 infection (PASC). They identify 17 common PASC conditions and find an overall ~12% increase in risk of PASC conditions in the post-acute period among people with a SARS-CoV-2 positive test compared to matched test-negative controls.

Analyses of real-world evidence from digital clinical practice data provide important insights for healthcare decision makers. Here, authors test reproducibility of 150 peer-reviewed studies, reporting strong reproducibility, which could be further improved through more complete reporting in future original studies

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).

Analysis of pre- and post-chemotherapy samples collected from 22 patients with high-risk neuroblastoma using single-nucleus RNA and ATAC sequencing and spatial omics characterizes therapy-related changes in cell composition and the tumor microenvironment.

To unravel structural regularities in neocortical networks, Gal et al. analyzed a biologically constrained model of a neocortical microcircuit. Using extended graph theory, they found multiple cell-type-specific wiring features, including small-word and rich-club topologies that might contribute to the large repertoire of computations performed by the neocortex.

FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

The blood circulation time is important to the biomedical application of nanomaterials. Here, the authors explore the effect of protein corona formation on the blood residency of nanomaterials and show circulation times are governed by the dynamic remodelling of protein opsonins in vivo.

Analysis of rare protein-truncating, damaging missense and copy number variants from exome sequencing of 63,237 individuals identifies 72 genes associated with autism spectrum disorder.

Estimating the effects of non-pharmaceutical interventions for COVID-19 is challenging, partly due to variations in testing. Here, the authors use viral sequence data as an alternative means of inferring intervention effects, and show that delays in implementation resulted in more severe epidemics.