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Integrin proteins regulate important cellular processes such as proliferation and differentiation. Here the authors show that siRNA-mediated knockdown of two integrin subunits slows down progression of hepatocellular carcinoma in mice by reducing activation of the METoncogene.

Addition of fluorine to organic structures is a unique strategy for tuning molecular properties, but approaches to integrate fluorometabolites into the biochemistry of living cells are scarce. Here, the authors develop a fluoride-responsive genetic circuit to enable in vivo biofluorination in engineered Pseudomonas putida.

In mouse models of pancreatic cancer, a cooperative interaction between tissue damage and Kras gene mutation rapidly induces cancer-associated chromatin states in pre-malignant tissue, leading to gene dysregulation and neoplastic transformation.

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.

REM-sleep behavior disorder often precedes Parkinson’s disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.

Serological analysis and infection outcomes of participants in the multi-center, prospectively enrolled OCTAVE cohort, comprising 2,686 participants with immune-suppressive diseases who recieved two COVID-19 vaccines, reveals specific clinical phenotypes that might benefit from specific COVID-19 therapeutic strategies.

Antibodies can have synergistic effects, but mechanisms are not well understood. Here, Ragotte et al. identify three antibodies that bind neighbouring epitopes on CyRPA, a malaria vaccine candidate, and show that lateral interactions between the antibodies slow dissociation and inhibit parasite growth synergistically.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

The authors developed a deep learning-based model to estimate the brain age gap based on metabolic and structural imaging data in cognitively normal individuals and in patients with dementia. An older brain age was associated with Alzheimer’s disease biomarkers and was predictive of future cognitive decline.

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.

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.

This study identifies and characterizes evolutionarily conserved cytosine methylation patterns related to age across mammals and establishes pan-mammalian epigenetic clocks.

Fusion genes have been proposed as a potential mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Here, the authors identify gene fusions that are associated with resistance to EGFR TKIs in non-small cell lung cancers, and test how these fusions impact the response to EGFR TKIs in vitro.

Confining plasma and managing disruptions in tokamak devices is a challenge. Here the authors demonstrate a method predicting and possibly preventing disruptions and macroscopic instabilities in tokamak plasma using data from JET.

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.

COVID-19-related travel restrictions were imposed in China around the same time as major annual holiday migrations, with unknown combined impacts on mobility patterns. Here, the authors show that restructuring of the travel network in response to restrictions was temporary, whilst holiday-related travel increased pressure on healthcare services with lower capacity.

Maternal genome-wide analyses identify variants associated with gestational duration and preterm delivery. Maternal alleles positively associated with gestational duration exhibit negative fetal effects on birth weight, likely reflecting antagonistic pleiotropy.

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.

High-throughput sequencing of RNA fragments generated from a single-strand RNA-specific nuclease followed by novel computational analysis yields structural insights into noncoding RNA at the transcriptome level.

A mathematical framework to estimate the fitness of cancer driver mutations by integrating mutational bias, oncogenicity and immunogenicity finds fundamental trade-offs in cancer evolution.

Non-coding RNA function is poorly understood, partly due to the challenge of determining RNA secondary (2D) structure. Here, the authors present a framework for the reproducible prediction and visualization of the 2D structure of a wide array of RNAs, which enables linking RNA sequence to function.

Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.

Prime editing sensor libraries evaluate diverse genetic variants in their endogenous genomic contexts.

Remaining drug-tolerant persistent (DTP) cancer cells limit the efficacy of targeted therapy in EGFR, ALK and KRAS mutant non-small cell lung cancer (NSCLC). Here, the authors show that focal adhesion kinase (FAK)-YAP signalling supports DTP cells promoting residual disease and targeting this pathway improved tumour response in NSCLC preclinical models.

Romer’s Gap describes the period with few known fossils when early tetrapods were becoming increasingly terrestrial. Here, five new species, three stem tetrapods and two stem amphibians, are described from a location in Scotland shedding light on the phylogeny and environment of this period.

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.

Head-fixation system is widely used in neuroscience research but has limitations in application due to restraint. Here the authors developed a magnetic voluntary head-fixation system that allows stable rat hippocampal imaging during complex behaviors.

Hippocampal place cells are active offline in ‘replay’ sequences reflecting speeded-up depictions of behavioral trajectories, suggesting a model of memory. The authors show that encoding of replay sequences requires behavioral experience and the activation of molecular mechanisms of synaptic plasticity, while retrieval does not.

Multi-ancestry genome-wide association analyses identify new risk loci for Parkinson’s disease, and fine-mapping and co-localization analyses implicate candidate genes whose expression is associated with disease susceptibility.

The use of cell-based therapies may be helpful in eradicating cancer cells. Here, the authors generate bifunctional mesenchymal stem cells and demonstrate their therapeutic efficacy in glioblastoma patient-derived models.

Manchado and colleagues combine CRISPR screening and transcriptomics to identify INPP5A as a dependency and therapeutic target in uveal melanoma driven by mutations in GNAQ/GNA11 and show that IP4 levels correlate with sensitivity to INPP5A loss.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

The human gut microbiota helps us to degrade complex dietary carbohydrates such as xylan and, in turn, the carbohydrate breakdown products control the structure of the microbiota. Here the authors characterize the xylan-degrading apparatus of a key member of the gut microbiota, Bacteroides ovatus.

Overexpression of the FOXM1 transcription factor occurs in several cancer and correlates with poor prognoses. Here, the authors identify a novel small molecule capable of displacing FOXM1 from its DNA consensus motif in vitro, displace it from target promoters and downregulate the expression of its target genes cancer cells.

The function of single-nucleotide variants can now be tested in a base editor mouse model.

RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.