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This work identified cyclic peptide inhibitors of a mammalian N-terminal cysteine oxidase, ADO, through mRNA display, one of which was used as a scaffold to graft substrate moieties, allowing key interactions to be assessed through structural and biochemical approaches.

Toxicities limit combination of PARP inhibitors (PARPi) and chemotherapy in patients with germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) breast cancer. Here, the authors report a preclinical study followed by a randomised phase II/III clinical trial investigating the addition of a gap between chemotherapy (carboplatin and paclitaxel) and PARPi (olaparib), in patients with early gBRCAm breast cancer.

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).

Estimating the risk of long COVID is challenging because many of its symptoms are associated with other conditions. Here, the authors conduct a systematic review and meta-analysis of studies that estimate long COVID risk while accounting for background symptoms using comparator control populations.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

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.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Experimental demonstration of quantum speedup that scales with the system size is the goal of near-term quantum computing. Here, the authors demonstrate such scaling advantage for a D-Wave quantum annealer over analogous classical algorithms in simulations of frustrated quantum magnets.

A magnetic galactic halo featuring coherent ridges several kiloparsecs above and below the Galactic Disk has been detected in multi-wavelength observations. The halo is probably a consequence of outflows driven by active star-forming regions in the disk.

Causal manipulations combined with simultaneous recordings of both interneurons and medium spiny neurons in the striatum reveal dissociable contributions of cholinergic and parvalbumin interneurons in movement initiation and termination.

Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by enzyme deficiencies leading to glycosaminoglycan accumulation and systemic degenerative disease. Here, the authors show that iPSC-derived microglia progenitors can reduce glycosaminoglycan accumulation and prevent behavioral deficits in MPS mouse models.

Here the authors show that lowering IGF-1R levels in endothelial cells improves insulin sensitivity, boosts energy use, and supports beneficial changes in adipose tissue, offering insights into potential treatments for obesity-related metabolic disorders.

Cha and colleagues present a translation- and rotation-equivariant autoencoder-based method for robust image recognition, which they demonstrate on diverse tasks from bioinformatics, material science and astronomy.

The cold dark matter paradigm predicts that Milky Way-like galaxies should have dwarf galaxies with dark matter halos as satellites. Ural et al.present a new model, independent of cosmological simulations, that constrains the pre-infall mass of the Milky Way satellite Carina to a value lower than expected.

The Vertebrate Genome Project has used an optimized pipeline to generate high-quality genome assemblies for sixteen species (representing all major vertebrate classes), which have led to new biological insights.

Genome-wide ancient DNA data from individuals from the Middle Bronze Age to Iron Age documents large-scale movement of people from the European continent between 1300 and 800 bc that was probably responsible for spreading early Celtic languages to Britain.

Ellis and colleagues show that combination of EZH2 inhibition and anti-PD-1 can increase antitumor immune responses in typically ‘immune cold’ prostate cancer, by increasing EZH2-regulated dsRNA–STING–ISG response signaling.

Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.

Using intracranial recordings in humans, the authors found decision conflict-related effects on firing rate in the dorsal anterior cingulate cortex (dACC), on spike-phase coupling in the dACC, and on spike-field coherence in the dorsolateral prefrontal cortex.

Deconvolution methods reveal individual cell types in complex tissues profiled by bulk methods. Here the authors present a Bayesian deconvolution method that outperforms existing methods when benchmarked on >700 datasets, especially in estimating cell-type-specific gene expression profiles.

Turajlic and colleagues assess longitudinal antibody and cellular immune responses against SARS-CoV-2 variants of concern in patients with cancer, following either recovery from SARS-CoV-2 infection or vaccination, in two back-to-back reports from the CAPTURE study.

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.

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.

In this study, the authors provide a global overview of SARS-CoV-2 genome sequencing, and estimate the proportion of cases sequenced and time to genome upload. They identify disparities and highlight the need to strengthen surveillance in lower and middle income countries.

Pancreatic adenosquamous carcinomas are rare but highly aggressive tumors, and our understanding of them is limited. In a new study, Miles Wilkinson and colleagues now report that they have identified somatic mutations in an RNA helicase encoded by UPF1 in some pancreatic adenosquamous carcinomas. UPF1 is required for nonsense-mediated RNA decay, suggesting that the aberrant accumulation of altered RNA transcripts may contribute to the malignant phenotype of these tumors and could be a target of diagnostic and therapeutic approaches for this tumor type.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.