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The APC/C ubiquitylates histones to regulate gene expression in pluripotent cells. Here, the authors pair cryo-EM and biochemical and biophysical assays to show that instead of modifying nucleosome-incorporated histones, the APC/C ubiquitylates extranucleosomal histone complexes through a mechanism that bypasses canonical substrate degrons.

Aarno Palotie and colleagues present results of a large genome-wide association study of migraine. They identified significant associations at 38 distinct loci and found enrichment for genes expressed in vascular and smooth muscle tissues.

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

Characterization of clinical isolates of the cryptic fungal pathogen Aspergillus latus revealed traits that distinguish it from other species. Steenwyck et al show that A. latus originated via allodiploid hybridization with both parental subgenomes actively expressed.

This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.

Daniel Benjamin, Meike Bartels, Philipp Koellinger and colleagues report a genome-wide association meta-analysis of subjective well-being, depressive symptoms and neuroticism. The study leverages a large sample size together with genetic correlations between the phenotypes to identify, with high confidence, loci associated with each phenotype.

Wedemeyer et al. find that age-associated waning of T-cell responses to infection and tolerance to self are regulated by a dynamic paracrine FGF21 signaling axis modulating mTORC1 and mTORC2 activity in thymic epithelial cells in mice.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Salvadó et al. developed and validated a CSF-based staging model for sporadic Alzheimer’s disease, which accurately reflects biomarker and clinical changes, enhancing diagnostic and prognostic assessments of participants for clinical setting and trials.

Selective protein degradation in disease-relevant cells or tissues has seen limited success. Hence, the authors develop Folate Receptor Targeting Chimeras (FRTACs) to specifically target proteins in cancer cells, aiming to reduce on-target, off-tumor toxicity.

Physical realizations of qubits are often vulnerable to leakage errors, where the system ends up outside the basis used to store quantum information. A leakage removal protocol can suppress the impact of leakage on quantum error-correcting codes.

Analyses of the genetic architecture of the human plasma metabolome in two large population-based cohorts identify associations between genetically determined metabolite levels and health.

Dietary restriction promotes healthy brain aging, but the mechanism is unknown. Here, the authors show that OXR1 is upregulated by dietary restriction and confers age-related neuroprotection by maintaining retromer-mediated protein and lipid trafficking.

A phase I trial of a neoantigen-targeting personalized cancer vaccine led to durable and polyfunctional T cell responses and antitumour recognition, and was associated with no recurrence in patients with high-risk clear cell renal cell carcinoma.

Multitrait genome-wide analysis of glaucoma and related phenotypes identifies new risk loci and enables development of a polygenic risk score to predict disease susceptibility and key clinical outcomes.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

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.

FUT10 and FUT11, originally annotated as α1,3-fucosyltransferases, are actually protein O-fucosyltransferases participating in a non-canonical ER quality control pathway for EMI domain-containing protein secretion.

Using single-cell DNA sequencing we show that most healthy women harbour rare populations of aneuploid epithelial cells with copy number alteration events in their breast tissue that expand and accumulate with age.

Manju Kurian and colleagues report heterozygous variants in KMT2B in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance. Their findings highlight a clinically recognizable form of dystonia and demonstrate a crucial role for KMT2B in the physiological control of voluntary movement.

Crossing the blood–brain barrier in primates is a major obstacle to gene delivery in the brain. Here an adeno-associated virus variant (AAV.CAP-Mac) is identified and demonstrated for crossing the blood–brain barrier and delivering gene sequences to the brain of different non-human primates species.

Certain specific antigens have been shown to activate T cells in an MHC independent manner. Here the authors show a phycoerythrin reactive mouse TCR which recognises native protein and characterise the molecular nature of this interaction and that this specific TCR can be selected in the thymus.

Double Asteroid Redirection Test (DART) mission impact on asteroid Dimophos resulted in an elliptical ejecta plume. Here, the authors show that this elliptical ejecta is due to the curvature of the asteroid and makes kinetic momentum transfer less efficient.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

CRISPR gene activation and inhibition has become a powerful synthetic tool for influencing the expression of native genes for foundational studies, cellular reprograming, and metabolic engineering. Here the authors demonstrate near leak-free, inducible expression of a polycistronic array containing up to 24 gRNAs from two orthogonal CRISPR/Cas systems.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

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.

Leveraging proximity ligation assays for the multiplexed profiling of protein–protein interactions enable the study of their subcellular co-localization and of how they change in response to drug-induced perturbations.

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Nanoparticle biomolecular corona fingerprints vary with disease state. Here, the authors use integrated multi-omics to show that inflammatory disease dynamics alter corona formation, immune cell interactions, and activation profiles via TLR4 signalling, which could impact nanoparticle uses.

Pyroptotic cell death results in inflammation. Here the authors find that F-actin-rich structures formed during macrophage pyroptosis persist after cell death to activate dendritic cells.

Persistent DNA lesions can occur throughout the human lifespan and can remain in the genome of affected cells for several years and generate a substantial proportion of the mutational burden.

Meehan and colleagues study access to running water in large US cities since 1970, finding that the 2008 financial crisis worsened household ‘plumbing poverty’ in many cities. This disproportionately impacted households of color and generally squeezed lower-income households into more precarious living situations.

Emission enhancement and extraction from quantum emitters is a major challenge for photon sources in e.g. quantum photonic networks. Here the authors propose a broadband waveguide platform which allows to boost, extract, and guide quantum emission within integrated photonic networks.

Genome-wide association analyses of two oral glucose tolerance test-derived measures of postprandial insulin resistance discover ten new loci. Functional characterization identifies nine candidate genes implicated in the regulation of GLUT4.

Focal stimulation of cortical tissue from within a blood vessel via an electrode array mounted on a minimally invasive endovascular stent elicits responses from specific facial muscles and limbs in sheep.

A study of more than 1000 paleoclimate datasets reveals that the ”4.2 ka event” is not a globally significant climate excursion, unlike the prominent 8.2 ka event. In the Holocene, site-level excursions are common, but global-scale events are rare.

A series of four storms appeared on Saturn’s northern polar region in 2018, unusually close to each other in space and time. By their dimension and the energy needed to form them, they appear to be a hitherto unobserved kind of storm at Saturn, intermediate between the regional- and the global-sized ones.