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Type I PRMT inhibition elicits potent antitumor activity associated with increased interferon response and intron-retained dsRNA accumulation, suggesting its potential combination with immune checkpoint inhibitors for cancer treatment.

HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16^INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug.

Orbital angular momentum takes several forms in structured light beams. Here, the authors demonstrate control of dynamic spatiotemporal beams combining two forms of orbital angular momenta, by coherently adding frequency comb lines.

Ken Ong and colleagues report meta-analysis of 32 genome-wide association studies for age at menarche. They identify 30 loci newly associated with age at menarche, including four that were previously associated with BMI.

Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1, or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.

This Brain Somatic Mosaicism Network analysis of 283 cases of malformations of cortical development identifies 69 candidate and known genes in 76 patients. Single-nucleus RNA sequencing and mouse modeling implicate radial glia and daughter excitatory neurons.

Resequencing and genome-wide association analysis of 683 common bean accessions across different latitudes identifies 505 loci associated with yield components, of which seed size, flowering and harvest maturity traits are stable across environments.

Diuretic hormone 31 secreted by the gut in response to feeding on protein-rich food excites brain neurons that promote switching from feeding to mating behaviour in Drosophila.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

The role of therapy in shaping the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single-cell RNA sequencing in PDAC samples before and after chemotherapy and suggest that chemotherapy may promote resistance to immunotherapy.

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

Mx proteins belong to the dynamin family of large GTPases and are highly induced by interferon in virally infected cells. The authors show that uninfected immune cells and hepatocytes also express MxB protein that associates with mitochondria to alter the morphology and genome of this organelle.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

Using Ultra-Expansion Microscopy of the malaria parasite, P. falciparum, Li et al. show that disruption of kinetochore components breaks a nexus between the mitotic spindle and the nascent apical organelles.

The attribution of negative longitudinal magnetoresistance (NLMR) in Weyl metals to a chiral anomaly is already challenged. Here, NLMR resembling that of Weyl metals is demonstrated in a non-Weyl-metal GaAs quantum well originating from different types of disorder.

Analysis of copy number alterations in 1,451 patient-derived xenografts (PDXs) and matched patient tumor samples shows strong conservation from patient tumors through late-passage PDXs and a lack of systematic copy number evolution driven by the mouse host.

We can flexibly coordinate our movements with external stimuli, but no circuit-level model exists to explain this ability. Inspired by fundamental concepts in control theory, the authors construct a modular neural circuit that captures human behavior in a wide range of temporal coordination tasks.

The comparison of the ability of native and engineered gene clusters transferred into bacteria that live on or inside cereal roots to regulate nitrogenase activity reveals different strategies to control nitrogen fixation in rhizobia and paves the way to engineer a bacterium able to deliver high nitrogen fluxes to crops.

Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Xu et al. show that satellite-measured urbanicity (living in a densely populated area) is correlated with brain volume, cortical surface area and brain network connectivity in a sample of 3,867 people from China and Europe.

Molecular aggregation is a widespread and important process in physiological metabolism, but details regarding conformational changes during the process are hard to probe. Here, the authors use circular dichroism to monitor in-situ the conformational changes occurring during molecular aggregation.

The molybdenum cofactor (Moco) is found in the active site of numerous enzymes, but the mechanism of molybdate insertion is not clear. Now, the mechanism of the final maturation step, in which adenylated molybdopterin and molybdate are the substrates, has been revealed. X-ray crystallography of an Mo-insertase identified adenylated Moco as an unexpected intermediate in this reaction sequence.

Mechanisms underlying the initiation and modulation of the firing activity in the cochlea and its dynamics in vivo are not fully understood. Here, the authors investigate the origin and regulation of spontaneous Ca2+ signals in the hair cells, supporting cells and afferent fibre terminals in the developing cochlea from live mice.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

Solanum pimpinellifolium (SP) is the progenitor of cultivated tomato and an important germplasm. Here, the authors assemble SP genome, identify structural variants (SVs) by comparing with modern cultivar, reveal SVs associated with important breeding traits, and detect SVs harboring master regulators of fruit quality traits.

Water-soluble peptides with stable α-helical conformations are desirable for a range of applications, but incorporating charged residues to improve solubility usually leads to reduced helical stability. Here, polypeptides produced from amino acids with elongated charged side chains are found to be water soluble and exhibit very high helical stability.

Proteinuric kidney diseases are on the rise and have limited treatment options. Here, the authors show soluble urokinase receptor (suPAR) orchestrates viral response proteinuria (VRP) which occurs in response to certain viral infections and podocyte integrin engagement.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

Diagnostic strategies for neurodegenerative diseases involve various data types, related to motor and cognitive signals. Endo et al. describe a data-driven subtyping approach for Parkinson’s disease, combining motion data (from videos) and brain functional connectivity data. The method reveals clinically relevant subtypes and digital biomarkers, uncovering movement-linked heterogeneities of Parkinson’s disease.

The authors perform meta-analysis of GWAS studies for asthma from multiancestral cohorts. They identify five new loci and find that the asthma-associated loci are enriched near enhancer marks in immune cells.

A CRISPR–Cas9 screen combined with heparan sulfate (HS)-binding reagents identifies genes involved in HS biosynthesis and assembly and reveals the unexpected role of histone demethylase KDM2B in regulating HS presentation on the cell surface.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.

Stephanie London, Martin Tobin and colleagues report meta-analyses of genome-wide association studies for forced vital capacity (FVC), a spirometric measure of pulmonary function that reflects lung volume. They identify six regions newly associated with FVC and demonstrate that candidate genes at these loci are expressed in lung tissue and primary lung cells.

Plant biosynthetic enzymes rapidly evolve to catalyze specialized reactions. Here, the authors present the crystal structure and mechanism of COSY, the enzyme involved in coumarin biosynthesis of the BAHD-acyltransferase family that catalyzes an intramolecular acyl transfer reaction through a proton exchange mechanism.

Deubiquitinases have been shown to be involved in double strand break repair pathways. Here the authors reveal that USP15 deybiquitinase plays a role in homologues recombination repair by targeting BARD1 and affecting cells response to PARP inhibitors.

The structure of a neutralizing human monoclonal antibody isolated from an individual immunized in a Plasmodium vivax Duffy binding protein vaccine clinical trial, in complex with its target, elucidates the mechanism by which parasite invasion of immature red blood cells is inhibited.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

A continuously evolved adenine base editor is compatible with various Cas proteins and mediates efficient A•T-to-G•C base conversions at a wide variety of PAM sites.

Despite the promise that machine learning (ML) can accelerate catalyst development, truly novel catalysts are challenging to find through ML approaches because of their inability to extrapolate. Here, the authors show an extrapolative ML approach to develop new multi-elemental catalysts.

There is a growing interest in the role of timing of physical activity (PA) in improving health. Here, using a large-scale cohort study, the authors show that moderate-to-vigorous PA at the optimal time of day robustly predicts lower mortality risk and may maximize the beneficial effect of PA.

A deep learning model trained on raw pixel data in hundreds of thousands of echocardiographic videos for the prediction of one-year all-cause mortality outperforms clinical scores and improves predictions by cardiologists.

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.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

The intensity of radio emission from a pulsar is shown to relate to the quantity of particles discharging in the magnetosphere rather than to changes of the structure of the magnetic field in the magnetosphere itself.

In a mouse model of breast cancer, a low-protein diet induces engulfment activities and mTORC1 signalling in tumour-associated macrophages to suppress engulfment-dependent mTORC1 signalling in MYC-overexpressing cancer cells through cell competition, serving as an innate immune defence mechanism to slow tumour growth.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.