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Enhanced polyamine depletion in neuroblastoma models decreases translation of mRNA codons with adenosine in the third position, reprogramming the tumour proteome away from cell cycle progression and towards differentiation.

Comparison between structures of human, mouse and rat P2X7 receptors define ortholog-specific pharmacology and facilitated structure-based drug design of UB-MBX-46, an antagonist that selectively inhibits the human P2X7 receptor with sub-nanomolar potency.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

The blood-brain barrier (BBB) regulates the extracellular composition of the central nervous system (CNS), but it is not known whether its properties differ across CNS regions. Here, the authors show in mice that the BBB exhibits regional specializations, and that such specializations can be important for the function of specific neural circuits.

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).

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Mathieson et al. carried out a genome-wide association study of reproductive success (number of children born) in humans, revealing the importance of diverse neuro-endocrine and behavioural factors.

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.

The authors show that terminal activity of dopaminergic neurons selectively projecting from the ventral tegmental area to the lateral septum is sufficient for promoting aggression and necessary for establishing baseline aggression in mice.

Roesch and colleagues use clinical datasets and mouse models of BRAF-mutant melanoma to reveal a role for IL-17A in positive responses to anti-PD-1 and anti-CTLA-4 therapy, which they also link to infiltrating neutrophils.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

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.

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.

A study reports single-cell RNA-sequencing profiles for more than 1.6 million cell nuclei from 101 whole mouse embryos including 22 mutant and 4 wild-type genotypes, from one experiment.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

A conjugate drug consisting of GLP-1 receptor agonist and the PPARɑ/ɣ dual-agonist tesaglitazar is shown to have superior anti-diabetic effects than monotherapy.

The perception of spatial patterns (form vision) is thought to rely on rod and cone cells in the retina. Here, the authors show that a third kind of retinal cell, melanopsin-expressing ganglion cells, can also detect form in humans, under particular conditions.

Pooled and sex-specific genome-wide association analyses identify new risk loci for restless legs syndrome and candidates for drug repurposing. Machine learning models combining genetic and other information show improved risk prediction performance.

How the circadian clock generates rhythms of arousal remains unclear. Here, authors show that a clock-output molecule reduces excitability of an arousal circuit during the active phase. These results suggest a multifaceted role for the clock in arousal.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Detailed insight into how the brain responds to Trypanosoma brucei infection is lacking. Here, single cell and spatial transcriptomics are integrated to characterise this response, identifying a unique crosstalk between microglia and plasma cells.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Long-acting GIPR agonists, individually or as part of GIPR–GLP-1R co-agonists, are shown to require GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake in mice.

The epigenetic mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) are not fully elucidated. Here, the authors reveal a druggable super-enhancer-mediated RNA-binding protein cascade that supports PDAC growth through enhanced mRNA translation.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

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

Analysis of fully clinically annotated and sequenced melanoma tumor samples collected before anti-PD1 treatment suggests that determinants of response differ on the basis of previous anti-CTLA4 therapy, and that tumor mutational burden may not be a strong predictor of response across melanoma subtypes.

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.

Unlike Amazonian forests, African forests have maintained their carbon sink until recently but by 2030 the African carbon sink will have shrunk by 14 per cent and the Amazonian sink will reach almost zero.

Tobacco smoking and cold exposure are environmental modulators of human energy metabolism suppressing appetite and increasing energy expenditure, respectively. Here, the authors develop a novel pharmacological strategy in which they simultaneously mimic the metabolic benefits of both phenomena through small-molecule combination therapy, and show that this treatment improves metabolic health of obese mice.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

Thomas and colleagues examine preinfection baseline parameters of cellular and serologic immunity. Their findings collectively show that peripheral cell composition provides better correlates of immune protection from symptomatic influenza infection than vaccination, demographics or serology alone.

Light increments and decrements are encoded in the retina by ON and OFF ganglion cells. The polarity of these cells' responses is thought to be fixed, but Tikidji-Hamburyan and colleagues now demonstrate in mouse and pig retina that they can change depending on ambient illuminance. For instance, an OFF cell can gain or lose an ON response at different light levels. Such changes in response polarity propagate to higher visual centers in vivo.

This Perspective presents a reliable and comprehensive source of information on pitfalls related to validation metrics in image analysis, with an emphasis on biomedical imaging.

Using whole-genome data for single-nucleotide polymorphism and results from genome-wide association studies, the authors show that people’s preference for pairing with those with similar phenotypic traits has genetic causes and consequences.