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Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

Little is known about von Economo neurons, which have been described in a subset of mammals and appear to be selectively lost in several human neurological diseases. Here, authors reveal the gene expression profile of these cells and show that they are likely long-distance projection neurons.

Whether marine microbes form strongly differentiated communities over time remains unknown. Here, Martin-Platero and colleagues develop a time series analysis to characterize marine bacteria and Eukarya communities at a fine temporal grain, revealing cohesive but rapidly changing communities.

A detailed molecular analysis of related yeast species shows that progressively opposed genetic logics can evolve while resulting in a conserved phenotypic output:mating-type determination. This is the first clear demonstration of the 'genetic drift' principle at a molecular level.

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.

The genomic features of precursor conditions of multiple myeloma provide multiple biological insights into disease origins and evolution, together with opportunities to identify those at highest risk of progression.

Here, the authors develop hydrocarbon-stapled paxillin-mimetic peptides that act as selective and potent focal adhesion kinase (FAK) scaffold inhibitors to displace FAK from focal adhesions. Treatment shows reduced cancer cell survival in vitro and reduced tumor burden in vivo.

Retinoic acid is known to be effective against bone marrow metastatic neuroblastoma cells, but not primary tumors. Here, authors discover that bone morphogenetic protein signaling is responsible for determining neuroblastoma cell fate and sensitivity to retinoic acid.

Multi-ancestry genome-wide association meta-analysis identifies new risk loci for CAC. Functional evidence implicates candidate causal genes as regulators of smooth muscle cell-mediated calcification.

Fatty acyl reductases (FARs) are critical enzymes in the biosynthesis of fatty alcohols and have the ability to directly acces acyl-ACP substrates. Here, authors couple machine learning-based protein engineering framework with gene shuffling to optimize a FAR for the activity on acyl-ACP and improve fatty alcohol production.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Induction of CD4 T follicular helper (Tfh) cells is important for antibody responses to viral infections. Here, the authors show in a rhesus macaque model of mild COVID-19 that SARS-CoV-2 infection results in transient accumulation of proliferating Tfh cells with a Th1 profile in peripheral blood and generation of germinal center Tfh cells specific for viral proteins.

Genome-wide association analyses comprising 14,256 cases and 1,199,156 controls and incorporating correlated cardiac magnetic resonance imaging traits provide insights into the molecular etiology of dilated cardiomyopathy.

Eukaryotic ribosome biogenesis involves a large number of maturations factors which are responsible for the stepwise assembly of the ribosomal subunits. Here the authors use an array of biochemical and structural biology methods to investigate the function of the UtpA and UtpB complexes as part of the small subunit processome.

Highly accurate antibody tests for SARS-CoV-2 are needed for surveillance in low-prevalence populations. Here, the authors find seroprevalence of less than 1% in two San Francisco Bay Area populations at the beginning of April, and that seroreactivity is generally predictive of in vitro neutralising activity.

PD-1 is a critical modulator of CD8⁺ T cell activation and exhaustion. Sen and colleagues show that a cell-state-specific enhancer tunes PD-1 expression exclusively in exhaustion and that deletion of this enhancer improves CD8⁺ T cell function.

The authors use Patch-seq and electron microscopy datasets to relate synaptic connectivity to the transcriptomic cell type of different types of inhibitory neuron.

Sengupta et al. show that the mesenchymal cell state in neuroblastoma is associated with heightened immunogenicity and anti-tumor immune responses compared with the adrenergic state, which is linked to sensitivity to immunotherapy in preclinical models.

Of 12 serology assays tested, four detect antibodies in more than 80% of patients with COVID-19.

Genome-wide analysis of chronic obstructive pulmonary disease identifies 82 loci, 35 of which are new. Integration of gene expression and genomic annotation data shows enrichment of signals in lung tissue, smooth muscle and several lung cell types.

GIANT, a genetically informed brain atlas, integrates genetic heritability with neuroanatomy. It shows strong neuroanatomical validity and surpasses traditional atlases in discovery power for brain imaging genomics.

Exome sequencing of 851 trios from more than 2,500 individuals finds 187 genes with de novo mutations that contribute to meningomyelocele (spina bifida) and highlights critical pathways required for neural tube closure.

Deconvolution methods infer levels of immune infiltration from bulk expression of tumour samples. Here, authors assess 6 published and 22 community-contributed methods via a DREAM Challenge using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells.

A design pipeline is presented whereby binding proteins can be designed de novo without the need for prior information on binding hotspots or fragments from structures of complexes with binding partners.

RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

AI decision support system non-homogenously influences clinical decisions in dynamic treatment regimen, as it depends on several factors including prior knowledge, preference, disease type, treatment modality, and AI’s learned behavior and inherent biases.

Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.

Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumour microenvironment. Here, the authors show that specialized subsets of tumour-infiltrating dendritic cells induce distinct CD4⁺ T cell programs and specifically identify a CD103^–CD11b⁺ subset which induces tumor-promoting FoxP3^– Type-1 regulatory T cells.

PD-L1 on tumor cells exerts an important dampening effect on T cells via their expression of PD-1. Miller and colleagues find that PD-L1 ‘back-signaling’ into T cells and macrophages can also dampen immune responses within the tumor microenvironment.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

A CRISPR–Cas9 screening-based structure–activity relationship profiling method reveals that LSD1 inhibitors suppress acute myeloid leukemia by disruption of the interaction between LSD1 and GFI1B instead of the enzyme activity of LSD1.

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.

RNA-sequencing analysis of cells in the human cortex enabled identification of diverse cell types, revealing well-conserved architecture and homologous cell types as well as extensive differences when compared with datasets covering the analogous region of the mouse brain.

The transition between conducting and non-conducting states of K⁺ channels has been explained by conformational changes at the intracellular entrance to the conduction pathway. Here authors demonstrate that control over K⁺ currents in Kir channels is not explained by the canonical pore-gating model, as conduction is not impaired by a constricted inner helix bundle.

Bacteroides species are prominent members of the human gut microbiota. Here the authors develop a platform technology (consortium transcriptional programming) in five human donor Bacteroides chassis cells—enabling complex decision-making within said community, which can be used for the development of living therapeutics.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.

In this work, authors develop a high-efficiency micro-combined heat and power system powered by an opposed-piston engine which enables simultaneous generation of electricity and heating to residential homes or light commercial buildings. The design is shown to be particularly effective for colder climates.

HCN and its isomer HNC are both observed in the interstellar medium and inelastic collisions with helium and other species strongly influence their derived abundances. Now it has been shown experimentally and theoretically that HNC is much more strongly excited than HCN in collisions with helium at the low temperatures of interstellar space.