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This work uses gene expression and single cell analyses to group extrapulmonary tuberculosis patients into three immune types, revealing immune pathways driving pathogenesis and markers that could improve diagnosis and guide tailored treatments.

Although FZDs are promising drug targets, so far no small molecules targeting them were described. Here, the authors report the a FZD7 core-targeting small molecule negative allosteric modulators of WNT-induced signaling, confirmed by pharmacology, structure determination and MD simulations.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

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.

This study used AI to map ~29,000 CDR studies—3–4 times more than expected—showing rapid but uneven growth. The map supports stronger evidence synthesis for climate goals and the IPCC. #CDR

The WNT/β-catenin signaling pathway regulates key physiological processes. Here, the authors show that FZD-LRP6 association alone is insufficient to activate β-catenin signaling, as seen with WNT−16B, but effective signaling instead requires higher-order receptor clustering to trigger the pathway.

Bedoui and colleagues describe a sequential process of integration of innate and CD40-delivered signals in APCs, which optimizes their capacity to drive antiviral CD8⁺ T cell responses.

Here the authors use single-cell RNA sequencing data to identify genetic variants associated with gene expression (eQTLs) within the context of “trained immunity”, the immunological memory of innate immune cells. They establish a framework for understanding the genetic basis of complex traits by combining single-cell eQTLs with multi-omics data from patients and public databases.

Swarm Learning is a decentralized machine learning approach that outperforms classifiers developed at individual sites for COVID-19 and other diseases while preserving confidentiality and privacy.

FZD₇ is a class F GPCR involved in intestinal epithelium homeostasis. Using cryo-EM, the authors determine the structure of inactive FZD₇ and compare it with the G-protein-bound form. They refine the FZD activation mechanisms and identify a water pocket and an allosteric cholesterol binding site.

Seismic amplifications arise from several cycles of circular recombination of circular extrachromosomal DNA formed as a result of chromothripsis. The process provides a mechanism for oncogene amplification in a number of different human tumor types.

Jan Molenaar and colleagues show that LIN28B is overexpressed and amplified in human neuroblastomas and that LIN28B regulates let-7 family miRNAs and MYCN. They create a transgenic mouse model of LIN28B overexpression and show that these mice develop neuroblastoma tumors.

Analyses of genomes from 914 children, adolescents, and young adults provide a comprehensive resource of genomic alterations across a spectrum of common childhood cancers.

John Maris, Jan Molenaar, Gudrun Schleiermacher and colleagues performed whole-genome sequencing of 23 paired diagnostic and relapsed neuroblastomas, showing enrichment for mutations in the RAS-MAPK signaling pathway. These mutations render neuroblastoma cell lines susceptible to MEK inhibition.

Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent risk loci. Comparisons with other psychiatric disorders and candidate gene analyses provide new insights into major depressive disorder.

A risk score based on a 34-gene signature for outcome prediction in meningioma was developed and validated in large multi-institutional cohorts and showed better performance in discriminating postoperative menignioma outcomes compared with existing meningioma classification systems.

Livestock greenhouse gas emissions are key to the sustainability of food systems. A spatially explicit analysis of global livestock supply chains shows large variability of nitrogen use efficiency across species, systems, production intensities and the origin and management of animal feed.

The development of neuroblastoma (NB) is regulated by multiple core transcription factors. Here, SOX11 is identified as a potential epigenetic master regulator upstream of the core regulatory circuitry in adrenergic high-risk neuroblastoma.

The endocardium lines the interior of the heart chambers and has been debated as a source of hematopoietic lineages. Here they show that the endocardium may act as a source of, and resident tissue for, hematopoietic stem and progenitor cells in zebrafish, providing evidence for diversity in origins and residences of hematopoietic cells.

Two papers by Kather and colleagues and Gerstung and colleagues develop workflows to predict a wide range of molecular alterations from pan-cancer digital pathology slides.

Quantum metrology allows surpassing the standard quantum limit, but methods relying on squeezing require to know the orientation of the squeezed quadrature with respect to the signal. Here, instead, the authors propose a phase-insensitive Fock-state-based protocol, and demonstrate it using trapped ions.

An integrated high-resolution genetic, physical and shotgun sequence assembly of the barley genome, one of the earliest domesticated and most important crops, is described; it will provide a platform for genome-assisted research and future crop improvement.

Precise control of quantum systems is important for numerous quantum information tasks, but becomes harder as the system size grows. Dolde et al.use dynamical decoupling techniques to obtain high-fidelity entangled states between electron spins in a nitrogen-vacancy-centre qubit system, with low cross-talk.

There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel Na_V1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model.

Catastrophic rock weakening upon impact of a meteorite, and hence flow, is shown to be followed by regained rock strength that enabled the formation of the peak ring during cratering.

In high-risk neuroblastoma cases, gains in chromosome 17q are common. Here, the authors investigate the epigenomics and transcriptomics of neuroblastoma, identifying TBX2 as a core regulatory circuitry component enhancing the reactivation of DREAM targets by MYCN/FOXM1.

While estrogen is known to change hippocampal activity in animals, it is not known if this effect extends to humans. Here, authors vary the doses of estrogen in young women and show that the effects on hippocampal activity can be described by linear and inverted-U shaped dose-response functions.

Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

Depression is correlated with many brain-related traits. Here, Shen et al. perform phenome-wide association studies of a depression polygenic risk score (PRS) and find associations with 51 behavioural and 26 neuroimaging traits which are further followed up on using Mendelian randomization and mediation analyses.

Regulation of gene expression and splicing are thought to be tissue-specific. Here, the authors obtain genomic and transcriptomic data from putamen and substantia nigra of 117 neurologically healthy human brains and find that splicing eQTLs are enriched for neuron-specific regulatory information.

Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.

Genome-wide analysis of self-reported dyslexia identifies 42 associated loci, including 27 not previously associated with cognitive traits. Dyslexia shows genetic correlation with ambidexterity but not neuroanatomical measures of language-related circuitry.