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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.

Atypical teratoid rhabdoid tumors (ATRT) are divided into three molecular subgroups, which could have different lineages of origin. Here, the authors use tumour imaging, multi-omics and genetically engineered mouse models to determine the anatomical region and cell lineage of origin of ATRT subtypes.

Microsatellite instability (MSI) due to alterations in DNA repair genes leads to carcinogenesis, but it also correlates with better prognosis and therapy response. Little is known of the contribution of altered noncoding sequences to MSI tumorigenesis. This report identifies a deletion in an MSI intronic region leading to the expression of a truncated chaperone, which shows dominant-negative effects on its wild-type counterpart. Acting as an endogenous inhibitor of a protumorigenic chaperone, the expression of the truncated variant associates with better prognosis in humans and may contribute to the overall limited malignancy of MSI tumors.

Lazarevic and colleagues show that T-bet-dependent NKp46⁺ innate lymphoid cells reside within the meninges of the CNS and initiate meningeal inflammation, thereby facilitating T cell entry into parenchymal CNS tissues and contributing to neuroinflammation.

The archetypal supergreenhouse Cretaceous Earth had an active cryosphere with permafrost in plateau deserts. A modern analogue is the aeolian–permafrost system from the Qiongkuai Lebashi Lake area, Xinjiang Uygur Autonomous Region, China.

Although acne vulgaris is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here the authors show that GATA6 is involved in maintaining homeostasis of the upper pilosebaceous unit of human skin and may contribute to acne pathogenesis.

Biallelic mutations in the sorbitol dehydrogenase gene SORD are identified as a common cause of hereditary neuropathy. Functional studies suggest that SORD deficiency may be treatable with aldose reductase inhibitors.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder.

tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

Type 1 diabetes is driven by T-cell autoimmunity to pancreatic islet cells. Here the authors show that autoreactive anti-IL-2 T and B cells are present in type 1 diabetes patients, and that anti-IL-2 antibodies precede diabetes onset in mice, suggesting their potential as a diagnostic marker.

Ferroptosis is an iron-dependent form of oxidative cell death. In this study, the authors show that NUPR1, a stress-inducible transcription factor, may be a driver of ferroptosis resistance.

Africa-specific genetic variation on chromosome 1 near CHD1L is associated with HIV replication in vivo.

In this study, Marlin et al. provide insights into the potential use of subunit vaccines that induce a high level of protection against SARS-CoV-2 in animal models.

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.

Single-cell multi-omic analyses show that chronic inflammation contributes to myeloproliferative neoplasm transformation to secondary acute myeloid leukemia by enhancing tumor protein 53 (TP53) mutant cell fitness and genetic evolution.

The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.

Kinesin-1 is a motor protein transporting cargo along microtubules. Here the authors show that kinesin-1 is required for antigen cross-presentation and coordinates endosome scission from early endosomes to allow sorting internalized cargoes towards the recycling endosomal or lysosomal compartments.

This study reports reduced expression of the chromatin and splicing regulator HP1γ in inflammatory bowel disease (IBD) and shows that HP1γ protects against pervasive RNA splicing leading to toxic mRNA products detected in IBD, like progerin.

An autoimmune-prone state of steady-state cytokinopathy, hyperactivated CD4 T cells and ongoing B cell activation contributes to a breach in immune tolerance in individuals with Down’s syndrome.

Protein modification by small ubiquitin-related modifier (SUMO) proteins is associated with antiviral responses. Here, the authors show that interferons increase the level of expression of SUMO proteins via a let-7 microRNA-controlled mechanism, and this contributes to the antiviral effects of interferons.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Multi-modal profiling reveals major alterations in colonic B cells in patients with ulcerative colitis, including reduced clonal diversity of plasma cells, and suggests that circulating gut-homing plasmablasts could serve as a biomarker for disease activity.

Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.

Xavier Jeunemaitre, Jean-Jacques Schott and colleagues report mutations of KLHL3 in familial hyperkalemic hypertension. KLHL3 encodes a BTB-BACK-kelch family actin-binding protein and regulates cell surface localization of the NaNa⁺-Cl⁻ cotransporter, a key regulator of ion resorption, at the distal nephron.

Mucosal surfaces of the respiratory tract are the first sites of entry and defense against SARS-CoV-2. Di Santo and colleagues perform paired analysis of the nasopharyngeal and systemic immune responses of SARS-CoV-2-infected patients and demonstrate distinct compartmentalization of immunity and shifts in the microbiome.

The molecular relationship between synaptic dysfunction and psychiatric disorders was investigated using a mouse model system; presynaptically localized Cntnap4 is required for the output of two disease-relevant neuronal subpopulations (cortical parvalbumin-positive GABAergic cells and midbrain dopaminergic neurons) and Cntnap4 mutants show behavioural abnormalities which can be pharmacologically reversed.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

Current preclinical models to investigate human HR + breast cancer progression and response to immunotherapy in vivo are limited. Here, the authors demonstrate that mammary tumours driven by a synthetic progestin combined with an oral carcinogen recapitulate several immunobiological features of human HR + breast cancers.

Huang et al. show that, in response to chemotherapy, PTEN directly interacts with NLRP3 in myeloid cells to enhance inflammasome activation and antitumour immune responses.

The efficacy of cancer drugs is profiled by measuring changes in the mass of single tumor cells.

Genome sequencing alone fails to provide a genetic diagnosis for many Mendelian disorder patients. Here, the authors utilize RNA sequencing to complement genotyping of patients with a rare mitochondrial disease by detecting aberrant RNA expression, splicing and allele-specific expression.

Foetal microchimeric cells (FMCs) are found in maternal circulation during pregnancy and migrate to injury sites, where they mediate repair, but how this is regulated is unclear. Here, the authors show in mice that the chemokine Ccl2 enhances delayed maternal wound healing through a subpopulation of Ccr2+ FMCs.

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.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

Regulatory T cells (Tregs) expand during pregnancy to promote tolerance towards the fetus. Here the authors show that Tregs induce proliferation of fetal and maternal cardiomyocytes during pregnancy and enhance myocardial repair via proliferation-promoting paracrine actions.

Gain-of-function mutations altering the PWWP domain of DNMT3A are identified as a new cause of microcephalic dwarfism. These mutations abrogate DNMT3A binding to H3K36me2 and H3K36me3 and lead to aberrant DNA methylation of Polycomb-marked regions.

Théry and colleagues find that the centrosome can participate in actin-filament assembly in a manner that is mediated by WASH and Arp2/3 and requires the presence of pericentriolar material.

Hedgehog signalling is known to be linked to oncogenic proliferation. Here, the authors identify structural events as a mechanism of Hedgehog activation in over one-third of driver unknown meningiomas.

Intranasally administrated fusion-inhibitory lipopeptides derived from the SARS-CoV-2 spike protect mice from different viral variants and induce cross-reactive immunity, offering a innovative antiviral approach against COVID-19

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Whole-genome sequence analysis identifies five independent risk loci for Lewy body dementia and demonstrates overlapping genetic architecture with Alzheimer’s and Parkinson’s diseases.

Christer Betsholtz, Christine Klein, Maria Sobrido and colleagues report the identification of mutations in the gene encoding PDGF-B that cause idiopathic basal ganglia calcification. They also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications.

Cerebral cavernous malformations associated with loss of function of Ccm1 are shown to be formed by endothelial cells undergoing endothelial-to-mesenchymal transition (EndMT) induced by TGF-β and BMP signalling; inhibition of TGF-β and BMP signalling prevents EndMT and the appearance of CCM lesions.