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Divergent white matter metabolic patterns reveal a mechanistic basis for cognitive resilience and enhance prediction of future cognitive decline beyond established aging and dementia biomarkers.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Donahue et al. show that ageing is associated with changes in ER morphology. ER-phagy drives age-associated ER remodelling through tissue-specific factors.

CDK4/6 inhibitors are promising treatments for ER+ breast cancer, however resistance remains a challenge. Here, the authors analyse the NeoPalANA cohort and indicate that a 33 gene signature was predictive of response to neoadjuvant anastrozole and palbociclib.

Antiphospholipid antibodies (aPL) are associated with an elevated risk of thromboembolic events in patients with antiphospholipid syndrome and, increasingly, in those without previous thrombosis. In this Review, Bikdeli and colleagues discuss the clinical relevance of aPL seropositivity in predicting the risk of thrombotic cardiovascular events, summarize potential management strategies and identify key knowledge gaps that warrant further research.

Hiʻiaka is the largest moon of the distant dwarf planet Haumea. Here, the authors report the first multi-chord stellar occultations of Hiʻiaka, revealing its size, shape, and density, suggesting an origin from Haumea’s icy mantle.

Barnes et al. report a dynamic and reciprocal crosstalk between tissue tension and glycocalyx bulkiness that promotes a mesenchymal, stem-like phenotype in GBM.

Burkholderia bacteria protect the offspring of Lagria beetles against pathogens. Here, Flórez et al. identify an antifungal polyketide that is likely encoded by a horizontally acquired gene cluster on the genome of a dominant, uncultured Burkholderia symbiont of Lagria villosa.

Single-cell gene expression analysis is challenging. This work describes a new droplet-based single cell RNA-seq platform capable of processing tens of thousands of cells across 8 independent samples in minutes, and demonstrates cellular subtypes and host–donor chimerism in transplant patients.

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.

DeNardo and colleagues show that tissue-resident macrophages (TRMs) have a protective role during pancreas inflammation by triggering the activation of fibroblasts, but that TRM-driven fibrosis drives pancreas cancer pathogenesis.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

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).

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.

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.

Targeted protein degradation of cell-surface glycoproteins suppresses cancer in mice.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Methods to probe DNA methylation in the majority of non-human mammals are lacking. Here the authors developed a Mammalian Methylation Array that includes 36k well-conserved CpGs in mammals which will facilitate cross-species comparisons. They annotate the conserved CpGs in > 200 species. The array allows one to measure methylation in all mammalian species including unsequenced ones.

A method that allows for the detection of mosaic chromosomal alterations from blood whole-genome sequencing data highlights ancestry-specific differences in the distribution of common and rare germline susceptibility variants.

A multi-ancestry meta-regression study analyses diverse genome-wide association studies and genome loci associated with tobacco and alcohol use.

Fjords line mountainous continental margins where icesheets and glaciers once stood. A two-dimensional model simulation suggests that fjords can be eroded within one million years, primarily in response to topographic ice steering and erosion from ice discharge. Subsequent glaciers that form on these landscapes are smaller and exhibit greater responses to climate change.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Rocks and dust from the asteroid Bennu contain some of the molecular building blocks of life on Earth, such as amino acids and nucleobases. They also carry ammonia that formed billions of years ago in cold, distant regions of our Solar System.

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.

Acetylation of tau at K174 is identified in Alzheimer's disease (AD) brain tissue and exacerbates tau-mediated neurodegeneration and memory impairments in mice. Pharmacological inhibition of tau acetylation ameliorates these phenotypes in a mouse model of AD.

Three mysterious features at Titan’s northern polar region appear as lakes when observed with Cassini’s radar during winter but as land when observed in the infrared during spring, providing evidence of liquid removal on Titan at seasonal scale.

In a prespecified interim analysis of a pivotal phase 2 trial, avapritinib, a selective KIT inhibitor, elicited robust clinical and molecular responses, was generally well tolerated and led to improved patient-reported outcomes in patients with advanced systemic mastocytosis.

The transits of two Sun-like stars by small planets in an open star cluster are reported; such a stellar environment is unlike that of most planet-hosting field stars, and suggests that the occurrence of planets is unaffected by the stellar environment in open clusters.

The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.

While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.

Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

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.

Strong genetic evidence points to a significant role for heterozygous mutations to general chromatin remodeling factors, such as CHD8, in autism. Gompers et al. combine genomic, neuroanatomical and behavioral approaches to present an initial integrative picture of transcriptional mechanisms and widespread impacts of Chd8 haploinsufficiency across brain development in mice.

Emerging SARS-CoV-2 variants raise concerns on immune evasion. Here, the authors evaluate the neutralization efficiency of COVID-19 mRNA vaccinee sera against representative viruses of 13 WHO-designated SARS-CoV-2 variants of concern/interest.

Drp1 is the master regulator of mitochondrial and peroxisomal fission. Here, the authors show that a C-terminal intrinsically disordered motif, named the CT-SLiM, constitutes an allosteric switch that controls Drp1 structure, assembly, and function.

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.

Transcriptomic and proteomic profiling of blood samples from individuals with COVID-19 reveals immune cell and hematopoietic progenitor cell alterations that are differentially associated with disease severity.

Results from the phase 2/3 clinical trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease reveal no beneficial effects on cognitive measures despite a significant reduction in amyloid plaques and other key biomarkers in those treated with gantenerumab.

Clouds on Titan result from the condensation of methane and ethane and, at present, cloud activity mainly occurs in the southern hemisphere; general circulation models predict that this distribution should change with the seasons on a 15-year timescale. Now, global spatial cloud coverage on Titan is reported to be in general agreement with the models.

Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Cellular fusion is essential for skeletal muscle development. Here the authors identify Minion as a microprotein required for myoblast fusion and skeletal muscle formation, and show that co-expression of Minion and Myomaker is sufficient to induce cytoskeletal rearrangement and cell fusion even in non-muscle cells.

Distinct subsets of fibroblasts, which differ in their expression of thymus cell antigen 1 (THY1), are responsible for inflammation and tissue damage in mouse models of arthritis.