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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.

The lowest-frequency gravitational wave background may be shaped by supermassive black hole binaries that scatter nearby stars or dark matter. In this case, the NANOGrav 15-year dataset favours dense galactic centres with 10⁶ solar masses per cubic parsec.

Models of turbulent flows are often simulated in the laboratory, in sampling areas with dimensions <1 m. Here, the authors exploit a natural snowstorm to quantify turbulent flows, exploring the complex dynamics of the atmospheric boundary layer around a 2.5-MW utility-scale wind turbine.

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.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Tree longevity is thought to increase in harsh environments, but global evidence of drivers is lacking. Here, the authors find two different pathways for tree longevity: slow growth in resource limited environments and increasing tree stature and/or slow growth in competitive environments.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

Here, a library of more than 300,000 chemicals was screened for activity against Plasmodium falciparum growing in red blood cells. Of these chemicals, 172 representative candidates were profiled in detail; one exemplar compound showed efficacy in a mouse model of malaria. The findings provide the scientific community with new starting points for drug discovery.

Current climate migration literature focuses on quantifying the link between climate drivers and migration, yet overlooks its broader and more complex interactions with mitigation, adaptation and climate impacts. This Perspective highlights key gaps and offers concrete solutions.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

The BioDIGS project is a nationwide initiative involving students, researchers and educators across more than 40 research and teaching institutions. Participants lead sample collection, computational analysis and results interpretation to understand the relationships between the soil microbiome, environment and health.

Lange et al. identify a lipid droplet quality control pathway in which FSP1 safeguards stored neutral lipids from lipid peroxidation, thereby preventing the induction of ferroptosis.

An optical detection and analysis platform quantifies aggregate density, distribution and size in fluorescently labelled post-mortem human brain tissue.

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).

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.

Joseph Testa, Michele Carbone and colleagues report that germline mutations in BAP1 predispose to malignant mesothelioma and uveal melanoma. They further hypothesize that mesothelioma predominates in BAP1 mutation carriers following exposure to asbestos.

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.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Here, the authors introduce AlphaFold-Metainference, which uses inter-residue distances predicted by AlphaFold to generate structural ensembles of disordered proteins.

Nixon-Abell et al. show that ANXA11 condensation on lysosomal membranes causes a coupled phase transition of the underlying lipids and mechanical stiffening of the overall ensemble involved in RNP granule-lysosome tethering and co-trafficking.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Electromagnetic responses can reveal the non-trivial properties of topological materials. Here, the authors demonstrate an anomalous planar Hall effect in trigonal crystals associated with the presence of topological nodal lines in trigonal-PtBi₂.

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.

Joseph et al. reveal that monoSUMOylated DDK kinase, implicated in replication initiation, acts with Rad51 recombinase to prevent replication fork uncoupling and to mediate recombination-dependent gap-filling in the presence of genotoxic stress.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Macrophages engulf microbes and cellular debris to protect us from disease and help repair wounded tissues. In cancer, they also infiltrate the tumor, but studies in humans and mice now uncover more sinister roles for these immune cells in cancer. In 'Bedside to Bench', Christiana Ruhrberg and Michele De Palma scrutinize a clinical study where the presence of macrophages correlates with a high risk of disease progression in people with Hodgkin's lymphoma, indicating a clinical value of macrophages as biomarkers of survival. The authors also emphasize how characterizing of the mechanisms by which subpopulations of macrophages promote tumor cell motility and angiogenesis might help in the development of antiangiogenic therapies to stop tumor progression. In 'Bench to Bedside', Joseph Qualls and Peter Murray examine a study that shows how stopping migration of macrophages into the tumor can impair tumor regrowth after radiation treatment.

Authors perform an analysis of the patient data and risk factors to evaluate unfavorable outcomes and adverse events in adults with pulmonary tuberculosis treated with a 4-month rifapentine based regimen. Low rifapentine exposure was the most clinically significant risk factor for treatment failure and tuberculosis relapse.

Sixteen years of data from a ‘double pulsar’ discovered by an Italian astronomer allow some of the most accurate tests ever of general relativity.

Sedici anni di dati su una "doppia pulsar" scoperta da un’astrofisica italiana hanno permesso alcuni dei test più accurati della relatività generale mai ottenuti.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

BAP1 is a deubiquitylase that is associated with multiprotein complexes that regulate key cellular pathways. Recent findings have indicated that germlineBAP1mutations might cause a novel cancer syndrome. Michele Carbone and colleagues discuss the evidence for this.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

A cross-reactive antibody and T cell response is identified in a large portion of patients with multisystem inflammatory syndrome in children.

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.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

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.

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.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.