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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.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

In this study, the authors describe SANA, a nitroalkene derivative of salicylate, as a potential activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue. Preclinical and clinical data from this paper also suggest that SANA improves glucose homeostasis and promotes weight loss in mice and humans.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Optimizing devices for electrochemical CO₂ reduction requires a comprehensive and quantitative understanding of the microenvironments where the reactions occur. Now, a multiscale modelling approach that explicitly accounts for electrolyte effects at all scales is developed and showcased for the electroreduction of CO₂ on silver.

Nucleotide Transformer is a series of genomics foundation models of different parameter sizes and training datasets that can be applied to various downstream tasks by fine-tuning.

The ability to reversibly control monobody binding affinity would find use in biotechnology and research applications. Here the authors fuse the light-sensitive AsLOV2 domain to a monobody against the Abl SH2 domain to obtain a light dependent monobody and apply it in vitro and in mammalian cells.

The ability to regulate nanobody affinity with light would expand the applications toolbox for these reagents. Here the authors insert an optimised photoswitchable AsLOV2 domain into multiple nanobodies and demonstrate photoswitchable binding to fluorescent proteins and endogenous proteins in cells.

Genomic studies often lack representation from diverse populations, limiting equitable insights. Here, the authors show that the BIG Initiative captures extensive genetic diversity and reveals ancestry-linked health disparities in a community-based Mid-South cohort.

An IgE antibody recognising Folate Receptor-alpha has been tested in clinical trials for ovarian cancer and preclinical studies show macrophage involvement in the anti-tumoural functions of IgE. Here the authors demonstrate that IgE induces proinflammatory activation of ovarian cancer patient macrophages, which reverses their immunosuppressive induction of Treg cells and promotes CD8⁺ T cell function.

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

A high-resolution kidney cellular atlas of 51 main cell types, including rare and previously undescribed cell populations, represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

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.

Association analyses in over 1 million individuals identify 535 new loci influencing blood pressure traits. The results provide new insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

In an exploratory analysis of the KEYNOTE-361 phase 3 trial that tested immunotherapy and chemotherapy in advanced urothelial carcinoma, different early circulating tumor DNA (ctDNA) dynamics were observed between the two treatments, and ctDNA levels were associated with response to pembrolizumab but not to chemotherapy.

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.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Reengineering of the lac operon in E. coli from a ligand-inducible to a blue-light-regulated gene expression system facilitates optogenetic control of biotechnological applications including metabolic engineering and protein expression.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Water and wastewater infrastructure worldwide faces unprecedented challenges. A new model can assess the environmental and economic implications of a hybrid water supply system that provides a centralized surface water supply with distributed direct potable reuse of municipal wastewater.

Post-acute sequelae of SARS-CoV-2 (PASC) is still not well understood. Here the authors provide patient reported outcomes from 590 hospitalized COVID-19 patients and show association of PASC with higher respiratory SARS-CoV-2 load and circulating antibody titers, and in some an elevation in circulating fibroblast growth factor 21.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

Genome-wide meta-analysis of SARS-CoV-2 susceptibility and severity phenotypes in up to 756,646 samples identifies a rare protective variant proximal to ACE2. A 6-SNP genetic risk score provides additional predictive power when added to known risk factors.

The impact of the DART spacecraft on the asteroid Dimorphos is reported and reconstructed, demonstrating that kinetic impactor technology is a viable technique to potentially defend Earth from asteroids.

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.

Genome-wide analyses identify variants associated with sinus node dysfunction, distal conduction disease and pacemaker implantation, implicating ion channel function, cardiac developmental programs and sarcomeric structure in bradyarrhythmia susceptibility.

Here the authors quantitatively characterize binding to transcription factor (TF) binding site clusters in vitro, followed by characterizing clusters in synthetic and native gene regulatory systems in yeast. They show low-affinity clusters achieve high TF occupancies in vitro and gene activation in vivo, suggesting occupancy rather than individual TF dwell times drive transcriptional activation.

Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

Natural isolates of Caenorhabditis elegans nematodes differ in their sensitivity to the anti-exploratory pheromone icas#9, yielding two distinct foraging strategies that possess different survival advantages depending on environmental conditions such as food distribution.

Understanding patterns in woody plant trait relationships and trade-offs is challenging. Here, by applying machine learning and data imputation methods to a global database of georeferenced trait measurements, the authors unravel key relationships in tree functional traits at the global scale.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

It is unclear how mimetic radiations, the evolution of a species to resemble different model species, contribute to speciation. Here, the authors show patterns of mating behaviour and genetic divergence, suggesting that mimetic divergence has promoted incipient speciation in a group of Peruvian poison frogs.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Two Prevotella copri metagenome-assembled genomes that are positively associated with ponderal growth are the principal contributors to MDCF-2-induced expression of metabolic pathways involved in utilizing the component glycans of MDCF-2—a microbiome-directed complementary food.

Ephemeral snow and ice melt contribute substantially to dry season runoff in the Rio Santa basin, with snowmelt accounting for up to 55% and ice melt up to 44% of inputs, according to results from a distributed glacio-hydrological model applied to quantify cryospheric contributions to the Andean water cycle.

Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.