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Mutation of conserved prolines enhances correct pairing of light and heavy chains for bispecific IgG-like antibody production.

A combination of adenovirus-vectored and subunit protein intranasal vaccine enhances immune response against SARS-CoV-2 variants in animal models and humans.

Heart failure can be caused by cardiac fibroblasts replacing myocytes. Here, the authors use functional genomic data from fibroblasts, genetic signals enriched in people with heart disease, and gene perturbation analyses to link disease-associated regulatory elements to protein-coding genes.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

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.

Friction consolidation transforms brittle Sm–Co powders into dense magnets via shear-driven redox reactions and localized heating, enabling phase-selective refinement and enhanced magnetization in a single-step, low-temperature process.

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.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Despite advances in machine learning approaches, de novo design of collagen-based materials remains difficult. In this study, based on the natural structure of the defense collagen family of proteins, designed triple helical peptide assemblies are found to form ribbons and a variety of bundled, porous architectures.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Converting CS₂ and COS pollutants into benign products is critical in eliminating waste exhaust fumes. Now, a series of air-stable palladium complexes mediate hydrolysis of both CS₂ carbon–sulfur bonds at 25 °C to produce CO₂. Oxidation of the resulting complexes regenerates the starting complexes with SO₂ and NO₂ release.

Telomere maintenance by telomerase depends on the correct assembly and the recruitment of the enzyme complex. Here, the authors reveal that the RNA/DNA binding proteins NONO, SFPQ, and PSPC1 interact with telomerase via the hTR RNA template, facilitating telomerase trafficking out of Cajal bodies and recruitment to the telomere.

A device architecture based on indium arsenide–aluminium heterostructures with a gate-defined superconducting nanowire allows single-shot interferometric measurement of fermion parity and demonstrates an assignment error probability of 1%.

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.

Remaining drug-tolerant persistent (DTP) cancer cells limit the efficacy of targeted therapy in EGFR, ALK and KRAS mutant non-small cell lung cancer (NSCLC). Here, the authors show that focal adhesion kinase (FAK)-YAP signalling supports DTP cells promoting residual disease and targeting this pathway improved tumour response in NSCLC preclinical models.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

A fibroblast lineage marked by FAP gives rise to POSTN-expressing fibroblasts resembling matrifibrocytes and IL-1β regulates FAP/POSTN fibroblast specification by directly signalling to cardiac fibroblasts, highlighting a role for immunomodulators in targeting cardiac fibrosis.

Treatment with the oncolytic herpes virus CAN-3110 is associated with improved survival responses in patients with recurrent glioblastoma, particularly in individuals who are seropositive for HSV1.

Antibodies targeting the HIV-1 fusion peptide rarely achieve more than 60% neutralization breadth. Here, the authors develop an anti-FP antibody enhancing its potency to 80% and structurally resolve the expanded FP-binding site that allows the antibody to target diverse viral variants.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

In order to design cancer immune therapies, it is important to understand how tumours evade the immune response that is mounted against them. Authors here analyse the distribution and properties of immune cells in hepatocellular carcinoma and describe a progressive tumour-immune co-evolution programme from early to late stage cancer.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Type-1 innate lymphoid cells have been shown to drive intestinal epithelial proliferation and extracellular matrix remodelling through TGF-β1 secretion, which could exacerbate inflammatory bowel disease comorbidities such as cancer and fibrosis.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

While antibodies neutralize HIV via Fab recognition of viral surface antigens, antibody Fc domains mediate effector functions, including antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), and complement (C') activity. Here, Spencer et al. modify bNAb 10E8v4 to enhance C'-mediated potency in SHIV challenged rhesus macaques to probe its function in protection, showing that in the absence of neutralization, enhancing C' activities in vitro adds no value toward reducing viremia in either blood or tissue.

There is an unmet medical need for the detection and treatment of early adenomas to prevent their progression to malignant disease. Here the authors show that orally administered E. coli Nissle 1917 can selectively colonize adenomas in mouse models and in patients as a detection tool, as well as deliver immunotherapeutics for colorectal neoplasia treatment.

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that Usp30 knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.

Exome-sequencing analyses of a large cohort of patients with type 2 diabetes and control individuals without diabetes from five ancestries are used to identify gene-level associations of rare variants that are associated with type 2 diabetes.

Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.

Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Expression of mdg4 retrotransposons during Drosophila metamorphosis activates the antiviral NF-κB factor Relish. Silencing of mdg4 or Relish at the pupal stage leads to an inability to clear exogenous viruses in adulthood.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

Sequencing of the sex-determining Y chromosomes of cattle and sheep has proved difficult in the past. Using modern methods, this study presents complete T2T assemblies of these chromosomes and uncovers differences between the species that are suggestive of divergent evolutionary trajectories.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

The inflammasome is normally activated by pathogens to induce tissue inflammation. Here the authors show that, in mouse experimental colitis models, Nlrp1 inflammasome sensor activates IL-18 to reduce beneficial colonic Clostridiales species, thereby decreasing microbial butyrate and its protective effects on colitis.

Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.

Temporal multi-omic analysis of tissues from rats undergoing up to eight weeks of endurance exercise training reveals widespread shared, tissue-specific and sex-specific changes, including immune, metabolic, stress response and mitochondrial pathways.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

MetaSTAAR enables functionally informed rare variant association analysis in biobank-scale cohorts using an efficient, sparse matrix approach for summary statistic storage.

The One Thousand Plant Transcriptomes Initiative provides a robust phylogenomic framework for examining green plant evolution that comprises the transcriptomes and genomes of diverse species of green plants.