Patients affected by inflammatory bowel disease (IBD) exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here we replicate these IBD hallmarks in human-derived organ-on-a-chip devices lined by colon epithelial cells from...
Kilohertz-frequency (KHF) waveforms are gaining traction in transcutaneous spinal cord stimulation (tSCS) for motor recovery after paralysis. However, the mechanisms by which these fast-alternating currents depolarize proprioceptive afferent and motor efferent fibres remain unknown. To address this gap, we conducted a study in 28 participants showing, through peripheral nerve...
Targeting DNA payloads into human induced pluripotent stem cells (hiPSCs) typically requires multiple inefficient steps, slowing the testing of gene circuits and cell-fate programmes. Here we show that STRAIGHT-IN Dual enables simultaneous, allele-specific, single-copy integration of two DNA constructs efficiently within 1 week. STRAIGHT-IN Dual leverages the STRAIGHT-IN platform...
Rapid identification of viral infections and specific variants in patient samples requires a simple and multiplexed RNA detection method that does not rely on DNA sequencing. Although recent direct detection assays based on CRISPR–Cas13a offer rapid RNA detection by avoiding reverse transcription and DNA amplification required of gold-standard PCR assays, these assays are not...
Zellweger spectrum disorder (ZSD) is caused by biallelic loss-of-function variants in PEX genes required for peroxisome biogenesis, which is critical for normal cellular metabolism and signalling. The PEX1-p.G843D (c.2528G>A) allele, present in approximately 30% of individuals with ZSD, frequently results in chronic liver disease that can progress to cirrhosis, hepatocellular...
Human bone marrow mesenchymal stromal/stem cells (BM-MSCs) are widely used in clinical trials and tissue engineering, yet their native microenvironment remains poorly understood. Here we introduce a tissue-clearing protocol, DeepBone, for human bones and integrate it with simultaneous mRNA and protein detection. Using this protocol, we spatially map BM-MSCs relative to key bone...
Head computed tomography (CT) imaging is a widely used imaging modality with multitudes of medical indications, particularly in assessing pathology of the brain, skull and cerebrovascular system. It is commonly used as the first-line imaging in neurologic emergencies given its rapidity of image acquisition, safety, cost and ubiquity. Deep learning models may facilitate detection...
Cardiac MRI allows for a comprehensive assessment of myocardial structure, function and tissue characteristics. Here we describe a foundational vision system for cardiac MRI, capable of representing the breadth of human cardiovascular disease and health. Our deep-learning model is trained via self-supervised contrastive learning, in which visual concepts in cine-sequence cardiac...
The search for biological mechanisms of human aging is stalled by a lack of suitable models, and it remains unknown whether and to what degree rejuvenation reported in rodents translates to people. Here we report a human induced pluripotent stem cell-derived microphysiological system modelling the white adipose tissue–liver axis in the presence of heterochronic human serum to...
Developing lung-targeting delivery systems is essential for treating pulmonary conditions such as genetic respiratory diseases, infections, fibrosis and cancer. We synthesized and evaluated 444 lung-targeting lipids (LuT lipids) that form lipid nanoparticles (LNPs) to efficiently deliver messenger RNA and CRISPR–Cas9 genome editors to lungs with minimal side effects. Empirical...
Current SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccines have shown robust induction of neutralizing antibodies and CD4+ T cell activation; however, CD8+ responses are variable, and the duration of immunity and protection against variants are limited. Here we repurpose our DNA origami vaccine nanotechnology DoriVac to target infectious viruses, namely, SARS...
Deep learning models that infer clinically relevant biomarker status from tissue images are being explored as rapid and low-cost alternatives to molecular testing. Here we show, through statistical analysis across multiple cancer types, datasets and modelling approaches, that the datasets used to train these models contain strong dependencies between biomarkers and...
Detecting antigen-specific lymphocytes is crucial for immune monitoring in vaccination, infection, cancer and autoimmunity. However, their low frequency and dispersed distribution make reliable detection challenging. We developed a strategy exploiting the functions of tissue-resident memory T cells (TRMs) to locally concentrate target circulating immune cells in the skin...
Human neural organoids are essential platforms for fundamental and applied research due partly to their complex, three-dimensional neuronal circuit geometries. Standard and recently developed neural interface technologies have shortcomings in their ability to electrically characterize and control neural activity in these systems, owing to their limited accessibility to neuron...
Many missense mutations identified in genetic testing are variants of uncertain significance (VUS), not yet classified as either benign or pathogenic. Systematic determination of their functional relevance is a pressing clinical need. CRISPR-mediated base editing can precisely introduce precise variants into model organisms for functional testing, but current editors face...