A phenome-wide structural variant map from 467,152 UK Biobank genomes.

October 15, 2026| Source: Cell

Structural variants (SVs) are large (>50 base pairs) genomic rearrangements that can significantly influence human phenotypes, yet their contribution to health and disease remains undercharacterized. We conducted a phenome-wide association study (PheWAS) of 1.6 million SVs identified in whole-genome sequencing data from 467,152 UK Biobank participants, across 13,322 binary, 2,018 quantitative, and 2,923 plasma protein traits. Of these, 82.25% of SVs were outside the detectable range of prior copy-number variant studies. Protein quantitative trait loci analysis linked 3,467 SVs to 1,690 proteins, with effects dependent on SV type and location. In SV-PheWAS, we detected 28,184 associations with human health outcomes. Notably, we uncovered rare SVs with strong phenotypic effects. Furthermore, we show that at known genome-wide association study loci, 32.21% of associated SVs overlapped functional genomic regions. This study underscores the underestimated role of SVs in human genetics and their potential to advance understanding of human biology and drug discovery.

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The honey bee stinger: An unusual pump with collapsible double pistons.

Most stinging animals deliver venom by contracting muscles around a venom reservoir, but honey bees employ a fundamentally different strategy. The stingers of worker bees have the unique ability to autotomize, separating from the body, to continue to sting independently. Despite more than a century of anatomical descriptions, the mechanics of venom pumping have remained unresolved due to the challenges of observing them in action. We recorded high-speed videos of active, autotomized stingers, co

Health & MedicineOctober 20, 2026

Chronic cigarette smoke exposure induces distinct stem cell states driving genetic driver-specific non-small cell lung cancer subtypes.

Cigarette smoke-induced chronic inflammation (CI) potentiates development of non-small cell lung cancer (NSCLC) by mediating genetic and epigenetic events. Using normal lung organoids (LOs), we define how chronic cigarette smoke condensate (CSC) exposure drives two separate stem cell populations to evolve premalignant states harboring progressive epigenetic and linked transcriptomic abnormalities in the absence of major driver mutations. These dynamics facilitate evolution of an immune evasive s

Health & MedicineOctober 20, 2026

Cell identity competes with surface tension to determine stromal organization in tumor spheroids beyond the CAF shell paradigm.

Cancer-associated fibroblasts (CAFs) are often found forming a peripheral stromal barrier around tumors. Here, this paradigm is challenged using microfabricated 3D cancer-CAF spheroid models combined with quantitative magnetic force tensiometry. A surface tension atlas is established for eight cancer cell lines, three CAF populations, and heterotypic tumor-CAF assemblies, spanning nearly two orders of magnitude. Surface tension is first shown to govern spheroid morphology and modulate drug respo

Health & MedicineOctober 15, 2026

Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression.

Ferroptosis is implicated as a vulnerability in multiple cancers, yet approaches for effectively inducing ferroptosis in vivo are limited. Bypassing conventional strategies targeting the antiferroptotic glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) proteins, we designed metabolic initiators of lipid peroxidation (MILPOs) and developed the compounds WMK-1/2, which contain tetraoxane radical-generating and mitochondria-targeting groups, as de novo ferroptosis inducers

Health & MedicineOctober 15, 2026

An opioid efficacy switch for reversible optical control of analgesia.

The mu-opioid receptor (MOR) is a major target for pain treatment, but its effectiveness is limited by dangerous side effects. However, the systemic administration of opioids makes it difficult both to decipher their underlying mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse effects. Here, we develop a reversibly photoswitchable morphinan agonist termed "azo-morphine-3" (AM-3) that interconverts from low to high effica