Luxia Yao

Metformin (MET), a worldwide used drug for type 2 diabetes, has been found with the largest amount by weight among all drugs in aquatic environment, including the drinking water systems where this emerging micropollutant is inevitably transformed during chlorination process. Whether MET chlorination byproducts Y (C4H6ClN5) and C (C4H6ClN3) exist in drinking water remains unknown. Although MET has health-promoting properties, whether or how its chlorination byproducts affect health is still uncharacterized. Here we reveal that MET and byproduct C are present in worldwide drinking water with the highest doses detected for MET and C as 1203.5 ng/L and 9.7 ng/L respectively. Under simulated chlorination conditions, we also demonstrate that both byproducts can be increasingly produced with increment of MET concentration, suggesting a hidden threat on the safety and sustainability of global water supply. Through systematic evaluations, we demonstrate that MET chlorination byproducts Y and C exhibit toxicities instead of genotoxicity to live worms and human HepG2 cells at millimolar doses. Moreover, both byproducts are harmful to mice and particularly Y at 250 ng/L destroys the mouse small intestine integrity. Unprecedentedly, we unveil boiling and activated carbon adsorption as effective alternative solutions that may be in urgent demand globally for removing these byproducts from drinking water.

Vitamin B12 (B12) deficiency is a critical problem worldwide. Such deficiency in infants has long been known to increase the propensity to develop obesity and diabetes later in life through unclear mechanisms. Here, we establish a Caenorhabditis elegans model to study how early-life B12 impacts adult health. We find that early-life B12 deficiency causes increased lipogenesis and lipid peroxidation in adult worms, which in turn induces germline defects through ferroptosis. Mechanistically, we show the central role of the methionine cycle-SBP-1/SREBP1-lipogenesis axis in programming adult traits by early-life B12. Moreover, SBP-1/SREBP1 participates in a crucial feedback loop with NHR-114/HNF4 to maintain cellular B12 homeostasis. Inhibition of SBP-1/SREBP1-lipogenesis signaling and ferroptosis later in life can reverse disorders in adulthood when B12 cannot. Overall, this study provides mechanistic insights into the life-course effects of early-life B12 on the programming of adult health and identifies potential targets for future interventions for adiposity and infertility.

The Notch signaling pathway controls cell growth, differentiation, and fate decisions. Dysregulation of Notch signaling has been linked to various human diseases. Notch receptor resides in multiple cellular compartments, and its translocation plays a central role in pathway activation. However, the spatial regulation of Notch receptor functions remains largely elusive. Using TurboID-based proximity labeling followed by affinity purification and mass spectrometry, we establish a spatially defined human Notch receptor interaction network. Notch receptors interact with different proteins in distinct subcellular compartments to perform specific cellular functions. This spatially defined interaction network also reveals that a large fraction of NOTCH is stored at the endoplasmic reticulum (ER)-Golgi intermediate compartment and recruits Ataxin-2-dependent recycling machinery for rapid recycling, Notch signaling activation, and leukemogenesis. Our work provides insights into dynamic Notch receptor complexes with exquisite spatial resolution, which will help in elucidating the detailed regulation of Notch receptors and highlight potential therapeutic targets for Notch-related pathogenesis.