Biology subjects

Zhu, Y. D.

Publications and source records attributed to Zhu, Y. D..

3 recordsLinked to original sources

bioRxiv2025

Multimodal MRI Insights into Glymphatic Clearance and Blood-Brain Barrier Integrity in Healthy Aging

Aging is associated with impaired CSF clearance in preclinical models, but its impact on blood-brain barrier (BBB) health and glymphatic function in humans remains unclear. We aimed to compare healthy younger and older adults using multimodal MRI to assess age-related changes in BBB permeability and glymphatic clearance, and to examine the relationships between these measures. Thirty participants were recruited (12 younger, 26 {+/-} 3 years; 18 older, 75 {+/-} 7 years). Diffusion-prepared arterial spin labeling measured the water exchange rate (Kw) across the BBB; free water (FW) imaging quantified extracellular free water in white matter; and diffusion tensor imaging along perivascular spaces (DTI-ALPS) assessed glymphatic function. Older individuals showed reduced whole-brain Kw (p=0.021), increased white matter FW (p=0.002), and reduced DTI-ALPS (p<0.001) compared to younger adults. Kw associated with both DTI-ALPS ({beta}=0.402x10-2, p=0.022) and FW ({beta}=-0.676x10-3, p=0.008). Reduced Kw may reflect impaired BBB function, while reduced DTI-ALPS and increased FW indicate impaired glymphatic clearance. FW partially mediated the relationship between Kw and DTI-ALPS, suggesting a potential mechanistic link. Overall, this study provides novel multimodal MRI insights into BBB and glymphatic alterations in healthy aging and may inform the development of MRI biomarkers to preserve cognitive health.

neuroscience↗

bioRxiv2020

ARID1A regulates R-loop associated DNA replication stress

ARID1A is lost in up to 7% of all cancers, and this frequency increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeller complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.

cell biology↗

bioRxiv2018

MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

Ectopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors such as RAD50. We show in yeast and human cells that R-loops accumulate during RAD50 depletion. In human cancer cell models, we find that RAD50 and its partners in the MRE11-RAD50-NBS1 complex regulate R-loop-associated DNA damage and replication stress. We show that a non-nucleolytic function of MRE11 is important for R-loop suppression via activation of PCNA-ubiquitination by RAD18 and recruiting anti-R-loop helicases in the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms of transcription-replication conflicts.

cell biology↗