Biology subjects

Lieu, D.

Publications and source records attributed to Lieu, D..

4 recordsLinked to original sources

bioRxiv2026

Increased medial collagen enhances aortic resilience against mural delamination from hydraulic fracturing

The aorta, normally resilient to hemodynamic stresses, becomes vulnerable to structural failure due to diverse conditions that weaken the wall. We injected fluid into excised specimens of human ascending aorta with pressure monitoring to quantify the impact of clinical and histological factors on mural damage. Two modes of medial injury emerged with distinct pressure tracings. Extravasation was characterized by diffuse infiltration of fluid with widespread damage of smooth muscle cells and collagen fibers but limited separation of elastic lamellae. By contrast, delamination was characterized by marked separation of elastic lamellae along a single plane with damage to cells and fibrillar matrix restricted to adjacent laminae. Aging, aortic dilatation, and family history associated with lower pressures causing delamination, whereas a diagnosis of hypertension associated with higher pressures suggesting resilience to dissection. Collagen fraction adjacent to delamination correlated with higher pressures as did decreased smooth muscle cell density and increased glycosaminoglycan fraction, although several clinical and histological variables were interrelated. Protein cross-linking strengthened and enzymatic digestion of collagen weakened the aortic wall, while acute cell lysis with detergent had no effect. We conclude that increased functional medial collagen has an adaptive protective role in aortic remodeling rather than signifying medial degeneration.

bioengineering↗

bioRxiv2025

Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues

High-throughput clonal tracing of primary human samples relies on naturally occurring barcodes, such as somatic mitochondrial DNA (mtDNA) mutations detected via single-cell ATAC-seq (mtscATAC-seq). Fresh-frozen clinical specimens preserve tissue architecture but compromise cell integrity, thereby precluding their use in multi- omic approaches such as mitochondrial genotyping at single-cell resolution. Here, we introduce Cryo-mtscATAC-seq, a broadly applicable method for diverse pathophysiological contexts to isolate nuclei with their associated mitochondria ("CryoCells") from frozen samples for high-throughput clonal analysis. We applied Cryo-mtscATAC-seq to the neurodegenerated human brain, glioblastoma (GBM), pediatric neuroblastoma, and human aorta, and implemented mitobender, a computational tool to reduce ambient mtDNA in single-cell assays. Our approach revealed regional clonal gliogenesis and microglial expansions in amyotrophic lateral sclerosis (ALS), persistence of oligodendrocyte progenitor cell (OPC)-like clones in GBM recurrence, mtDNA depth heterogeneity after neuroblastoma chemotherapy, and oligoclonal proliferation of smooth muscle cells in human aorta. In conclusion, Cryo-mtscATAC-seq broadly extends mtDNA genotyping to archival frozen specimens across tissue types, opening new avenues for investigation of cell state- informed clonality in human health and disease.

systems biology↗

bioRxiv2025

A scalable organoid model of urothelial aging for metabolic interrogation, infection modeling, and reversal of age-associated changes

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue-specific mechanisms of aging, specifically the contributions of the aged urothelium remain elusive. Here, we introduce mouse bladder epithelium-derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age-associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic Escherichia coli (UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial-immune interactions, and genetic perturbation. Using the mBEDO platform, we also identify urothelium-specific changes in purine, amino acid, and glycerophospholipid metabolism which may contribute to age-associated cellular perturbations. Lastly, supplementation with depleted metabolites, nicotinamide (NAM) and D-mannose, reduce DNA damage and oxidative stress and restore mitochondrial integrity in aged mBEDOs. These findings establish mBEDOs as an effective platform for investigating molecular and cellular underpinnings of urothelial aging and exploring metabolism-based interventions for age-associated bladder dysfunction.

bioengineering↗

bioRxiv2020

Xpert MTB/XDR: A ten-color reflex assay suitable for point of care settings to detect isoniazid-, fluoroquinolone-, and second line injectable drug-resistance directly from Mycobacterium tuberculosis positive sputum.

We describe the design, development, analytical performance and a limited clinical evaluation of the 10-color Xpert MTB/XDR assay (CE-IVD only, not for sale in the US). This assay is intended as a reflex test to detect resistance to Isoniazid (INH), Fluoroquinolones (FLQ), Ethionamide (ETH) and Second Line Injectable Drugs Drugs (SLID) on unprocessed sputum samples and concentrated sputum sediments which are positive for Mycobacterium tuberculosis. The Xpert MTB/XDR assay simultaneously amplifies eight genes and promoter regions in M. tuberculosis and analyzes melting temperatures (Tms) using sloppy molecular beacon probes (SMB) to identify mutations associated with INH, FLQ, ETH and SLID resistance. Results can be obtained under 90 minutes and requires 10-color GeneXpert modules. The assay can differentiate low versus high-level resistance to INH and FLQ as well as cross-resistance versus individual resistance to SLIDs by identifying mutation-specific Tms or Tm patterns generated by the SMB probes. The assay has a Limit of Detection comparable to the Xpert MTB/RIF assay and succesfully detected 16 clinically significant mutations in a challenge set of clinical isolate DNA. In a clinical study performed at two sites with 100 sputum and 214 clinical isolates, the assay showed a sensitivity of 94-100% and a specificity of 100% for all drugs except for ETH when compared to sequencing. The sensitivity and specificity when compared to phenotypic drug susceptibility testing were in the same range. Used in combination with a primary tuberculosis diagnostic test, this assay is expected to expand the capacity for detection of drug-resistant tuberculosis.

microbiology↗