Biology subjects

Hung, T.

Publications and source records attributed to Hung, T..

5 recordsLinked to original sources

bioRxiv2026

Genetic and pharmacologic modulation of RAGE rescues the diabetes-mediated impairments to bone at multiple length scales

The bone matrix is precisely maintained and optimized to resist fractures. However, aging and disease deteriorate the bone matrix and increase fragility. Individuals with type 2 diabetes (T2D) have an elevated risk of bone fracture despite apparently normal bone mass. The chronic hyperglycemia in T2D promotes the formation of advanced glycation end-products (AGEs) in the bone tissue and modify the matrix mechanics. AGEs also bind to its receptor, RAGE, to activate inflammation and alter homeostasis. Using a leptin-receptor deficient mouse model of diabetes, we used a combination of high-resolution methods across multiple scales to evaluate the microarchitectural-, material- and cellular- level changes affected by the modulation of RAGE. To demonstrate the relevance of RAGE, we genetically ablated RAGE (RAGE-null) before the onset of diabetes; and to demonstrate the potency of RAGE as a disease modifying therapy, a RAGE antagonist (FPS-ZM1) was administered after prolonged diabetes. Diabetes impaired bone microstructure, the homeostatic actions of bone cells, the bone matrix nanomechanics, and whole- bone strength. The constitutive ablation of RAGE in diabetic animals prevented AGEs accumulation and the decline of trabecular connectivity; protected against the loss of osteocyte lacunae density and morphology; and maintained the matrix nanomechanics and bone strength. The inhibition of RAGE after the onset of diabetes reversed AGE accumulation and loss of bone volume; rescued osteocyte lacunae density and osteoclast activity; and restored matrix nanomechanics and bone strength. These results suggest that RAGE is a viable therapeutic target for diabetes-mediated impairments of bone quality. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/716153v1_ufig1.gif" ALT="Figure 1000"> View larger version (26K): org.highwire.dtl.DTLVardef@8b4ce4org.highwire.dtl.DTLVardef@1652394org.highwire.dtl.DTLVardef@10301a8org.highwire.dtl.DTLVardef@61c23d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

The sex-specific effects of RAGE signaling and Type 2 Diabetes on mouse cortical bone mechanics, structure, and material properties

Individuals with type 2 diabetes (T2D) are prone to fracture at numerous skeletal sites despite presenting with a higher bone mineral density (BMD). The accumulation of Advanced Glycation End-products (AGEs) in the bone tissues of patients with T2D could be contributing to this paradox, of increased skeletal fragility with higher BMD. AGEs can impair bone cell homeostasis via the receptor for AGEs (RAGE). To investigate the effects of diabetes, AGE accumulation, and RAGE signaling on mouse cortical bone, we utilized male and female leptin receptor-deficient (db/db) mice from three age groups ranging from 3-14 months of age, which were crossed with animals carrying constitutively RAGE-deficient alleles (RAGE-/-). The morphological, mechanical and material outcomes were measured using microCT, 3-pt bending, and an AGE assay. We observed significant impairments dependent on age and sex to the bone matrix and whole-bone mechanical behavior due to diabetes with some impairments alleviated with the ablation of RAGE. In older female diabetic mice, the removal of RAGE signaling prevented the deficits in bone mechanics, morphology and tissue mineral density (TMD). Male diabetic mice without RAGE signaling exhibited improved material properties. The study demonstrated that some bone impairments associated with T2D are prevented with RAGE ablation and may be partially reversible with the inhibition of RAGE signaling. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=145 HEIGHT=200 SRC="FIGDIR/small/631018v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@75acedorg.highwire.dtl.DTLVardef@1ac01fforg.highwire.dtl.DTLVardef@1b70d34org.highwire.dtl.DTLVardef@c3f3a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2021

Whole Genome and Exome Sequencing Reference Datasets from A Multi-center and Cross-platform Benchmark Study

With the rapid advancement of sequencing technologies in the past decade, next generation sequencing (NGS) analysis has been widely applied in cancer genomics research. More recently, NGS has been adopted in clinical oncology to advance personalized medicine. Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from errors or artifacts introduced during NGS processes or data analysis. Therefore, there is an urgent need to develop best practices in cancer mutation detection using NGS and the need for standard reference data sets for systematically benchmarking sequencing platforms, library protocols, bioinformatics pipelines and for measuring accuracy and reproducibility across platforms and methods. Within the SEQC2 consortium context, we established paired tumor-normal reference samples, a human triple-negative breast cancer cell line and a matched normal cell line derived from B lymphocytes. We generated whole-genome (WGS) and whole-exome sequencing (WES) data using 16 NGS library preparation protocols, seven sequencing platforms at six different centers. We systematically interrogated somatic mutations in the paired reference samples to identify factors affecting detection reproducibility and accuracy in cancer genomes. These large cross-platform/site WGS and WES datasets using well-characterized reference samples will represent a powerful resource for benchmarking NGS technologies, bioinformatics pipelines, and for the cancer genomics studies.

bioinformatics↗

bioRxiv2020

Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine.

Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor-AB and 5-Azacytidine into multipotent stem cells with stromal cell characteristics. To generate a product that is amenable for therapeutic application, we have modified and optimised culture conditions to reprogram human adipocytes into induced multipotent stem cells (iMS) and expand them in vitro. The basal transcriptomes of adipocyte-derived iMS cells and matched adipose-tissue-derived mesenchymal stem cells were remarkably similar. However, there were distinct changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to new muscle, bone, cartilage and blood vessels with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibres without ectopic tissue formation. Taken together, human adipocyte derived iMS cells regenerate tissues in a context dependent manner without ectopic or neoplastic growth.

cell biology↗

bioRxiv2019

Establishing reference samples for detection of somatic mutations and germline variants with NGS technologies

We characterized two reference samples for NGS technologies: a human triple-negative breast cancer cell line and a matched normal cell line. Leveraging several whole-genome sequencing (WGS) platforms, multiple sequencing replicates, and orthogonal mutation detection bioinformatics pipelines, we minimized the potential biases from sequencing technologies, assays, and informatics. Thus, our \"truth sets\" were defined using evidence from 21 repeats of WGS runs with coverages ranging from 50X to 100X (a total of 140 billion reads). These \"truth sets\" present many relevant variants/mutations including 193 COSMIC mutations and 9,016 germline variants from the ClinVar database, nonsense mutations in BRCA1/2 and missense mutations in TP53 and FGFR1. Independent validation in three orthogonal experiments demonstrated a successful stress test of the truth set. We expect these reference materials and \"truth sets\" to facilitate assay development, qualification, validation, and proficiency testing. In addition, our methods can be extended to establish new fully characterized reference samples for the community.

bioinformatics↗