Biology subjects

Dinh, A.

Publications and source records attributed to Dinh, A..

7 recordsLinked to original sources

bioRxiv2026

Asporin Improves Cardiac Myocyte Response to Ischemia and Reperfusion Stress

BackgroundMyocardial Infarction (MI) remains a leading cause of mortality worldwide, despite advancements in clinical therapies and interventions. MI results from prolonged ischemia, leading to hypoxia-induced damage to cardiac tissue and reperfusion-injury (R/I) that aggravates cardiomyocyte (CM) loss. One key cellular event during this process is accumulation of dysfunctional mitochondria, resulting from environmental hypoxia and subsequent oxidative stress upon reperfusion. Post-MI cardiac-remodeling involves changes in both cellular and extracellular matrix (ECM). Ubiquitin-dependent and independent autophagy are crucial for cardio protection during this phase. The ECM provides structural integrity and functions as a reservoir for signaling molecules. Asporin (ASPN), a small leucine-rich proteoglycan, plays a role in modulating cardiac-remodeling by limiting excessive fibrosis and protecting CMs from cell death. MethodsWe investigated the therapeutic potential of ASPN by using an exogenous recombinant peptide of ASPN (rASPN), testing its effects using an in-vitro ischemia-reperfusion (I/R) model simulating MI conditions. Two I/R models were developed using an immortalized human embryonic cardiac cell line to reflect the hypoxia-reperfusion (H/R) phases of MI. In the No-Reoxygenation (No-ReOx) model, cells were subjected to hypoxia for 18 hours, with or without exogenous rASPN. In the Reoxygenation (ReOx) model, cells underwent 18 hours of hypoxia, then 12 hours of reoxygenation (simulating reperfusion), with or without rASPN. ResultsProteomics revealed that ASPN modulates key pathways involved in apoptosis, non-canonical autophagy, and metabolic reprogramming. Additionally, ASPN influenced immune response pathways and significantly affected TGF-{beta} signaling, a central mediator of cardiac fibrosis and remodeling post-MI. These findings indicate that ASPN plays a multifaceted role in regulating cellular responses to hypoxia and R/I. ConclusionsOur H/R model simulates key aspects of MI and R/I. The protective role of ASPN observed in this model suggests it as a promising candidate for developing cardioprotective therapies to minimize R/I and adverse cardiac-remodeling following MI.

physiology↗

bioRxiv2025

Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice

The nocebo effect, the evil twin of the better-known placebo effect, in which anticipation of harm worsens pain and other symptoms, is increasingly thought to be responsible for poor clinical outcomes. In humans, nocebo hyperalgesia (i.e., increased pain sensitivity) is blocked by proglumide, a cholecystokinin (CCK) receptor antagonist. Yet, the neural circuitry underlying nocebo hyperalgesia remains unidentified, largely due to a lack of appropriate animal models. Independently, our two laboratories developed unique animal models of CCK-dependent nocebo hyperalgesia in which the expectation of pain was elicited by environmental or social cues. We find that both nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This previously unrecognized pathway could represent a promising target for therapeutic interventions in pain-related disorders. One-Sentence SummaryPain expectations, whether environmentally conditioned or socially transmitted, are mediated by a shared neural circuit involving cholecystokinin (CCK) projections from the anterior cingulate cortex (ACC) to the lateral periaqueductal gray (PAG).

neuroscience↗

bioRxiv2024

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart

BackgroundMetabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. MethodsWe utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. ResultsHere, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. ConclusionsThis study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

molecular biology↗

bioRxiv2023

An RNA Damage Response Network Mediates the Lethality of 5-FU in Clinically Relevant Tumor Types

5-fluorouracil (5-FU) is a successful and broadly used anti-cancer therapeutic. A major mechanism of action of 5-FU is thought to be through thymidylate synthase (TYMS) inhibition resulting in dTTP depletion and activation of the DNA damage response. This suggests that 5-FU should synergize with other DNA damaging agents. However, we found that combinations of 5-FU and oxaliplatin or irinotecan failed to display any evidence of synergy in clinical trials, and resulted in sub-additive killing in a panel of colorectal cancer (CRC) cell lines. In seeking to understand this antagonism, we unexpectedly found that an RNA damage response during ribosome biogenesis dominates the drugs efficacy in tumor types for which 5-FU shows clinical benefit. 5-FU has an inherent bias for RNA incorporation, and blocking this greatly reduced drug-induced lethality, indicating that accumulation of damaged RNA is more deleterious than the lack of new RNA synthesis. Using 5-FU metabolites that specifically incorporate into either RNA or DNA revealed that CRC cell lines and patient-derived colorectal cancer organoids are inherently more sensitive to RNA damage. This difference held true in cell lines from other tissues in which 5-FU has shown clinical utility, whereas cell lines from tumor tissues that lack clinical 5-FU responsiveness typically showed greater sensitivity to the drugs DNA damage effects. Analysis of changes in the phosphoproteome and ubiquitinome shows RNA damage triggers the selective ubiquitination of multiple ribosomal proteins leading to autophagy-dependent rRNA catabolism and proteasome-dependent degradation of ubiquitinated ribosome proteins. Further, RNA damage response to 5-FU is selectively enhanced by compounds that promote ribosome biogenesis, such as KDM2A inhibitors. These results demonstrate the presence of a strong RNA damage response linked to apoptotic cell death, with clear utility of combinatorially targeting this response in cancer therapy.

cancer biology↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part I: 2D Space Perception by 2D Linear Translation

Visual perception plays a critical role in navigating space and extracting useful semantic information crucial to survival. To identify distant landmarks, we constantly shift gaze vectors through saccades, while still maintaining the visual perception of stable allocentric space. How can we sustain stable allocentric space so effortlessly? To solve this question, we have developed a new concept of NHT (Neural Holography Tomography). This model states that retinotopy is invisible (not available to consciousness) and must be converted to a time code by traveling alpha brainwaves to perceive objects consciously. According to this framework, if identical alpha phases are continually assigned to a landmark, we perceive its exact and consistent allocentric location. To test this hypothesis, we designed reaction time (RT) experiments to observe evidence of the predicted space-to-time conversion. Various visual stimuli were generated at a wide range of eccentricities either on a large TV (up to 40{degrees}) or by LED strips on a hemispherical dome (up to 60{degrees}). Participants were instructed to report the observed patterns promptly under either covert (no eye movement) or overt (with eye movement) conditions. As predicted, stimuli presented at the center of fixation always produced the fastest RTs. The additional RT delay was precisely proportional to the eccentricity of the peripheral stimulus presentation. Furthermore, both covert and overt attention protocols created the same RT delays, and trajectories of saccadic eye motions were in parallel to the overt RT vs. eccentricity. These findings strongly support our NHT model, in which the observed RT-eccentricity dependence is indicative of the spatiotemporal conversion required for maintaining a stable allocentric frame of reference. That is, we perceive space by time.

neuroscience↗

bioRxiv2019

Genomic epidemiology of vancomycin 1 resistant Enterococcus faecium (VREfm) in Latin America: Revisiting the global VRE population structure

The prevalence of vancomycin-resistant Enterococcus faecium varies across geographical regions yet little is known about its population structure in Latin America. Here, we provide a complete genomic characterization of 55 representative Latin American VREfm recovered from 1998-2015 in 5 countries. We found that VREfm population in the region is structured into two main clinical clades without geographical clustering. To place our regional findings in context, we reconstructed the global population structure of VREfm by including 285 genomes from 36 countries from 1946-2017. Our results differ from previous studies showing an early branching of animal related isolates and a further split of clinical isolates into two sub-clades, all within clade A. The overall phylogenomic structure was highly dependent on recombination (54% of the genome) and the split between clades A and B is estimated to have occurred more than 3585 years BP. Furthermore, while the branching of animal isolates and clinical clades was predicted to have occur [~]894 years BP, our molecular clock calculations suggest that the split within the clinical clade occurred around [~]371 years BP. By including isolates from Latin America, we present novel insights into the population structure of VREfm and revisit the evolution of this pathogen.

microbiology↗

bioRxiv2017

Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells

Tuberculosis (TB) is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobac-terium tuberculosis (MTB), is estimated to have infected up to a third of the worlds population; however, only approximately 10% of infected healthy individuals progress to active TB. Despite evidence for heritability, it is not currently possible to predict who may develop TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from active TB. We measured gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms nearby the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated decent performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.

genomics↗