Biology subjects

Hoang, A.

Publications and source records attributed to Hoang, A..

11 recordsLinked to original sources

bioRxiv2025

High throughput quantitative tracking of single parasite in Plasmodium falciparum

New systematic profiling of drug effects is in demand due to limitations in existing approaches to evaluate comprehensive drug effects and distinguish heterogeneity in mixed populations. One challenge is the underdeveloped methods for investigation of causal association between artemisinin induced dormancy and recrudescence in Plasmodium falciparum. We developed Quantitative Tracking After Chemotherapy Exposure (qTRACE) and an artificial intelligence (AI) mode to evaluate cytotoxic and cytostatic effects simultaneously at single parasite resolution in a high throughput platform. qTRACE is based upon the observation that individual parasites grow into colonies that can be quantified for numbers of viability and growth rate. Applying qTRACE, we revealed parasite-drug killing dynamics after artemisinin exposure, finding up to 50% of viable parasites arise directly from recovery of artemisinin induced dormancy. We further developed next generation qTRACE integrated with deep learning-based segmentation and analysis, thereby directly linking continuous, time-lapse phenotypes of label-free live P. falciparum. Our results confirmed the viability of dormant ring stages and that recovery rates differ between artemisinin-susceptible and -resistant P. falciparum.

cell biology↗

bioRxiv2025

InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics

Certain forms of mitochondrial impairment confer longevity, while mitochondrial dysfunction arising from aging and disease-associated mutations triggers severe pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. We find that the InsP3R promotes mitochondrial respiration, but the mitochondrial calcium uniporter is dispensable for both respiration and lifespan extension in Complex I mutants, suggesting InsP3R action is independent of matrix Ca2+ flux. Transcriptomic profiling and imaging reveal a previously unrecognized role for the InsP3R in regulating mitochondrial scaling, where InsP3R impairment results in maladaptive hyper-expansion of dysfunctional mitochondrial networks. We reveal a conserved InsP3R signaling axis through which calmodulin and actomyosin remodeling machineries, including Arp2/3, formin FHOD-1, and MLCK, constrain mitochondrial expansion and promote longevity. Disruption of actin remodeling or autophagy mimics InsP3R loss. Conversely, driving fragmentation ameliorates mitochondrial expansion and rescues longevity, supporting a model in which InsP3R-dependent actin remodeling sustains mitochondrial turnover. These findings establish an inter-organelle signaling axis by which ER calcium release orchestrates mitochondrial-based longevity through cytoskeletal effectors.

physiology↗

bioRxiv2025

Nanostructured lipid carriers overcome the low immunogenicity of M2e peptide via surface click chemistry conjugation, improving the anti-M2e antibody response

Influenza vaccines are considered the most effective measure for preventing influenza. The key antigen of commercial vaccines is hemagglutinin (HA), the main protein on the surface of influenza viruses. This protein is genetically variable, necessitating the annual redefinition of the vaccine formulation. Furthermore, these vaccines do not offer protection against pandemic viral strains. The M2e peptide, a small surface protein conserved among influenza type A strains, could enable cross-immunity when used as an antigen. Nevertheless, its limited immunogenicity has restricted its application in universal influenza vaccines. To enhance the immune responses to M2e, we associated it with Nanostructured Lipid Carriers (NLCs). These NLCs are stable over time and their small diameter (<100 nm) enhances interactions with antigen-presenting cells and improve lymphatic drainage, facilitating their uptake by the immune system. The M2e specific antibody response in mice was enhanced by using "click" chemistry to conjugate the M2e peptide to the NLC surface. Also, the incorporation of PADRE-specific CD4+ T cells stimulating peptide between M2e peptide and its linking region greatly enhanced the specific antibody response to M2e and generated immune response levels that could be compatible with influenza protection. This promising M2e formulation vectorized by NLC represents a potential universal influenza vaccine candidate warranting further preclinical investigations and clinical evaluation.

immunology↗

bioRxiv2024

Reservoir Computing with Bacteria

We introduce a systems-level approach to sensing and computing in which Escherichia coli acts as a living reservoir computer, performing complex information processing through its native growth responses without requiring genetic modification or specialized instrumentation. We validate this framework by accurately classifying early-stage COVID-19 plasma samples (mild vs. severe) using only bacterial growth data, highlighting a diagnostic potential without infrastructure-dependent methods. By controlling nutrient media compositions, we also demonstrate that E. coli growth encodes nonlinear transformations that outperform linear regression, support vector machines, and multilayer perceptrons across diverse regression and classification tasks. Using simulations across genome-scale metabolic models from multiple bacterial species, we establish a strong link between phenotypic diversity and computational capacity, showing that learning capacities scale with the diversity of metabolic phenotypes. These findings position biological reservoir computing as a robust, scalable, and low-cost platform for intelligent biosensing, diagnostics, and hybrid bio-digital computation, while providing new mechanistic insights into the computational capabilities of living systems.

synthetic biology↗

bioRxiv2024

VieMedKG: Knowledge Graph and Benchmark for Traditional Vietnamese Medicine

Traditional Vietnamese Medicine (TVM) and Traditional Chinese Medicine (TCM) have shared significant similarities due to their geographical location, cultural exchanges, and hot and humid climatic conditions. However, unlike TCM, which has substantial works published to construct a knowledge graph, there is a notable absence of a comprehensive knowledge graph for TVM. This paper presents the first endeavor to build a knowledge graph for TVM based on extensive existing resources from TCM. We name our knowledge graph as VieMedKG. We propose a translation and filtration process to adapt TCM knowledge graphs to TVM, identifying the overlapping and unique elements of TVM. In addition, the constructed knowledge graph is then exploited further for developing a curated benchmark for the knowledge graph-based question-answering problem with the potential to support doctors and patients in assisting doctors and patients in identifying various diseases. Our work will not only bridge the gap between TCM and TVM but also set the foundation for future research into traditional Vietnamese medicine community. Our source code is publicly available at https://github.com/HySonLab/VieMedKG/.

bioinformatics↗

bioRxiv2024

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models

Mutations in isocitrate dehydrogenase 1 (IDH1) impart a neomorphic reaction that produces D-2-hydroxyglutarate (D2HG), which can inhibit DNA demethylases to drive tumorigenesis. Mutations affect residue R132 and display distinct catalytic profiles for D2HG production. We show that catalytic efficiency of D2HG production is greater in IDH1 R132Q than R132H mutants, and expression of R132Q in cellular and xenograft models leads to higher D2HG concentrations in cells, tumors, and sera compared to R132H. Though expression of IDH1 R132Q leads to hypermethylation in DNA damage pathways, DNA hypomethylation is more notable when compared to R132H expression. Transcriptome analysis shows increased expression of many pro-tumor pathways upon expression of IDH1 R132Q versus R132H, including transcripts of EGFR and PI3K signaling pathways. Thus, IDH1 mutants appear to modulate D2HG levels via altered catalysis, resulting in distinct epigenetic and transcriptomic consequences where higher D2HG levels appear to be associated with more aggressive tumors.

genomics↗

bioRxiv2022

Nanopore sequencing identifies a higher frequency and expanded spectrum of mitochondrial DNA deletion mutations in human aging

BackgroundMitochondrial DNA (mtDNA) deletion mutations cause many human diseases and are linked to age-induced mitochondrial dysfunction. Mapping the mutation spectrum and quantifying mtDNA deletion mutation frequency is challenging with next generation sequencing methods. We hypothesized that long-read sequencing of human mtDNA across the lifespan would detect a broader spectrum of mtDNA rearrangements and provide a more accurate measurement of their frequency. ResultsWe employed nanopore Cas9-targed sequencing (nCATS) to map and quantitate mtDNA deletion mutations and develop analyses that are fit-for-purpose. We analyzed total DNA from vastus lateralis muscle in 15 males ranging from 20 to 81 years of age and substantia nigra from three 20-year-old and three 79-year-old men. We found that mtDNA deletion mutations detected by nCATS increased exponentially with age and mapped to a wider region of the mitochondrial genome than previously reported. Using simulated data, we observed that large deletions are often reported as chimeric alignments. To address this, we developed two algorithms for deletion identification which yield consistent deletion mapping and identify both previously reported and novel mtDNA deletion breakpoints. The identified mtDNA deletion frequency measured by nCATS correlates strongly with chronological age and predicts the deletion frequency as measured by digital PCR approaches. In substantia nigra, we observed a similar frequency of age-related mtDNA deletions to those observed in muscle samples, but noted a distinct spectrum of deletion breakpoints. ConclusionsNCATS-mtDNA sequencing allows identification of mtDNA deletions on a single molecule level, characterizing the strong relationship between mtDNA deletion frequency and chronological aging.

genomics↗

bioRxiv2022

Exercise induces myonuclear remodelling in humans independently of age

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with nuclear lamina protein Lamin A regulating nuclear shape, nuclear mechanics, and ultimately gene expression. Defective Lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals. Complementary to this, exercise resulted in increased levels of Lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan. Key pointsO_LIThe nucleus plays an active role in translating forces into biochemical signals C_LIO_LIMyonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function. C_LIO_LIHere, we present striking differences in myonuclear shape and mechanics associated with exercise, in both young and old humans. C_LIO_LIMyonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals. C_LIO_LIWe conclude that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan. C_LI

cell biology↗

bioRxiv2022

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats

Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivirs effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. For the 33-month-old control rats, the average mtDNA copy number per nucleus was 2567, 1100, and 1869 for heart, kidney, and quadriceps, respectively. MtDNA deletion mutation frequency was 2.6x10-4, 1.6x10-4 and 4.7x10-3for heart, kidney, and quadriceps, respectively. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.

molecular biology↗

bioRxiv2022

Long read mitochondrial genome sequencing using Cas9-guided adaptor ligation

The mitochondrial genome (mtDNA) is an important source of disease-causing genetic variability, but existing sequencing methods limit understanding, precluding phased measurement of mutations and clear detection of large sporadic deletions. We adapted a method for amplification-free sequence enrichment using Cas9 cleavage to obtain full length nanopore reads of mtDNA. We then utilized the long reads to phase mutations in a patient with an mtDNA-linked syndrome and demonstrated that this method can map age-induced mtDNA deletions. We believe this method will offer deeper insight into our understanding of mtDNA variation.

genomics↗

bioRxiv2020

An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity

Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP+-dependent conversion of isocitrate to -ketoglutarate (-KG) to provide critical cytosolic substrates and drive NADPH-dependent reactions like lipid biosynthesis and glutathione regeneration. In biochemical studies, the forward reaction is studied at neutral pH, while the reverse reaction is typically characterized in more acidic buffers. This led us to question whether IDH1 catalysis is pH-regulated, which would have functional implications under conditions that alter cellular pH, like apoptosis, hypoxia, cancer, and neurodegenerative diseases. Here, we show evidence of catalytic regulation of IDH1 by pH, identifying a trend of increasing kcat values for -KG production upon increasing pH in the buffers we tested. To understand the molecular determinants of IDH1 pH sensitivity, we used the pHinder algorithm to identify buried ionizable residues predicted to have shifted pKa values. Such residues can serve as pH sensors, with changes in protonation states leading to conformational changes that regulate catalysis. We identified an acidic residue buried at the IDH1 dimer interface, D273, with a predicted pKa value upshifted into the physiological range. D273 point mutations had decreased catalytic efficiency and, importantly, loss of pH-regulated catalysis. Based on these findings, we conclude that IDH1 activity is regulated, at least in part, by pH. We show this regulation is mediated by at least one buried acidic residue [~]12 [A] from the IDH1 active site. By establishing mechanisms of regulation of this well-conserved enzyme, we highlight catalytic features that may be susceptible to pH changes caused by cell stress and disease.

biochemistry↗