Biology subjects

Vo, S.

Publications and source records attributed to Vo, S..

6 recordsLinked to original sources

bioRxiv2026

In vitro-reconstituted Drosophila Arc capsids deliver gene editors to dystrophic muscle

The intracellular delivery of therapeutic macromolecules remains a major challenge in biomedicine. Here we reconstitute the Drosophila melanogaster Arc1 (dArc1) retroelement-derived capsid entirely from purified recombinant protein components and in vitro transcribed RNA, creating a fully defined, cell-free assembled protein nanoparticle system. Through affinity engineering of the dArc1 RNA-binding domain, we enable efficient encapsulation of mRNA payloads and Cas9 ribonucleoproteins. Unexpectedly, we discover that dArc1 capsids bind mammalian cells through a direct interaction with the surface receptor SORCS2. Leveraging this interaction, we show that intramuscular injection of dArc1 capsids carrying Cas9 gene editors achieves up to 18% exon skipping and restores dystrophin expression in muscle fibers of mdx mice, a model of Duchenne muscular dystrophy. Enhanced delivery efficiency in regenerating and dystrophic muscle correlates with upregulated SORCS2 expression, supporting our finding that SORCS2 facilitates cellular uptake of dArc1 capsids. This work demonstrates the potential of in vitro-assembled protein nanoparticles for delivery of molecular cargoes.

molecular biology↗

bioRxiv2025

Structure-Guided Development of a Potent BioA Inhibitor ValidatesBiotin Synthesis Inhibition as a Therapeutic Strategy forTuberculosis

Conditionally essential pathways - such as the biotin biosynthesis - represent promising targets for new antibiotics. However, the chemical interrogation of the biotin pathway with an orally effective lead remains elusive, and the preclinical development of biotin inhibitors for mycobacterial infections in vivo is challenging due to the unusually high concentration of biotin in standard mouse models. Structure-guided optimization was applied to develop the first oral lead targeting aminotransferase BioA, a key enzyme in bacterial biotin biosynthesis, resulting in C48, a picomolar inhibitor displaying sub-micromolar MICs against Mycobacterium tuberculosis (Mtb). Mechanism of action was confirmed by biochemical, structural, and genetic studies. C48 demonstrated favorable pharmacokinetics and excellent oral bioavailability resulting in over 39,000-fold improved exposure. We next developed an easy-to-operate, low-biotin mouse model that recapitulates human biotin physiology. C48 significantly reduced Mtb burden in this low-biotin mouse model, providing the first in vivo proof-of-concept for targeting biotin biosynthesis in Mtb.

microbiology↗

bioRxiv2025

Streamlining Spatial Transcriptomics for Human Kidney Tissue

Single-cell spatial technologies have emerged in recent years, enabling tissue architecture and organization characterization at unprecedented resolution. However, computational analysis of spatial transcriptomics data is often a bottleneck for scientific discoveries in the absence of a dedicated bioinformatician. Here, we describes a workflow to annotate cell types from a dataset generated using NanoStrings CosMx single-cell resolution spatial transcriptomic technology, enabling a comparison between healthy kidney biopsies and diseased tissue. We validated our pipelines accuracy with both gene expression analysis and pathological changes associated with biopsy-proven diabetic kidney disease (DKD). Through precise cell type annotation, we observed significant changes in the proportions of podocytes and immune cells in DKD, with DKD tissue showing regional enrichment of immune cells and differential gene expression. Notably, injured proximal tubules had the expected increased expression of HAVCR1 and VCAM1 and genes associated with diabetes, including IL18, ITGA3 and ITGB1. The entire workflow, now fully integrated into the BioTuring SpatialX (Lens V2.0), is available as a platform designed for users with no formal bioinformatics training.

bioinformatics↗

bioRxiv2024

Thiol Stress Fuels Pyrazinamide Action Against Mycobacterium tuberculosis

Pyrazinamide (PZA) is a cornerstone of first-line antitubercular drug therapy and is unique in its ability to kill nongrowing populations of Mycobacterium tuberculosis through disruption of coenzyme A synthesis. Unlike other drugs, PZA action is conditional and requires potentiation by host-relevant environmental stressors, such as low pH and nutrient limitation. Despite its pivotal role in tuberculosis therapy, the durability of this crucial drug is challenged by the emergent spread of drug-resistance. To advance drug discovery efforts, we characterized the activity of a more potent PZA analog, morphazinamide (MZA). Here, we demonstrate that like PZA, MZA acts in part through impairment of coenzyme A synthesis. Unexpectedly, we find that, in contrast to PZA, MZA does not require potentiation and maintains bactericidal activity against PZA-resistant strains due to an additional mechanism involving aldehyde release. Further, we find that the principal mechanism for resistance to the aldehyde component is through promoter mutations that increase expression of the mycothiol oxidoreductase MscR. Our findings reveal a dual action synergistic mechanism of MZA that results in a faster kill rate and a higher barrier to resistance. These observations provide new insights for discovery of improved therapeutic approaches for addressing the growing problem of drug-resistant tuberculosis. Significance StatementPyrazinamide is the only antitubercular drug of its kind, capable of targeting persistent Mycobacterium tuberculosis through disruption of the coenzyme A biosynthetic pathway. With the emergent spread of drug-resistant tuberculosis, it is imperative to identify more effective next-generation drugs. In this study, we characterized the mechanism of action of a more potent analog of pyrazinamide, morphazinamide. We demonstrate that like pyrazinamide, morphazinamide impairs coenzyme A metabolism. In contrast to pyrazinamide, we find that morphazinamide has an additional aldehyde-dependent mechanism that mediates potent bactericidal activity against both pyrazinamide-susceptible and pyrazinamide-resistant strains of M. tuberculosis. These findings open up new opportunities for the development of next-generation antitubercular drugs to tackle the increasing challenge of drug-resistant tuberculosis.

microbiology↗

bioRxiv2024

Quantifying Contributions from TopologicalCycles in the Brain Network towards Cognition

This study proposes a novel metric called Homological Vertex Importance Profile (H-VIP), utilizing topological data analysis tool persistent homology, to analyze human brain structural and functional connectomes. Persistent homology is a useful tool for identifying topological features such as cycles and cavities within a network. The salience of persistent homology lies in the fact that it offers a global view of the network as a whole. However, it falls short in precisely determining the relative relevance of the vertices of the network that contribute to these topological features. Our aim is to quantify the contribution of each individual vertex in the formation of homological cycles and provide insight into local connectivity. Our proposed H-VIP metric captures, quantifies, and compresses connectivity information from vertices even at multiple degrees of separation and projects back onto each vertex. Using this metric, we analyze two independent datasets: structural connectomes from the Human Connectome Project and functional connectomes from the Alzheimers Disease Neuroimaging Initiative. Our findings indicate a positive correlation between various cognitive measures and H-VIP, in both anatomical and functional brain networks. Our study also demonstrates that the connectivity in the frontal lobe has a higher correlation with cognitive performance compared to the whole brain network. Furthermore, the H-VIP provides us with a metric to easily locate, quantify, and visualize potentially impaired connectivity for each subject and may have applications in the context of personalized medicine for neurological diseases and disorders.

bioinformatics↗

bioRxiv2021

Syndecan-1 is overexpressed in human thoracic aneurysm but is dispensable for the disease progression in vivo

Glycosaminoglycans (GAGs) pooling has been considered since long as one of the histopathological characteristics defining thoracic aortic aneurysm (TAA) together with smooth muscle cells (SMCs) apoptosis and elastin fibers degradation. However, few information is provided about GAGs composition or potential implication in TAA pathology. Syndecan-1 (Sdc-1) is a heparan sulfate proteoglycan that is implicated in extracellular matrix (ECM) interaction and assembly, regulation of SMCs phenotype and various aspects of inflammation in the vascular wall. In the current work, the regulation of Sdc-1 protein was examined in human TAA by ELISA and immunohistochemistry. In addition, the role of Sdc-1 was evaluated in descending TAA in vivo using a mouse model combining both aortic wall weakening and hypertension. Our results showed that Sdc-1 protein is over expressed in human TAA aortas compared to healthy counterparts and that SMCs are the major cell type expressing Sdc-1. Similarly, in the mouse model used, Sdc-1 expression was increased in TAA aortas compared to healthy samples. Although its protective role against abdominal aneurysm has been reported, we observed that Sdc-1 was dispensable for TAA prevalence or rupture. In addition, Sdc-1 deficiency did not alter the extent of aortic wall dilatation, elastin degradation, collagen deposition, or leukocyte recruitment in our TAA model. These findings suggest that Sdc-1 could be a biomarker revealing TAA pathology. Future investigations could uncover the underlying mechanisms leading to Sdc-1 expression alteration in TAA.

pathology↗