Biology subjects

Gao, Y.-G.

Publications and source records attributed to Gao, Y.-G..

4 recordsLinked to original sources

bioRxiv2026

An Inositol Receptor Orchestrates Carbon Utilization and Fungal Virulence

Nutrient sensing and utilization are critical for microbes to adapt to their environment and evade predators. The encapsuled yeast Cryptococcus neoformans has a unique ability to sense and utilize the sugar inositol as both a signaling molecule, and as a carbon source. This trait is advantageous not only in the natural environment, but to promote its pathogenesis, including invasion of the central nervous system. Unlike many other fungal species, which utilize the canonical carbon catabolite repression (CCR) mechanism to prioritize glucose metabolism, we have identified a novel inositol transporter-like receptor (transceptor) Itr4 that also regulates CCR genes to maintain inositol metabolism activity even under high glucose conditions. Itr4 binds inositol and regulates the function of other inositol transporters (ITRs) and its loss leads to a significant decrease in inositol uptake activity, resulting in a lack of mating, reduced capsule size, reduced blood brain barrier (BBB) penetration, and virulence attenuation. Mutagenesis analysis of Itr4 protein identified an essential N-terminal tail and two amino acids, Q388 and Q389, as sites of functional importance. The ITR4Q388A, Q389A allele showed a dominant phenotype with increased inositol uptake, enlarged capsule and significantly attenuated virulence. In summary, we identify a new C. neoformans inositol transceptor, Itr4, the first such example in eukaryotes, with novel regulatory roles in both inositol and glucose metabolism and fungal virulence.

microbiology↗

bioRxiv2023

Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage

Advancing age is the primary risk factor for pulmonary diseases. Our investigation revealed an 8-fold increase in aging induced isoDGR-damaged proteins in lung tissue from human pulmonary fibrosis patients compared to healthy tissues, accompanied by elevated frequencies of CD68+/CD11b+ macrophages, indicating lung tissue is susceptible to time-dependent accumulation of isoDGR-proteins. To elucidate the mechanisms through which isoDGR-proteins may exacerbate aging lung disorders for potential therapeutic targeting, we assessed the functional role of this isoDGR-motif in naturally-aged mice and mice lacking the corresponding isoDGR repair enzyme (Pcmt1-/-). IsoDGR-protein accumulation in mouse lung tissue and blood vessels correlated with chronic low-grade inflammation, pulmonary edema, and hypoxemia. IsoDGR accretion induced mitochondrial and ribosomal dysfunctions, cellular senescence, and apoptosis, contributing to progressive lung damage over time. Treatment with anti-isoDGR antibodies suppressed TLR pathway activity, mitigated cytokine-driven inflammation, restored mtDNA expression, and significantly reduced lung pathology in-vivo. Similarly, exposure of lung endothelial cells to isoDGR-modified fibronectin impaired oxygen consumption, increased reactive oxygen species levels, and disrupted acidification, but these effects were efficiently reversed by target-specific antibody therapy. Collectively, our findings underscore the significant contribution of isoDGR-damaged proteins to age-linked lung pathology. IsoDGR-specific therapy emerges as a promising treatment approach for pulmonary disorders in older patients.

pathology↗

bioRxiv2023

Antibody targeting of aging damaged isoDGR-protein doubles lifespan in a mouse model of chronic inflammation

Aging is the result of the accumulation of molecular damages that impair normal biochemical activities. We previously reported that aging-damaged amino acid sequence NGR (Asn-Gly-Arg) results in a gain-of-function conformational switching to isoDGR (isoAsp-Gly-Arg) motif. This integrin-binding motif activates leukocytes to induce chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy doubles lifespan in mouse model of chronic inflammation. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-KO and old WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1mg/kg) was sufficient to significantly reduce isoDGR-modified proteins and pro-inflammatory cytokine expression, improve behaviour and coordination, and double the average lifespan of Pcmt1-KO mice. Mechanistically, isoDGR-mAb mediated the immune clearance of damaged isoDGR-proteins by antibody-dependent cellular phagocytosis. These results indicate that immunotherapy targeting aging-damaged proteins may represent effective interventions for a range of age-linked degenerative disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/532237v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@81610borg.highwire.dtl.DTLVardef@a22aaorg.highwire.dtl.DTLVardef@169fe50org.highwire.dtl.DTLVardef@1b73d11_HPS_FORMAT_FIGEXP M_FIG Anti-isoDGR immunotherapy induces immune clearance of aging damaged isoDGR-proteins to reduce chronic inflammation, improve behaviour and coordination, and double lifespan in PCMT-/- mice. C_FIG

biochemistry↗

bioRxiv2020

A CRISPR-based SARS-CoV-2 diagnostic assay that is robust against viral evolution and RNA editing

Extensive testing is essential to break the transmission of the new coronavirus SARS-CoV-2, which causes the ongoing COVID-19 pandemic. Recently, CRISPR-based diagnostics have emerged as attractive alternatives to quantitative real-time PCR due to their faster turnaround time and their potential to be used in point-of-care testing scenarios. However, existing CRISPR-based assays for COVID-19 have not considered viral genome mutations and RNA editing in human cells. Here, we present the VaNGuard (Variant Nucleotide Guard) test that is not only specific and sensitive for SARS-CoV-2, but can also detect the virus when its genome or transcriptome has evolved or has been edited by deaminases in infected human cells. We show that an engineered AsCas12a enzyme is more tolerant of mismatches than wildtype LbCas12a and that multiplexed Cas12a targeting can overcome the presence of single nucleotide variations. Our assay can be completed in 30 minutes with a dipstick for a rapid point-of-care test.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗