Biology subjects

Li, Y.-P.

Publications and source records attributed to Li, Y.-P..

4 recordsLinked to original sources

bioRxiv2025

MAESTRO uncovers tandem paralog dynamics as a core driver of fungal stress adaptation

Understanding how fungi adapt to diverse stresses is critical for mitigating emerging drug resistance and harnessing their robustness for biotechnology. Pichia kudriavzevii is a stress-tolerant and intrinsically drug-resistant yeast, with dual industrial and clinical importance. We analyzed 170 strains using MAESTRO, a machine-learning-assisted GWAS pipeline optimized for small cohorts. MAESTRO identified biologically meaningful features and revealed that copy number variation (CNV) of tandem paralogs (TPs) is a core mechanism of multi-stress adaptation. TPs were recurrently linked to tolerance of industrial inhibitors (HMF, phenolics, heat) and antifungal drugs (fluconazole, azoles), and deletion of the TP pair gene4260/gene4261 confirmed pleiotropic effects across stresses. These findings support a TP CNV model where recombination-driven TP CNVs and gene fusions enable rapid stress adaptation. Importantly, our results suggest that antifungal resistance can arise through co-option of mechanisms originally evolved for environmental stressors, raising a One Health concern about the environmental origins of drug-resistant pathogens.

genomics↗

bioRxiv2024

Cbfβ regulates Wnt/β-catenin, Hippo/Yap, and TGFβ signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis

As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that Cbf{beta}, (subunit of a heterodimeric Cbf{beta}/Runx1,Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion of Cbf{beta} in tamoxifen-induced Cbf{beta}f/fCol21-CreERT mice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed that Cbf{beta} deficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/YAP signaling and TGF-{beta} signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreased Cbf{beta} and Yap expression and increased active {beta}-catenin expression in articular cartilage, while local AAV-mediated Cbf{beta} overexpression promoted Yap expression and diminished active {beta}-catenin expression in OA lesions. Remarkably, AAV-mediated Cbf{beta} overexpression in knee joints of mice with OA showed the significant protective effect of Cbf{beta} on articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression of Cbf{beta} may be the cause of OA. Moreover, Local admission of Cbf{beta} may rescue and protect OA through decreasing Wnt/{beta}-catenin signaling, and increasing Hippo/Yap signaling and TGF{beta}/Smad2/3 signaling in OA articular cartilage, indicating that local Cbf{beta} overexpression could be an effective strategy for treatment of OA.

pathology↗

bioRxiv2022

Spike-specific CXCR3+ TFH cells play a dominant functional role in supporting antibody responses in SARS-CoV-2 infection and vaccination

CD4+ T follicular helper (TFH) cells are required for high-quality antibody generation and maintenance. However, the longevity and functional role of these cells are poorly defined in COVID-19 convalescents and vaccine recipients. Here, we longitudinally investigated the dynamics and functional roles of spike-specific circulating TFH cells and their subsets in convalescents at the 2nd, 5th, 8th, 12th and 24th months after COVID-19 symptom onset and in vaccinees after two and three doses of inactivated vaccine. SARS-CoV-2 infection elicited robust spike-specific TFH cell and antibody responses, of which spike-specific CXCR3+ TFH cells but not spike-specific CXCR3- TFH cells and neutralizing antibodies were persistent for at least two years in more than 80% of convalescents who experienced symptomatic COVID-19, which was well coordinated between spike-specific TFH cell and antibody responses at the 5th month after infection. Inactivated vaccine immunization also induced spike-specific TFH cell and antibody responses; however, these responses rapidly declined after six months with a two-dose standard administration, and a third dose significantly promoted antibody maturation and potency. Functionally, spike-specific CXCR3+ TFH cells exhibited better responsiveness than spike-specific CXCR3- TFH cells upon spike protein stimulation in vitro and showed superior capacity in supporting spike-specific antibody secreting cell (ASC) differentiation and antibody production than spike-specific CXCR3- TFH cells cocultured with autologous memory B cells. In conclusion, spike-specific CXCR3+ TFH cells played a dominant functional role in antibody elicitation and maintenance in SARS-CoV-2 infection and vaccination, suggesting that induction of CXCR3-biased spike-specific TFH cell differentiation will benefit SARS-CoV-2 vaccine development aiming to induce long-term protective immune memory. HighlightsO_LISARS-CoV-2 infection elicited robust spike-specific TFH cell and antibody responses, which persisted for at least two years in the majority of symptomatic COVID-19 convalescent patients. C_LIO_LIInactivated vaccine immunization also elicited spike-specific TFH cell and antibody responses, which rapidly declined over time, and a third dose significantly promoted antibody maturation and potency. C_LIO_LISpike-specific CXCR3+ TFH cells exhibited more durable responses than spike-specific CXCR3- TFH cells, correlated with antibody responses and showed superior capacity in supporting ASC differentiation and antibody production than spike-specific CXCR3- TFH cells. C_LI

immunology↗

bioRxiv2018

Process-specific somatic mutation distributions vary with three-dimensional genome structure

Somatic mutations arise during the life history of a cell. Mutations occurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutations throughout the neoplastic process and during cancer evolution (Martincorena and Campbell, 2015). Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations (Zhang and Pellman, 2015). Understanding the underlying factors generating somatic mutations is crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timing (Stamatoyannopoulos et al., 2009) and chromatin modifications (Schuster-Bockler and Lehner, 2012) are associated with variations in mutational density. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutational processes share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organization and specific individual mutational processes, we report here a study of 3000 tumor-normal pair whole genome datasets from more than 40 different human cancer types. Our analyses revealed that different mutational processes lead to distinct somatic mutation distributions between chromatin folding domains. APOBEC- or MSI-related mutations are enriched in transcriptionally-active domains while mutations occurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, and we show that mutational distributions shift during cancer evolution upon mutational processes switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosome leads to distinct somatic mutation distribution on X chromosome in females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancer.

genomics↗