Biology subjects

Yong, A.

Publications and source records attributed to Yong, A..

8 recordsLinked to original sources

bioRxiv2025

Enhanced Medium-Chain Fatty Acid Production in Megasphaera elsdenii via Adaptive Laboratory Evolution and Genomic Insights

The shift toward a sustainable bioeconomy has increased interest in microbial platforms capable of producing valuable fatty acids. Megasphaera elsdenii is emerging as a promising candidate for fatty acid bioproduction, although its performance varies depending on the strain. This study compares two M. elsdenii strains, JCM 1772 (ATCC 25940) and JCM 35779, revealing that JCM 35779 produces up to 5.8 times more hexanoic acid than JCM 1772. Comparative genomic analysis identified key differences between the strains, including the loss of enzymes involved in the pyruvate-to-butyric acid pathway in JCM 35779, indicating a rerouting of carbon flux that favors chain elongation toward hexanoic acid instead of butyric acid. Overall, this work links genomic variation to metabolic phenotype, establishes JCM 35779 as a superior medium-chain fatty acid producer, and supports the development of M. elsdenii as an effective platform for sustainable production of medium-chain fatty acids. HighlightsO_LIPig-feces M. elsdenii shows >5 times higher HA production than its rumen strain. C_LIO_LIGenomic analysis reveals strain-specific deletions in pathways for MCFA synthesis. C_LIO_LIThis includes etfB2, cat1 and abfD. C_LI

microbiology↗

bioRxiv2025

Mitochondrial DNA Mutations Determine Favourable Molecular Responses to Targeted Kinase Inhibitor Therapy and Impair Oxidative Phosphorylation

Somatic mutations in mitochondrial DNA (mtDNA) are not typically considered key oncogenic drivers of cancer, primarily because of a high synonymous to non-synonymous variant ratio. Here, we surveyed 248 matched diagnosis and remission samples from patients with chronic myeloid leukemia (CML) and found a 75% had mitochondrial mutations with a median number of 2 mutations per patient. mtDNA mutations were predominantly non-synonymous, enriched in the D-loop control region, and likely originated from replication and transcriptional errors. Functionally, mtDNA mutations were associated with reduced oxidative phosphorylation (OXPHOS), as measured by Seahorse analyser. This metabolic vulnerability could be phenocopied by treatment with the complex I inhibitor IACS-10759 in combination with the targeted tyrosine kinase inhibitor (TKI) imatinib, which significantly reduced the colony-forming potential of TKI resistant leukemic stem/progenitor cells (LSPCs). Strikingly, we show that mtDNA mutations were associated with increased sensitivity to imatinib therapy in the clinic. Patients with [≥]3 mutations and patients with mutations in the D-loop showed significantly higher cumulative incidence of major molecular response at 24 months (90% vs. 68%, p = 0.004, and 89% vs 68%, p = 0.004 respectively). Single-cell RNA sequencing further revealed enrichment in non-synonymous mtDNA variants in LSPCs from TKI-sensitive patients, while TKI-resistant cells exhibited upregulated gene signatures related to glycerolipid and phospholipid metabolism and mitochondrial biogenesis. Together, our findings demonstrate that mtDNA mutations are key determinants of sensitivity to targeted therapy, rather than oncogenic drivers of leukemogenesis. Mechanistically, non-synonymous mtDNA mutations appear to restrict mitochondrial metabolic plasticity, with widespread implications for precision oncology.

cancer biology↗

bioRxiv2025

An Experimental and Multiphysics Simulations Study of Clostridium carboxidivorans sp. 624 for Acid and Alcohol Production in CO2/H2

Biotechnological advances in CO2 utilization through gas fermentation offer a sustainable alternative to energy-intensive chemical processes. This study investigates and optimizes fermentation dynamics of Clostridium carboxidivorans sp. 624 for enhanced production of C2-C6 acids via combined experimental and computational methods. A systematic experimental evaluation of temperature and medium conditions, along with time-course analysis elucidates metabolic pathway regulation. Experimental optimisation, complemented by modelling, identified gas-liquid volumetric ratios VL/VG = 4 as optimal for maximizing longer-chain acids production, attributed to enhanced gas solubility and substrate bioavailability. Additionally, a hybrid model combining dynamic-kinetic model and computational fluid dynamics (CFD) successfully predict product formation. By capturing spatial inhomogeneities in gas-liquid interactions, the model also provides critical insights for optimizing fermentation performance and establishes a framework for improving process design parameters for CO2/H2 fermentation, paving the way for scalable and efficient CO2-based bioprocesses.

microbiology↗

bioRxiv2025

Single-cell transcriptomics-guided development of flow cytometric tests predicting chronic myeloid leukemia blast crisis transformation at chronic phase diagnosis

Clinical risk scores in chronic myeloid leukemia (CML) are inadequate for identifying chronic phase (CP) patients at high-risk of blast crisis (BC) progression. The lack of accurate predictive tests hamper timely interventions, including stem cell transplants, that are more effective in early disease. By interrogating a single cell atlas of primary imatinib resistance for a BC-like gene expression signature, we identify aberrant CD42A+ megakaryocytic and CD10+CD19+ lymphoid progenitor expansion, as well as STAT1- and IFN{gamma}-related inflammatory programs, as consistent features in the bone marrow and peripheral blood of CP patients at high-risk of BC transformation. We develop multi-color flow cytometry-based tests (MFC) to detect these features in CP patients at the time of diagnosis. Validating our MFC panels on a combined Australia-Singapore cohort comprising 28 CP patients, including 14 who underwent transformation, we demonstrate their ability to detect 100% of CP patients who transform with no false positives. Our findings highlight small populations of inflamed hematopoietic stem and progenitor cells, present at CP diagnosis, as powerful harbingers of future BC transformation. The ability of MFC panels to detect these cells at diagnosis support their inclusion as accurate risk-assessment tools to improve management of high-risk patients.

cancer biology↗

bioRxiv2023

Delivery of mRNA encoding an anti-Tau monoclonal antibody and engineered scFv intrabody results in functional antibody expression in SH-SY5Y cells

Monoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimers disease. In the last year, two anti-amyloid monoclonal antibodies, lecanemab and aducanumab, have been approved in the USA for the treatment of Alzheimers disease, whilst several tau-targeting monoclonal antibodies are currently in clinical trials. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease-modifying effects. Synthetic in vitro-transcribed mRNA encoding antibodies for endogenous protein expression holds the potential to overcome many of the limitations associated with protein antibody production. Here, we have generated synthetic in vitro-transcribed mRNA encoding a tau specific monoclonal antibody as a full-sized IgG and as a single chain variable fragment (scFv). In vitro transfection of human neuroblastoma SH-SY5Y cells demonstrated the ability of the synthetic mRNA to be translated into functional tau-specific antibodies. Furthermore, we show that the translation of the tau-specific scFv as an intrabody results in the specific engagement of intracellular tau. This work highlights the utility of mRNA for the delivery of antibody therapeutics, including intrabodies, for the targeting of tau in tauopathies.

neuroscience↗

bioRxiv2021

Epigenetic therapy suppresses endocrine-resistant breast tumour growth by re-wiring ER-mediated 3D chromatin interactions

Three-dimensional (3D) epigenome remodelling is an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome therapy resistance remains largely unaddressed. Here we show that FDA-approved epigenetic therapy Decitabine (5-Aza-mC) suppresses tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associated domain boundary insulation. Significant DNA hypomethylation at ER-enhancer elements was associated with gain in ER binding, creation of ectopic 3D enhancer-promoter interactions and concordant activation of ER-mediated transcription pathways. Importantly long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in loss of ectopic 3D enhancer-promoter interactions and associated gene repression. Our study illustrates how epigenetic therapy has potential to target ER+ endocrine-resistant breast cancer by DNA methylation-dependent rewiring of 3D chromatin interactions associated with suppression of tumour growth.

molecular biology↗

bioRxiv2020

MDM2 Inhibition in Combination with Endocrine Therapy and CDK4/6 Inhibition for the Treatment of ER-Positive Breast Cancer.

BackgroundResistance to endocrine therapy is a major clinical challenge in the management of estrogen receptor (ER)-positive breast cancer. In this setting p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment resistant ER-positive breast cancer. MethodsWe used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate antitumor effects in p53 wildtype and p53 mutant ER positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and -resistant ER positive breast cancer. ResultsWe demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant resistant patient derived xenograft model. ConclusionsWe conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programs.

cancer biology↗

bioRxiv2020

Cyclin E1 protein is stabilized in BRCA1 mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1 gene expression. Instead, BRCA1 loss stabilized cyclin E1 during the cell cycle. Using siRNA we showed that BRCA1 loss leads to stabilization of cyclin E1 by reducing phospho-cyclin E1-T62, and conversely the overexpression of BRCA1 increased phospho-T62. Mutation of cyclin E1-T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in BRCA1 mutated cell lines. Treatment of BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.

cancer biology↗