Biology subjects

Kim, J. W.

Publications and source records attributed to Kim, J. W..

3 recordsLinked to original sources

bioRxiv2018

Bacterial clearance enhanced by α2, 3- and α2, 6-sialyllactose via receptor-mediated endocytosis and phagocytosis

Sialyllactose (SL) is a representative human milk oligosaccharide (HMO) of human breast milk. The roles of SL in infant brain development and immunity have been reported in previous studies. In this study, we identified the impact of SL on innate immunity. Our results showed that the administration of SL had significant efficacy on bacterial clearance in Pseudomonas aeruginosa K-infected mice. We also examined the role of SL in the human THP-1 macrophage-like cell line. SL effectively promoted receptor-mediated endocytosis and phagocytosis. Furthermore, SL accelerated the recruitment of Rac1 to the cell membrane, leading to the generation of reactive oxygen species for the elimination of phagocytosed bacteria. Our findings provide a new perspective on the role of SL in breast milk and suggest its potential application as a therapeutic agent to treat bacterial and viral infections.

immunology↗

bioRxiv2018

Modelling bistable tumour population dynamics to design effective treatment strategies

Despite recent advances in targeted drugs and immunotherapy, cancer remains \"the emperor of all maladies\" due to inevitable emergence of resistance. Drug resistance is thought to be driven by mutations and/or dynamic plasticity that deregulate pathway activities and regulatory programs of a highly heterogeneous tumour. In this study, we propose a modelling framework to simulate population dynamics of heterogeneous tumour cells with reversible drug resistance. Drug sensitivity of a tumour cell is determined by its internal states, which are demarcated by coordinated activities of multiple interconnected oncogenic pathways. Transitions between cellular states depend on the effects of targeted drugs and regulatory relations between the pathways. Under this framework, we build a simple model to capture drug resistance characteristics of BRAF-mutant melanoma, where two cell states are described by two mutually inhibitory - main and alternative - pathways. We assume that cells with an activated main pathway are proliferative yet sensitive to the BRAF inhibitor, and cells with an activated alternative pathway are quiescent but resistant to the drug. We describe a dynamical process of tumour growth under various drug regimens using the explicit solution of mean-field equations. Based on these solutions, we compare efficacy of three treatment strategies: static treatments with continuous and constant dosages, periodic treatments with regular intermittent phases and drug holidays, and treatments derived from optimal control theory (OCT). Based on these analysis, periodic treatments outperform static treatments with a considerable margin, while treatments based on OCT outperform the best periodic treatment. Our results provide insights regarding optimal cancer treatment modalities for heterogeneous tumours, and may guide the development of optimal therapeutic strategies to circumvent drug resistance and due to tumour plasticity.

cancer biology↗

bioRxiv2018

Functionally redundant forms of extended-spectrum beta-lactamases and aminoglycoside modifying enzymes drive the evolution of two distinct multidrug resistance gene clusters in clinical populations of EXPEC

We evaluate the distribution of genetic markers for antibiotic resistance in 276 genomic sequences of Extraintestinal Pathogenic E. coli from two hospitals on the U.S. West coast. Plasmid-borne genes encoding drug-inactivating enzymes dominate the distribution of aminoglycoside and {beta}-lactam resistance markers. These genes can be assigned based on their distribution to two mutually exclusive complementarity groups (CGs: CG1 and CG2) with each displaying genetic linkage and minimal functional overlap. CG1 includes genes encoding OXA-1 and AAC(6)-Ib-cr, frequently also CTX-M-15, and sometimes AAC(3)-IIe.2, a variant of AAC(3)-IIe; CG2 includes AAC(3)-IId tightly linked to TEM-1, and occasionally also to genes encoding CTX-M-14-like {beta}-lactamases. This binary distribution of aminoglycoside and {beta}-lactamase resistance genes suggests a convergence between two different evolutionary solutions, and results in a ubiquitous functional redundancy in the clinical populations. CG1 and CG2 are largely carried in IncF plasmids, of which we distinguish seven classes based on Rpt-A1 sequence homology. Both CG1 and CG2 genes are found in two different IncF plasmid classes, demonstrating their pervasive mobility across plasmid backbones. Different CG genes and IncF plasmid classes are found in a wide range of MLSTs, highlighting the prevalence of horizontal gene transfer. We also identify at least five clonally expanding MLSTs, which represent high-risk clones: ST131, ST95, ST73, ST127, and ST69. The identification of clonally-expanding types, the discovery of CGs that are ubiquitously spread in diverse clinical strains, and the functional redundancy that these two groups represent have significant implications for monitoring and controlling the spread of resistance.

microbiology↗