Biology subjects

Lim, A.

Publications and source records attributed to Lim, A..

3 recordsLinked to original sources

bioRxiv2018

Genomic Surveillance for Antimicrobial Resistance in Mannheimia haemolytica Using Nanopore Single Molecule Sequencing Technology

Disruptive innovations in long-range, cost-effective direct template nucleic acid sequencing are transforming clinical and diagnostic medicine. A multidrug resistant strain and a pan-susceptible strain of Mannheimia haemolytica, isolated from pneumonic bovine lung samples, were respectively sequenced at 146x and 111x coverage with Oxford Nanopore Technologies MinION. De novo assembly produced a complete genome for the non-resistant strain and a nearly complete assembly for the drug resistant strain. Functional annotation using RAST (Rapid Annotations using Subsystems Technology), CARD (Comprehensive Antibiotic Resistance Database) and ResFinder databases identified genes conferring resistance to different classes of antibiotics including beta lactams, tetracyclines, lincosamides, phenicols, aminoglycosides, sulfonamides and macrolides. Antibiotic resistance phenotypes of the M. haemolytica strains were confirmed with minimum inhibitory concentration (MIC) assays. The sequencing capacity of highly portable MinION devices was verified by sub-sampling sequencing reads; potential for antimicrobial resistance determined by identification of resistance genes in the draft assemblies with as little as 5,437 MinION reads corresponded to all classes of MIC assays. The resulting quality assemblies and AMR gene annotation highlight efficiency of ultra long-read, whole-genome sequencing (WGS) as a valuable tool in diagnostic veterinary medicine.

microbiology↗

bioRxiv2018

SREBP1 drives KRT80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer

Approximately 30% of women diagnosed with ER breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies1,2. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD)3 undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse in vivo while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 14 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of prospective patients shows that KRT80 levels correlate with stiffer tumors in vivo. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

cancer biology↗

bioRxiv2017

Estrogen receptor inhibition enhances cold-induced adipocyte beiging and glucose sensitivity

Low estrogen states, exemplified by postmenopausal women, are associated with increased adiposity and metabolic dysfunction. We recently reported a paradox, in which a conditional estrogen receptor-alpha (ER) mutant mouse shows a hyper-metabolic phenotype with enhanced brown/beige cell formation (\"browning/beiging\"). These observations led us to consider that although systemic deficiency of estrogen or ER in mice results in obesity and glucose intolerance at room-temperature, cold-exposure might induce enhanced browning/beiging and improve glucose metabolism. Remarkably, studying cold-exposure in mouse models of inhibited estrogen signaling - ERKO mice, ovariectomy, and treatment with the ER antagonist Fulvestrant - supported this notion. ER/estrogen deficient mice demonstrated enhanced cold-induced beiging, reduced adiposity and increased glucose sensitivity. Fulvestrant was also effective in diet-induced obesity settings. Mechanistically, ER inhibition sensitized cell-autonomous beige cell differentiation and stimulation, including {beta}3-adrenoreceptor-dependent adipocyte beiging. Taken together, our findings highlight a therapeutic potential for obese/diabetic postmenopausal patients.

developmental biology↗