Biology subjects

Bae, J.

Publications and source records attributed to Bae, J..

23 records · Page 2Linked to original sources

bioRxiv2021

Novel amiloride derivatives that inhibit bacterial motility across multiple strains and stator types

The bacterial flagellar motor (BFM) is a protein complex that confers motility to cells and contributes to survival and virulence. The BFM consists of stators that are ion-selective membrane protein complexes and a rotor that directly connects to a large filament, acting as a propeller. The stator complexes couple ion transit across the membrane to torque that drives rotation of the motor. The most common ion gradients that drive BFM rotation are protons (H+) and sodium ions (Na+). The sodium-powered stators, like those in the PomAPomB stator complex of Vibrio spp, can be inhibited by sodium channel inhibitors, in particular, by phenamil, a potent and widely used inhibitor. However, relatively few new sodium-motility inhibitors have been described since the discovery of phenamil. In this study, we characterised two possible motility inhibitors HM2-16F and BB2-50F from a small library of previously reported amiloride derivatives. We used three approaches: effect on rotation of tethered cells, effect on free swimming bacteria and effect on rotation of marker beads. We showed that both HM2-16F and BB2-50F stopped rotation of tethered cells driven by Na+ motors comparable to phenamil at matching concentrations, and could also stop rotation of tethered cells driven by H+ motors. Bead measurements in presence and absence of stators confirmed that the compounds did not inhibit rotation via direct association with the stator, in contrast to the established mode of action of phenamil. Overall, HM2-16F and BB2-50F stopped swimming in both Na+ and H+ stator types, and in pathogenic and non-pathogenic strains. ImportanceHere we characterised two novel amiloride derivatives in the search for antimicrobial compounds that target bacterial motility. Our two compounds were shown to inhibit flagellar motility at 10 M across multiple strains, from non-pathogenic E. coli with flagellar rotation driven by proton or chimeric sodium-powered stators, to proton-powered pathogenic E. coli (EHEC/UPEC) and lastly in sodium-powered Vibrio alginolyticus. Broad anti-motility compounds such as these are important tools in our efforts control virulence of pathogens in health and agricultural settings.

microbiology↗

bioRxiv2021

Ablating Ku70 phosphorylation results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma

Multiple pathways mediate the repair of DNA double-strand break (DSB), with numerous mechanisms responsible for driving choice between the pathways. Previously, we reported that phosphorylation of the non-homologous end joining (NHEJ) factor, Ku70, is required for the dissociation of the Ku heterodimer from DNA ends to allow DSB repair via homologous recombination (HR). A knock-in mouse, in which phosphorylation is ablated in the three conserved sites of Ku70 (Ku703A/3A), was generated in order to test the hypothesis that Ku70 phosphorylation is required for initiation of HR and that blocking this process results in enhanced genomic instability and tumorigenesis. Here, we show that Ku703A/3A mice develop spontaneous and have accelerated chemical-induced hepatocellular carcinoma (HCC) compared to wild-type (Ku70+/+) littermates. The HCC tumors from the Ku703A/3A mice have increased {gamma}H2AX and 8-oxo-G staining, suggesting DNA repair is decreased in these mice. Spontaneous transformed cell lines from Ku703A/3A mice are more radiosensitive, have a significant decrease in DNA end resection, and are more sensitive to the DNA cross-linking agent mitomycin C compared to cells from Ku70+/+ littermates. Collectively, these findings demonstrate that phosphorylation-mediated dissociation of Ku heterodimer from DNA ends is required for efficient DNA damage repair and disruption of this process results in genomic instability and accelerated development of HCC.

cancer biology↗

bioRxiv2020

An alternative miRISC targeting a coding mutation site in FOXL2 links to granulosa cell tumor

Recent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) in FOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which induces haploinsufficiency of the tumor-suppressor FOXL2. This miR-1236-mediated selective degradation of the variant FOXL2 mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and mouse model of AGCT, the inversely regulated variant FOXL2 abundance with the miR-1236 levels was highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conserved FOXL2 CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC.

cancer biology↗

bioRxiv2019

Transfer Learning for Predicting Conversion from Mild Cognitive Impairment to Dementia of Alzheimer Type based on 3D-Convolutional Neural Network

Dementia of Alzheimers Type (DAT) is associated with a devastating and irreversible cognitive decline. As a pharmacological intervention has not yet been developed to reverse disease progression, preventive medicine will play a crucial role for patient care and treatment planning. However, predicting which patients will progress to DAT is difficult as patients with Mild Cognitive Impairment (MCI) could either convert to DAT (MCI-C) or not (MCI-NC). In this paper, we develop a deep learning model to address the heterogeneous nature of DAT development. Structural magnetic resonance imaging was utilized as a single biomarker, and a three-dimensional convolutional neural network (3D-CNN) was developed. The 3D-CNN was trained using transfer learning from the classification of Normal Control and DAT scans at the source task. This was applied to the target task of classifying MCI-C and MCI-NC scans. The model results in 82.4% classification accuracy, which outperforms current models in the field. Furthermore, by implementing an occlusion map approach, we visualize key brain regions that significantly contribute to the prediction of MCI-C and MCI-NC. Results show the hippocampus, amygdala, cerebellum, and pons regions as significant to prediction, which are consistent with current understanding of disease. Finally, the models prediction value is significantly correlated with rates of change in clinical assessment scores, indicating the model is able to predict an individual patients future cognitive decline. This information, in conjunction with the identified anatomical features, will aid in building a personalized therapeutic strategy for individuals with MCI. This model could also be useful for selection of participants for clinical trials.

bioinformatics↗

bioRxiv2019

Sarcopenia is an independent predictor of hospitalization in chronic kidney disease outpatients

BackgroundPatients with chronic kidney disease (CKD) experience much more marked and earlier muscle wasting than subjects who do not have chronic illnesses. However, a few studies that have examined sarcopenia have been reported in CKD patients. We investigated the prevalence of sarcopenia in predialysis and dialysis outpatients with CKD and explored its relationship with the clinical outcomes.\n\nMeasurementsSarcopenia was defined as reduced muscle strength accompanied by decreased adjusted appendicular skeletal muscle (ASM), while those patients who exhibited only one of these characteristics were categorized as presarcopenic patients. ASM was measured by bioimpedence analysis, and muscle strength was evaluated by handgrips. ASM was adjusted by weight (ASM/wt). Patients were prospectively followed for up to 2 years.\n\nResultsOne hundred seventy-nine patients were recruited (114 male and 65 female patients who were classified into 103 predialysis patients and 76 dialysis patients, with 44.7% having diabetes). Their mean age was 60.6 {+/-} 13.5 years old. The prevalence of sarcopenia was 9.5%, while 55.9% of the patients were categorized as presarcopenic. The ASM/wt index showed significant correlations with age, handgrip strength, HOMA-IR and frailty scores. Multivariate Cox proportional hazards models demonstrated that the risk of hospitalization was significantly higher for patients with presarcopenia [hazard ratio (HR), 2.48; 95% confidence interval (CI), 1.180-5.230], and the risk of hospitalization was much higher for patients with sarcopenia than for patients in the nonsarcopenic group (HR, 9.11; 95% CI, 2.295-25.182)\n\nConclusionsSarcopenia and presarcopenia, which were defined using the ASM/wt index and handgrip strength, predicted a poorer, hospitalization-free survival in CKD patients

scientific communication and education↗