Mode of Action Study of Para-aminosalicylic Acid and Structure, Function and Inhibitor Study of the Isocitrate Dehydrogenase-2 in Mycobacterium tuberculosis

Tuberculosis (TB) killed 1.5 million people and rivaled AIDS, becoming the leading cause of death from infectious disease in 2014. The prevalence of multidrug resistant TB has intensified the current therapeutic procedure, making it urgent to find novel anti-tubercular agents and to come up with solutions to retard the emergence of the drug resistance. This dissertation focuses on the identification of drug targets, the exploration of drug resistance mechanisms, and the identification of novel inhibitors. In the first part, the mechanism of action of the classic anti-tubercular drug, para-aminosalicylic acid (PAS), was explored through genetic, cell viability and molecular modeling studies. Dihydrofolate reductase (DHFR) was identified to be the putative intracellular target of PAS. In addition, the molecular mechanism of PAS resistance was intensively investigated for the clinically relevant Rv2671 up-regulation mutant. Biochemical assays showed that Rv2671 exhibited a low DHFR activity with a high Km for the substrate, 7, 8-dihydrofolate. X-ray crystal structure of the Rv2671 in complex with NADP+ and tetrahydrofolate (THF) further confirmed the structural similarity between Rv2671 and DHFR. These studies together suggested that PAS resistance of this mutant is derived from the ability to complement the DHFR activity with the high level of Rv2671. The second part of this dissertation details the characteristics of Mycobacterium tuberculosis isocitrate dehydrogenase-2 (Mtb IDH2). The kinetic study of Mtb IDH2 suggested that it catalyzes an ordered sequential reaction by binding NADP+ first. X-ray crystal structure revealed the fairly conserved active site and dissimilar overall structure compared to human IDHs (HIDHs), suggesting a potential for drug selectivity. A screening of known inhibitors of mutant HIDHs and a high-throughput screening of Mtb whole cell active compounds were further implemented to identify inhibitors for Mtb IDH2. Two compounds from the screenings exhibited IC50s below 10 μM. The enzyme structure and the modest potency inhibitors of Mtb IDH2 can serve as viable starting points for the follow-up inhibitor development of Mtb IDH2

Mode of Action Study of Para-aminosalicylic Acid and Structure, Function and Inhibitor Study of the Isocitrate Dehydrogenase-2 in Mycobacterium tuberculosis

Tuberculosis (TB) killed 1.5 million people and rivaled AIDS, becoming the leading cause of death from infectious disease in 2014. The prevalence of multidrug resistant TB has intensified the current therapeutic procedure, making it urgent to find novel anti-tubercular agents and to come up with solutions to retard the emergence of the drug resistance. This dissertation focuses on the identification of drug targets, the exploration of drug resistance mechanisms, and the identification of novel inhibitors. In the first part, the mechanism of action of the classic anti-tubercular drug, para-aminosalicylic acid (PAS), was explored through genetic, cell viability and molecular modeling studies. Dihydrofolate reductase (DHFR) was identified to be the putative intracellular target of PAS. In addition, the molecular mechanism of PAS resistance was intensively investigated for the clinically relevant Rv2671 up-regulation mutant. Biochemical assays showed that Rv2671 exhibited a low DHFR activity with a high Km for the substrate, 7, 8-dihydrofolate. X-ray crystal structure of the Rv2671 in complex with NADP+ and tetrahydrofolate (THF) further confirmed the structural similarity between Rv2671 and DHFR. These studies together suggested that PAS resistance of this mutant is derived from the ability to complement the DHFR activity with the high level of Rv2671. The second part of this dissertation details the characteristics of Mycobacterium tuberculosis isocitrate dehydrogenase-2 (Mtb IDH2). The kinetic study of Mtb IDH2 suggested that it catalyzes an ordered sequential reaction by binding NADP+ first. X-ray crystal structure revealed the fairly conserved active site and dissimilar overall structure compared to human IDHs (HIDHs), suggesting a potential for drug selectivity. A screening of known inhibitors of mutant HIDHs and a high-throughput screening of Mtb whole cell active compounds were further implemented to identify inhibitors for Mtb IDH2. Two compounds from the screenings exhibited IC50s below 10 μM. The enzyme structure and the modest potency inhibitors of Mtb IDH2 can serve as viable starting points for the follow-up inhibitor development of Mtb IDH2

Integrated Degradation Models in R Using iDEMO

Degradation models are widely used to assess the lifetime information for highly reliable products with quality characteristics whose degradation over time can be related to reliability. The performance of a degradation model largely depends on an appropriate model description of the product's degradation path. The cross-platform package iDEMO (integrated degradation models) is developed in R and the interface is built using the Tcl/Tk bindings provided by the tcltk and tcltk2 packages included with R. It is a tool to build a linear degradation model which can simultaneously consider the unit-to-unit variation, time-dependent structure and measurement error in the degradation paths. The package iDEMO provides the maximum likelihood estimates of the unknown parameters, mean-time-to-failure and q-th quantile, and their corresponding confidence intervals based on the different information matrices. In addition, degradation model selection and goodness-of-fit tests are provided to determine and diagnose the degradation model for the user's current data by the commonly used criteria. By only enabling user interface elements when necessary, input errors are minimized

Fintech in Taiwan: Prospects and Implications for Incumbents

Purpose –The purpose of this research project is to investigate how fintech affects corporate finance business in banks and SMEs finance in Taiwan. Design/Methodology/approach –This research adopts secondary data analysis as the research method. The involving readings include journals, theses, government information, news and websites related to the topic of this project. Findings – Currently, the negative effect of fintech lending caused on banks is limited due to the regulation is strict on offering loans. In addition, due the slow adoption in fintech and strict regulation, lending business of banks in Taiwan has not met fierce competition from fintech players. Banks can take advantage of innovative technologies and integrate it into existing system to maintain its competitive advantages. Research limitations – Limitations are related to the constraints on data acquisition of first hand information of incumbents and time restriction. The research provide Key words –Bank, Fintech, Financial technology, Financial institution, SMEs, Lending, Financial services, Taiwan

A LOW-COST METHOD FOR REAL-TIME EVALUATION OF MEDIAN FREQUENCY DURING CYCLIC CONTRACTIONS

The appropriate exercise intensity can be used to improve physical strength as well as to prevent musculoskeletal injuries, and scientific analysis can evaluate the effectiveness of resistance training. The goal of the study was to test a low-cost method for real-time evaluation of median frequency (MDF) during cyclic contractions. Surface electromyography (sEMG) is an objective, non-invasive and pain-free method for assessing and monitoring muscle fatigue in humans performing resistance exercise. In the study, we provided a low-cost method for real-time evaluation of MDF during cyclic contractions. For a well designed program that controls the accumulation of fatigue, local muscle fatigue must be quantified