Evaluation of a Hybrid Boltzmann-Continuum Method for High Speed Nonequilibrium Flows

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83556/1/AIAA-2010-1569-683.pd

Real-time digital simulation of switching power circuits

grantor: University of TorontoSophisticated power electronic apparatus and their digital control systems are finding increasing applications in electric power systems at generation, transmission, distribution and utilization levels. It is essential to carry out rigorous performance evaluation of the power electronic equipment and their digital controllers prior to their commissioning on the host power system. The current trend to achieve that goal is to interface a real-time digital simulator representing the power electronic apparatus and the host power system with the digital controller. This thesis addresses the issue of synchronization between the output signals of the digital controller for firing power electronic switches and the discrete time-step of the real-time simulator. It is shown that lack of such synchronization can lead to severe inaccuracies in the simulation results. A novel real-time simulation algorithm is proposed for accounting incoming switching events in fixed step-size digital simulation. This algorithm relies on the registration of the timing of the switching events and a subsequent correction procedure to calculate the system state. Off-line time domain simulations of a Pulse Width Modulated (PWM) Voltage Source Inverter (VSI) system demonstrate a ten-fold improvement in accuracy of the proposed algorithm over the fixed step-size algorithm using the same step-size. Practical feasibility of the proposed algorithm is demonstrated by implementation on a digital computing platform comprising of a DSP and a FPGA. The hardware and software design process follows a modular approach which makes it amenable for implementation on next generation processors. A 5kVA experimental set-up of the PWM VSC system is used to verify the results of the real-time simulation.Ph.D

One Year of Romosozumab Followed by Two Years of Denosumab Maintains Fracture Risk Reductions: Results of the FRAME Extension Study

Romosozumab, a humanized monoclonal antibody that binds and inhibits sclerostin, has the dual effect of increasing bone formation and decreasing bone resorption. As previously reported in the pivotal FRActure study in postmenopausal woMen with ostEoporosis (FRAME), women with a T-score of ≤ -2.5 at the total hip or femoral neck received subcutaneous placebo or romosozumab once monthly for 12 months, followed by open-label subcutaneous denosumab every 6 months for an additional 12 months. Upon completion of the 24-month primary analysis period, eligible women entered the extension phase and received denosumab for an additional 12 months. Here, we report the final analysis results through 36 months, including efficacy assessments of new vertebral, clinical, and nonvertebral fracture; bone mineral density (BMD); and safety assessments. Of 7180 women enrolled, 5743 (80%) completed the 36-month study (2851 romosozumab-to-denosumab; 2892 placebo-to-denosumab). Through 36 months, fracture risk was reduced in subjects receiving romosozumab versus placebo for 12 months followed by 24 months of denosumab for both groups: new vertebral fracture (relative risk reduction [RRR], 66%; incidence, 1.0% versus 2.8%; p < 0.001), clinical fracture (RRR, 27%; incidence, 4.0% versus 5.5%; p = 0.004), and nonvertebral fracture (RRR, 21%; incidence, 3.9% versus 4.9%; p = 0.039). BMD continued to increase for the 2 years with denosumab treatment in both arms. The substantial difference in BMD achieved through 12 months of romosozumab treatment versus placebo was maintained through the follow-up period when both treatment arms received denosumab. Subject incidence of adverse events, including positively adjudicated serious cardiovascular adverse events, were overall balanced between groups. In conclusion, in postmenopausal women with osteoporosis, 12 months of romosozumab led to persistent fracture reduction benefit and ongoing BMD gains when followed by 24 months of denosumab. The sequence of romosozumab followed by denosumab may be a promising regimen for the treatment of osteoporosis. © 2018 American Society for Bone and Mineral Research.status: publishe

Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development

Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer

Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development

Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer