Optimizing fare structure and service frequency for an intercity transit system

This study presents an approach to jointly optimize service headway and differentiated fare for an intercity transit system with an objective of total profit maximization and with consideration given to the economic and social sustainability of the system. Service capacity and fleet size constraints are considered. The optimization problem is structured into four scenarios which are comprised of the combinations of whether the Ranges of Travel Distance (RTD) is fixed or variable and if the time period is for a single period or for multiple periods. A successive substitution method (specifically, a modified Gauss Southwell method) is applied to solve for the optimal solutions when the RTD is considered fixed, while a heuristic solution algorithm (specifically, a Genetic Algorithm) is developed to find the optimal solutions when the RTD is considered to be optimized. The methodology discussed in this dissertation contributes to the field of transportation network modeling because it establishes how to solve the fare and headway design problem for an intercity transit system. Intercity transit agencies are faced with the challenge of determining fares for a very complicated setting in which demand elasticity, realistic geographic conditions, and facility locations of the transit system all must be taken into account. A real world case study - Taiwan High Speed Rail is used to demonstrate the applicability of the developed methodology. Numerical results of optimal solutions and sensitivity analyses are presented for each scenario. The sensitivity analyses enable transit planners to quantify the impact of fare policies and address social equity issues, which can be a major hurdle of implementing optimal fare policy to achieve maximum profit operation. According to the sensitivity analysis, the total profit surfaces for various headways, fares, and RTD are relatively flat near the optimum. This indicates that the transit operator has flexibility in shifting the solution marginally away from the optimum without significantly reducing the maximum profit. By varying the elasticity parameters of fare and demand one can observe how these variables affect the optimized RTD. The results indicate that as the elasticity parameters of fare increase or demand decreases, the optimal number of RTD increase while the boundaries of RTD are concentrated in the range of shorter travel distances

Functional and pharmacological importance of the composite ATP binding site 1 in CFTR chloride channels

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion channel whose defects cause the deadly genetic disease cystic fibrosis (CF). Like other ATP binding cassette (ABC) proteins, CFTR encompasses two cytoplasmic nucleotide binding domains (NBDs). Upon ATP binding, the two NBDs can coalesce into a head-to-tail dimer with ATP buried at two interfacial composite sites (sites 1 and 2). Although evidence suggests that gating of CFTR is mainly controlled by site 2, the role of site 1 remains less understood. I have used pyrophosphate as a probe or adopted a ligand exchange protocol to investigate ATP binding status in site 1 in real time. With these novel approaches, I have identified a “partial” NBD dimer state mediated by an ATP molecule tightly bound in site 1. A molecular model of CFTR gating was then established with opening and closing of CFTR coupled to the formation and partial separation of the NBD dimer. Moreover, I discovered several mutations that enhance ATP binding in site 1 and demonstrated that the activity of CF-associated mutant channels, ΔF508- and G551D-CFTR, can be significantly improved by these mutations, thus providing evidence that site 1 is a potential target for developing pharmaceutical reagents to treat patients with CF

Modulation of the slow/common gating of CLC channels by intracellular cadmium.

Members of the CLC family of Cl(-) channels and transporters are homodimeric integral membrane proteins. Two gating mechanisms control the opening and closing of Cl(-) channels in this family: fast gating, which regulates opening and closing of the individual pores in each subunit, and slow (or common) gating, which simultaneously controls gating of both subunits. Here, we found that intracellularly applied Cd(2+) reduces the current of CLC-0 because of its inhibition on the slow gating. We identified CLC-0 residues C229 and H231, located at the intracellular end of the transmembrane domain near the dimer interface, as the Cd(2+)-coordinating residues. The inhibition of the current of CLC-0 by Cd(2+) was greatly enhanced by mutation of I225W and V490W at the dimer interface. Biochemical experiments revealed that formation of a disulfide bond within this Cd(2+)-binding site is also affected by mutation of I225W and V490W, indicating that these two mutations alter the structure of the Cd(2+)-binding site. Kinetic studies showed that Cd(2+) inhibition appears to be state dependent, suggesting that structural rearrangements may occur in the CLC dimer interface during Cd(2+) modulation. Mutations of I290 and I556 of CLC-1, which correspond to I225 and V490 of CLC-0, respectively, have been shown previously to cause malfunction of CLC-1 Cl(-) channel by altering the common gating. Our experimental results suggest that mutations of the corresponding residues in CLC-0 change the subunit interaction and alter the slow gating of CLC-0. The effect of these mutations on modulations of slow gating of CLC channels by intracellular Cd(2+) likely depends on their alteration of subunit interactions

Novel CMOS RFIC Layout Generation with Concurrent Device Placement and Fixed-Length Microstrip Routing

With advancing process technologies and booming IoT markets, millimeter-wave CMOS RFICs have been widely developed in re- cent years. Since the performance of CMOS RFICs is very sensi- tive to the precision of the layout, precise placement of devices and precisely matched microstrip lengths to given values have been a labor-intensive and time-consuming task, and thus become a major bottleneck for time to market. This paper introduces a progressive integer-linear-programming-based method to gener- ate high-quality RFIC layouts satisfying very stringent routing requirements of microstrip lines, including spacing/non-crossing rules, precise length, and bend number minimization, within a given layout area. The resulting RFIC layouts excel in both per- formance and area with much fewer bends compared with the simulation-tuning based manual layout, while the layout gener- ation time is significantly reduced from weeks to half an hour.Comment: ACM/IEEE Design Automation Conference (DAC), 201