Structural/functional insights derived from studies of human and zebrafish CFTR orthologs

Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels play a critical role in regulating the trans-epithelial movement of water and electrolyte in exocrine tissues and the malfunctions of CFTR result in cystic fibrosis, the most prevalent lethal autosomal recessive hereditary disease among the Caucasian populations. Despite decades of biochemical and biophysical studies of CFTR, our understanding of CFTR’s structure and gating mechanism remains limited. My dissertation research started with a focus on the structural and functional contribution of the fifth transmembrane segment (TM5) of human CFTR in forming the chloride permeation pathway and continued into tackling the role of the electrostatic profile in the pore for anion flux. These studies have led to the following conclusions: First, TM5 indeed contributes to forming the chloride permeation pathway but TM7 does not line the pore. Unlike the well-studied TM1, TM6, and TM12, the six identified pore-lining residues (A299, R303, N306, S307, F310 and F311) in TM5 only line the internal vestibule of the pore, not the narrow region nor the outer vestibule. Second, changing the side-chain properties of several pore-lining residues along TM5 resulted in channels with two distinct subconductance levels, small conductance O1 state and large conductance O2 state, respectively. Intriguingly, the preferred gating transition C→O1→O2→C over C→O2→O1→C (namely the O1O2 phenotype) as reported previously for R352 mutations suggests the existence of an irreversible gating process attributed to the input of the free energy from ATP hydrolysis. Then the timely solution of the cryo-EM structures of human and zebrafish CFTR offers a great opportunity to interweave the structural and functional data for a comprehensive understanding of CFTR. Taking a full advantage of this opportunity, I launched a thorough investigation of zebrafish CFTR to fill the blank of functional data for this ortholog. Although current cryo-EM data show minimal structural differences between human and zebrafish CFTR, my electrophysiological characterization of zebrafish CFTR revealed unexpected functional differences, which subsequently offer novel mechanistic insights regarding the mechanism of CFTR gating by ATP binding and hydrolysis

Efficient aircraft spare parts inventory management under demand uncertainty

In airline industries, the aircraft maintenance cost takes up about 13% of the total operating cost. It can be reduced by a good planning. Spare parts inventories exist to serve the maintenance planning. Compared with commonly used reorder point system (ROP) and forecasting methods which only consider historical data, this paper presents two non-linear programming models which predict impending demands based on installed parts failure distribution. The optimal order time and order quantity can be found by minimizing total cost. The first basic mathematical model assumes shortage period starts from mean time to failure (MTTF). An iteration method and GAMS are used to solve this model. The second improved mathematical model takes into account accurate shortage time. Due to its complexity, only GAMS is applied in solution methodology. Both models can be proved effective in cost reduction through revised numerical examples and their results. Comparisons of the two models are also discussed

Optimization Of Branching Structures For Free-Form Surfaces Using Force Density Method

Branching structures are mechanically efficient in supporting large-span structures, such as free-form roofs. To support a roof with a specified geometry, we present a novel shape and topology optimization method to find the optimal branching structure in this paper. In the proposed method, the branching structure is modelled as a cable-net, while the reaction forces from the roof are taken as external loads. The force densities of the members are the design variables. The optimal branching structure can be obtained by minimizing one of the several proposed objective functions. The shape of the branching structure represented by the nodal coordinates is determined by solving the linear equilibrium equations. The topology is optimized by removing the members with small axial forces and incorporating the closely spaced nodes. The cross-sectional areas can be easily calculated, if the allowable stress is assigned. Hence, it is very convenient to simultaneously optimize the cross-section, shape, and topology of a branching structure. Numerical examples show that this method can be easily applied to a 2D problem. For a 3D problem, the constraints on the reaction forces should be relaxed. Considering the roof supports as variables is also an effective solution for 3D problems

BP-NTT: Fast and Compact in-SRAM Number Theoretic Transform with Bit-Parallel Modular Multiplication

Number Theoretic Transform (NTT) is an essential mathematical tool for computing polynomial multiplication in promising lattice-based cryptography. However, costly division operations and complex data dependencies make efficient and flexible hardware design to be challenging, especially on resource-constrained edge devices. Existing approaches either focus on only limited parameter settings or impose substantial hardware overhead. In this paper, we introduce a hardware-algorithm methodology to efficiently accelerate NTT in various settings using in-cache computing. By leveraging an optimized bit-parallel modular multiplication and introducing costless shift operations, our proposed solution provides up to 29x higher throughput-per-area and 2.8-100x better throughput-per-area-per-joule compared to the state-of-the-art.Comment: This work is accepted to the 60th Design Automation Conference (DAC), 202

A 2-dimentional contact analysis using second-order virtual element method

In the present study, we exploit the use of second-order virtual element method (VEM) for contact analysis in 2-dimension within the context of linear elasticity and small deformation. By virtue of mesh flexibility in the VEM, the non-matching meshes at the contact interface are transformed into matching meshes, and therefore the node-to-node contact discretization can be constructed. The frictional contact is considered as stick condition, and no tangential movement is allowed due to the assumption of small deformation condition. The normal and frictional contact constraints are imposed using the Lagrange multiplier method and the penalty method, respectively, and the candidate contact interface is determined by a series of adaptive trial and error tests as well as prior experience. Several numerical examples are investigated to illustrate the effectiveness of the proposed method in contact analysis, and the results show that the proposed method is able to handle problem with complex non-matching meshes at contact interface. Properties of shear wall consisting of units with fitting joints are also investigated as a practical application

GENOME-WIDE DISCOVERY AND ANNOTATION OF HUMAN ENHANCERS RELEVANT TO DEVELOPMENT AND DISEASE

Ph.DDOCTOR OF PHILOSOPH

Throughput improvement for multi-hop UAV relaying

Unmanned aerial vehicle (UAV) relaying is one of the main technologies for UAV communications. It uses UAVs as relays in the sky to provide reliable wireless connection between remote users. In this paper, we consider a multi-hop UAV relaying system. To improve the spectrum efficiency of the system, we maximize the average end-to-end throughput from the source to the destination by jointly optimizing the bandwidth allocated to each hop, the transmit power for the source and relays, and the trajectories of the UAVs, subject to constraints on the total spectrum bandwidth, the average and peak transmit power, the UAV mobility and collision avoidance, and the information-causality of multi-hop relaying. The formulated optimization is non-convex. We propose an efficient algorithm to approximate and solve it, using the alternating optimization and successive convex optimization methods. Numerical results show that the proposed optimization significantly outperforms other benchmark schemes, verifying the effectiveness of our scheme