Knowledge diffusion vs. technological progress: the optimal strength of IPRs protection

By adjusting the strength of IPRs protection, the government can change the extent of knowledge spillovers in R&D. A large spillover rate helps to improve the productivity of the less efficient firms and save on the overall production costs. But, at the same time, it reduces the innovator's incentives to conduct R&D and results in a lower equilibrium innovation level. So, there is an inherent tension between knowledge diffusion and technological progress. In this paper, we formalized this relationship in a two stage asymmetric duopoly model and discussed the optimal IPRs protection policy. The main conclusion is that, to maximize social welfare the strength of IPRs protection should rise as the increase of the innovating firm's R&D efficiency.spillovers, knowledge diffusion, technological progress, IPRs

Ion Mobility-Mass Spectrometry and Collision Induced Unfolding of Multi-Protein Ligand Complexes.

Mass spectrometry (MS) serves as an indispensable technology for modern pharmaceutical drug discovery and development processes, where it is used to assess ligand binding to target proteins and to search for biomarkers that can be used to gauge disease progression and drug action. However, MS is rarely treated as a screening technology for the structural consequences of drug binding. Instead, more time-consuming technologies capable of projecting atomic models of protein-drug interactions are utilized. In this thesis, ion mobility-mass spectrometry (IM-MS) methods are developed in order to fill these technology gaps. Principle among these is collision induced unfolding (CIU), which leverages the ability of IM to separate ions according to their size and charge, in order to fingerprint gas-phase unfolding pathways for non-covalent protein complexes. Following a comprehensive introductory chapter, we demonstrate the consequences of sugar binding on the CIU of Concanavalin A (Con A) in Chapter 2. Our CIU assay reveals cooperative stabilization upon small molecule binding, and such effect cannot be easily detected by solution phase assays, or by MS alone. In Chapter 3, the underlying mechanism of multi-protein unfolding is systematically investigated by IM-MS and molecular modeling approaches. Our results show a strong positive correlation between monomeric Coulombic unfolding and the tetrameric CIU process. This provides strong evidence that multi-protein unfolding events are initiated primarily by charge migration from the complex to a single monomer. In Chapter 4, the interactions between human histone deacetylase 8 (HDAC8) and poly-r(C)-binding protein 1 (PCBP1) are investigated by IM-MS. Our data suggest that these proteins interact with each other in a specific manner, a fact revealed by our optimized ESI-MS workflow for quantifying binding affinity (KD) for weakly-associated hetero-protein complexes. In Chapter 5, the translocator protein (TSPO) dimer from Rhodobacter sphaeroides, as well as its disease-associated variant forms, is analyzed by IM-MS and CIU assays. By utilizing a combination of CIU and collision induced dissociation (CID) stability data, an unknown endogenous ligand bound to TSPO is detected and identified.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/116693/1/shuainiu_1.pd

An Accelerated DC Programming Approach with Exact Line Search for The Symmetric Eigenvalue Complementarity Problem

In this paper, we are interested in developing an accelerated Difference-of-Convex (DC) programming algorithm based on the exact line search for efficiently solving the Symmetric Eigenvalue Complementarity Problem (SEiCP) and Symmetric Quadratic Eigenvalue Complementarity Problem (SQEiCP). We first proved that any SEiCP is equivalent to SEiCP with symmetric positive definite matrices only. Then, we established DC programming formulations for two equivalent formulations of SEiCP (namely, the logarithmic formulation and the quadratic formulation), and proposed the accelerated DC algorithm (BDCA) by combining the classical DCA with inexpensive exact line search by finding real roots of a binomial for acceleration. We demonstrated the equivalence between SQEiCP and SEiCP, and extended BDCA to SQEiCP. Numerical simulations of the proposed BDCA and DCA against KNITRO, FILTERED and MATLAB FMINCON for SEiCP and SQEiCP on both synthetic datasets and Matrix Market NEP Repository are reported. BDCA demonstrated dramatic acceleration to the convergence of DCA to get better numerical solutions, and outperformed KNITRO, FILTERED, and FMINCON solvers in terms of the average CPU time and average solution precision, especially for large-scale cases.Comment: 24 page

On the convergence analysis of DCA

In this paper, we propose a clean and general proof framework to establish the convergence analysis of the Difference-of-Convex (DC) programming algorithm (DCA) for both standard DC program and convex constrained DC program. We first discuss suitable assumptions for the well-definiteness of DCA. Then, we focus on the convergence analysis of DCA, in particular, the global convergence of the sequence $\{x^k\}$ generated by DCA under the Lojasiewicz subgradient inequality and the Kurdyka-Lojasiewicz property respectively. Moreover, the convergence rate for the sequences $\{f(x^k)\}$ and $\{\|x^k-x^*\|\}$ are also investigated. We hope that the proof framework presented in this article will be a useful tool to conveniently establish the convergence analysis for many variants of DCA and new DCA-type algorithms

Collisional unfolding of multiprotein complexes reveals cooperative stabilization upon ligand binding

Cooperative binding mechanisms are a common feature in biology, enabling a diverse range of protein‐based molecular machines to regulate activities ranging from oxygen uptake to cellular membrane transport. Much, however, is not known about such cooperative binding mechanisms, including how such events typically add to the overall stability of such protein systems. Measurements of such cooperative stabilization events are challenging, as they require the separation and resolution of individual protein complex bound states within a mixture of potential stoichiometries to individually assess protein stabilities. Here, we report ion mobility‐mass spectrometry results for the concanavalin A tetramer bound to a range of polysaccharide ligands. We use collision induced unfolding, a relatively new methodology that functions as a gas‐phase analog of calorimetry experiments in solution, to individually assess the stabilities of concanavalin A bound states. By comparing the differences in activation voltage required to unfold different concanavalin A–ligand stoichiometries, we find evidence suggesting a cooperative stabilization of concanavalin A occurs upon binding most carbohydrate ligands. We critically evaluate this observation by assessing a broad range of ligands, evaluating the unfolding properties of multiple protein charge states, and by comparing our gas‐phase results with those obtained from calorimetry experiments carried out in solution.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112216/1/pro2699.pd