The E3 ubiquitin ligase c-IAP1 regulates PCSK9-mediated LDLR degradation: Linking the TNF-α pathway to cholesterol uptake

Proprotein convertase subtilisin/kexin type 9 (PCSK9), in addition to LDLR (low-density lipoprotein receptor) and APOB (apolipoprotein B), is one of three loci implicated in autosomal dominant hypercholesterolaemia (ADH)^1^. A number of PCSK9 gain-of-function mutations and loss-of-function mutations have been identified from families afflicted with ADH with hypercholesterolaemia or hypocholesterolaemia, respectively^1-4^. In humans, the main function of PCSK9 appears to be the post-transcriptional regulation of the number of cell-surface LDL receptors^5-7^. To date, only LDLR and its closest family members VLDLR and ApoER2 have been shown to bind with PCSK9^8,9^. To find new binding partners for PCSK9, we used a shotgun proteomic method to analyse the protein complex pulled down by immunoprecipitation against FLAG-tagged PCSK9 protein. Among 22 potential novel binding proteins identified, we found that the cellular inhibitor of apoptosis protein 1 (c-IAP1^10^) and the TNF receptor-associated factor 2 (TRAF2^11^) complex are regulated differently in different dominant PCSK9 mutations that occur naturally. Further immunoprecipitation analysis showed that c-IAP1 is a direct binding partner for PCSK9. One of the "gain-of-function" mutants, PCSK9-S127R, which has impaired autocatalytic activity, is defective in binding to c-IAP1. The other dominant mutation, PCSK9-D374Y^12^, which is 10-fold more potent in degrading the LDLR protein than wild-type PCSK9, can be significantly ubiquitinated by c-IAP1 in vitro. The ubiquitinated PCSK9-D374Y is unable to degrade LDLR, which is its main cause of hypercholesterolaemia in patients. These results indicate that there is a novel cholesterol uptake regulation pathway linking PCSK9/LDLR to the E3 ubiquitin ligase c-IAP1 in a TNF-[alpha] response pathway. This highlights the possibility of developing new treatments for human cardiovascular diseases through ubiquitin ligase-mediated ubiquitination of target proteins in cholesterol metabolism

Dynamic Analysis Of Turbine-generator-foundation Systems

In this dissertation a comprehensive investigation on the dynamic characteristics of turbine-generator-foundation systems is performed. All the major components of the system, including turbine-generator casing, shaft, rotors, journal bearings, deck, piers, foundation mat, piles, and soil medium, have been included. Full interaction between the turbine-generator set, the foundation superstructure, and the soil medium, is considered.;A hybrid method is proposed to establish the mathematical model for the turbine-generator-foundation system, which includes finite element discretization of turbine-generator and foundation superstructure, combined with a soil stiffness matrix derived from the dynamic Green functions of the soil. The soil is modeled as a transversely isotropic layered medium over a rigid bedrock. The analysis is conducted in frequency domain through complex frequency response analysis. The response in time domain is obtained by Fourier transform. The seismic excitation is represented as the control motion on the ground surface, which is generated as an artificial earthquake. Both inertial and kinematic interactions are included.;Several computer programs, including a general purpose finite element program, a program to formulate soil stiffness matrices, and a program to generate artificial earthquake ground motion records, have been written by the author, which can be used to analyze most soil-structure interaction problems, such as machine foundations, buildings, piles and pile groups, tunnels, and dams. A series of parametric studies on strip foundations, single piles, pile groups, and three-dimensional mat foundations is presented to demonstrate these applications. Particular attention is paid to the effect of soil anisotropy on the structural response. The effect of soil anisotropy on the foundation response is found to be significant in most cases.;A 300MW turbine-generator-foundation system is analyzed as an application of the developed mathematical model and computer codes. Excitations from rotor unbalances and earthquakes are considered. The influence of turbine-generator casing and soil anisotropy on the response of the system is explored. It is found that the presence of casing and soil anisotropy strongly influences the displacements and internal forces of the system under rotor unbalance excitation. Under seismic excitation, however, although the presence of casing and soil anisotropy does affect the displacements of the system, their effect on the internal forces of the system is minimal

Reasoning about Cardinal Directions between Extended Objects

Direction relations between extended spatial objects are important commonsense knowledge. Recently, Goyal and Egenhofer proposed a formal model, known as Cardinal Direction Calculus (CDC), for representing direction relations between connected plane regions. CDC is perhaps the most expressive qualitative calculus for directional information, and has attracted increasing interest from areas such as artificial intelligence, geographical information science, and image retrieval. Given a network of CDC constraints, the consistency problem is deciding if the network is realizable by connected regions in the real plane. This paper provides a cubic algorithm for checking consistency of basic CDC constraint networks, and proves that reasoning with CDC is in general an NP-Complete problem. For a consistent network of basic CDC constraints, our algorithm also returns a 'canonical' solution in cubic time. This cubic algorithm is also adapted to cope with cardinal directions between possibly disconnected regions, in which case currently the best algorithm is of time complexity O(n^5)

Unified Gas-kinetic Wave-Particle Methods III: Multiscale Photon Transport

In this paper, we extend the unified gas-kinetic wave-particle (UGKWP) method to the multiscale photon transport. In this method, the photon free streaming and scattering processes are treated in an un-splitting way. The duality descriptions, namely the simulation particle and distribution function, are utilized to describe the photon. By accurately recovering the governing equations of the unified gas-kinetic scheme (UGKS), the UGKWP preserves the multiscale dynamics of photon transport from optically thin to optically thick regime. In the optically thin regime, the UGKWP becomes a Monte Carlo type particle tracking method, while in the optically thick regime, the UGKWP becomes a diffusion equation solver. The local photon dynamics of the UGKWP, as well as the proportion of wave-described and particle-described photons are automatically adapted according to the numerical resolution and transport regime. Compared to the $S_n$ -type UGKS, the UGKWP requires less memory cost and does not suffer ray effect. Compared to the implicit Monte Carlo (IMC) method, the statistical noise of UGKWP is greatly reduced and computational efficiency is significantly improved in the optically thick regime. Several numerical examples covering all transport regimes from the optically thin to optically thick are computed to validate the accuracy and efficiency of the UGKWP method. In comparison to the $S_n$ -type UGKS and IMC method, the UGKWP method may have several-order-of-magnitude reduction in computational cost and memory requirement in solving some multsicale transport problems.Comment: 27 pages, 15 figures. arXiv admin note: text overlap with arXiv:1810.0598