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

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

TaylorAECNet: A Taylor Style Neural Network for Full-Band Echo Cancellation

This paper describes aecX team's entry to the ICASSP 2023 acoustic echo cancellation (AEC) challenge. Our system consists of an adaptive filter and a proposed full-band Taylor-style acoustic echo cancellation neural network (TaylorAECNet) as a post-filter. Specifically, we leverage the recent advances in Taylor expansion based decoupling-style interpretable speech enhancement and explore its feasibility in the AEC task. Our TaylorAECNet based approach achieves an overall mean opinion score (MOS) of 4.241, a word accuracy (WAcc) ratio of 0.767, and ranks 5th in the non-personalized track (track 1)

Dimensionality Reduction and Dynamical Mode Recognition of Circular Arrays of Flame Oscillators Using Deep Neural Network

Oscillatory combustion in aero engines and modern gas turbines often has significant adverse effects on their operation, and accurately recognizing various oscillation modes is the prerequisite for understanding and controlling combustion instability. However, the high-dimensional spatial-temporal data of a complex combustion system typically poses considerable challenges to the dynamical mode recognition. Based on a two-layer bidirectional long short-term memory variational autoencoder (Bi-LSTM-VAE) dimensionality reduction model and a two-dimensional Wasserstein distance-based classifier (WDC), this study proposes a promising method (Bi-LSTM-VAE-WDC) for recognizing dynamical modes in oscillatory combustion systems. Specifically, the Bi-LSTM-VAE dimension reduction model was introduced to reduce the high-dimensional spatial-temporal data of the combustion system to a low-dimensional phase space; Gaussian kernel density estimates (GKDE) were computed based on the distribution of phase points in a grid; two-dimensional WD values were calculated from the GKDE maps to recognize the oscillation modes. The time-series data used in this study were obtained from numerical simulations of circular arrays of laminar flame oscillators. The results show that the novel Bi-LSTM-VAE method can produce a non-overlapping distribution of phase points, indicating an effective unsupervised mode recognition and classification. Furthermore, the present method exhibits a more prominent performance than VAE and PCA (principal component analysis) for distinguishing dynamical modes in complex flame systems, implying its potential in studying turbulent combustion.Comment: research paper (18 pages, 1 table 10 figures) with supplementary material (8 pages, 1 table, 5 figures

Overexpression of OsRAN2 in rice and Arabidopsis renders transgenic plants hypersensitive to salinity and osmotic stress

Nucleo-cytoplasmic partitioning of regulatory proteins is increasingly being recognized as a major control mechanism for the regulation of signalling in plants. Ras-related nuclear protein (Ran) GTPase is required for regulating transport of proteins and RNA across the nuclear envelope and also has roles in mitotic spindle assembly and nuclear envelope (NE) assembly. However, thus far little is known of any Ran functions in the signalling pathways in plants in response to changing environmental stimuli. The OsRAN2 gene, which has high homology (77% at the amino acid level) with its human counterpart, was isolated here. Subcellular localization results showed that OsRan2 is mainly localized in the nucleus, with some in the cytoplasm. Transcription of OsRAN2 was reduced by salt, osmotic, and exogenous abscisic acid (ABA) treatments, as determined by real-time PCR. Overexpression of OsRAN2 in rice resulted in enhanced sensitivity to salinity, osmotic stress, and ABA. Seedlings of transgenic Arabidopsis thaliana plants overexpressing OsRAN2 were overly sensitive to salinity stress and exogenous ABA treatment. Furthermore, three ABA- or stress-responsive genes, AtNCED3, AtPLC1, and AtMYB2, encoding a key enzyme in ABA synthesis, a phospholipase C homologue, and a putative transcriptional factor, respectively, were shown to have differentially induced expression under salinity and ABA treatments in transgenic and wild-type Arabidopsis plants. OsRAN2 overexpression in tobacco epidermal leaf cells disturbed the nuclear import of a maize (Zea mays L.) leaf colour transcription factor (Lc). In addition, gene-silenced rice plants generated via RNA interference (RNAi) displayed pleiotropic developmental abnormalities and were male sterile