Since Flood and Garber (1980), the debate surrounding speculative bubbles has never subsided. A key obstacle to resolve this issue is the identification problem. A bubble is usually inferred from some assumed fundamental determinants of a price. These assumptions could be over-simplified. Furthermore, there might be data measurement errors. In this paper, we attempt to capture such errors with a latent state variable. This variable is extracted with Kalman filter. Based on our empirical comparisons, we find that it is possible to attribute the observed large price swings in the property market of Hong Kong during the 1980s and 1990s to a periodically collapsing rational speculative bubble.
Graph neural networks (GNNs) have accomplished great success in learning complex systems of relations arising in broad problem settings ranging from e-commerce, social networks to data management. Training GNNs over large-scale graphs poses challenges for constrained compute resources due to the heavy data dependencies between the nodes. Moreover, modern relational data is constantly evolving, which creates an additional layer of learning challenges with respect to the model scalability and expressivity. This paper introduces a simple and efficient learning algorithm for large discrete-time dynamic graphs (DTDGs) – a widely adopted data model for many applications. We particularly tackle two critical challenges: (1) how the model can be efficiently trained on large-scale DTDGs to exploit hardware accelerators with small memory footprint, and (2) how the model can effectively capture the changing dynamics of the graphs. To the best of our knowledge, existing GNNs fail to address both challenges in their models. Hence, we propose a scalable evolving inception GNN, called SEIGN. Specifically, SEIGN features two connected evolving components that adapt the graph model to the arriving snapshot and capture the changing dynamics of the node embeddings, respectively. To scale up the model training, SEIGN introduces a parameter-free message passing step for DTDGs to substantially remove the data dependencies in training. Furthermore, it significantly reduces the training memory footprint and allows us to construct a succinct graph mini-batch without performing neighborhood sampling. We further optimize the proposed evolving strategies by extracting features from neighbors at varying scales to increase the expressive power of the node representations. Our experimental evaluation, on both public benchmark and real industrial datasets, demonstrates that SEIGN achieves 2%–20% improvement in Area Under Curve (AUC) and Average Precision (AP) on the prediction task over the state-of-the-art baselines. SEIGN also supports efficient graph mini-batch training and gains 2–16 times speedup in epoch computation time over the entire DTDGs.
Supplementary Data from Phase I Trial of a Novel Anti-HER2 Antibody–Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer
Supplementary Data from Phase I Trial of a Novel Anti-HER2 Antibody–Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder that typically presents with early-onset cognitive decline or personality change. The disease is associated with heterozygous mutations in the colony stimulating factor-1 receptor (CSF1R) gene. CSF1R activation regulates microglial survival, proliferation and differentiation. The different gene mutations may be related to the various clinical phenotypes. Here, we described comprehensive clinical, neuroimaging, neuropathological and genetic analyses of a family with HDLS. A novel splicing mutation in intron 13 (c.1858+1G>T) of CSF1R was found in this family. It is located at the splice site of intron 13, resulting in a splice donor site leading to exon 13 skipping from the CSF1R mRNA. The mother and two elderly siblings of the proband had the same CSF1R mutation as the proband but showed very mild neuroimaging abnormalities and mild memory loss, which did not affect daily life, indicating very uneven penetrance and distinctly different disease progression among family members. This report provides diverse neuroimaging and clinical characteristics of a novel CSF1R mutation with different disease penetrance. The large clinical heterogeneity in the same family who all had the same mutation indicates that modifying genes and environmental factors may play a role in the pathogenesis of HDLS.
The beta amyloid (Abeta) cascade has been at the forefront of the hypothesis used to describe the pathogenesis of Alzheimer's disease (AD). It is generally accepted that drugs that can regulate the processing of the amyloid precursor protein (APP) toward the non-amyloidogenic pathway may have a therapeutic potential. Previous studies have shown that protein kinase C (PKC) hypofunction has an important role in AD pathophysiology. Therefore, the effects of a new PKC activator, alpha-APP modulator [(2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB)], on APP processing were investigated. Using PC12 cells and SH-SY5Y(APP695) cells, it was found that TPPB promoted the secretion of sAPPalpha without affecting full-length expression of APP. The increase in sAPPalpha by TPPB was blocked by inhibitors of PKC, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and tyrosine kinase, suggesting the involvement of these signal transduction pathways. TPPB increased alpha-secretase activity [a disintegrin and metalloproteinase (ADAM)10 and 17], as shown by direct fluorescence activity detection and Western blot analysis. TPPB-induced sAPPalpha release was blocked by the metalloproteinase inhibitor TAPI-2, furin inhibitor CMK and by the protein-trafficking inhibitor brefeldin. The results also showed that TPPB decreased beta-secretase activity, Abeta40 release and beta site APP-cleaving enzyme 1 (BACE1) expression, but did not significantly affect neprilysin (NEP) and insulin-degrading enzyme (IDE) expression. Our data indicate that TPPB could direct APP processing towards the non-amyloidogenic pathway by increasing alpha-secretase activity, and suggest its therapeutic potential in AD.
The most common inherited form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motoneurons, is caused by dominant mutations in the ubiquitously expressed Cu 2+ /Zn 2+ superoxide dismutase (SOD1). Recent studies suggest that glia may contribute to motoneuron injury in animal models of familial ALS. To determine whether the expression of mutant SOD1 (mSOD1 G93A ) in CNS microglia contributes to motoneuron injury, PU.1 −/− mice that are unable to develop myeloid and lymphoid cells received bone marrow transplants resulting in donor-derived microglia. Donor-derived microglia from mice overexpressing mSOD1 G93A , an animal model of familial ALS, transplanted into PU.1 −/− mice could not induce weakness, motoneuron injury, or an ALS-like disease. To determine whether expression of mSOD1 G93A in motoneurons and astroglia, as well as microglia, was required to produce motoneuron disease, PU.1 −/− mice were bred with mSOD1 G93A mice. In mSOD1 G93A /PU.1 −/− mice, wild-type donor-derived microglia slowed motoneuron loss and prolonged disease duration and survival when compared with mice receiving mSOD1 G93A expressing cells or mSOD1 G93A mice. In vitro studies confirmed that wild-type microglia were less neurotoxic than similarly cultured mSOD1 G93A microglia. Compared with wild-type microglia, mSOD1 G93A microglia produced and released more superoxide and nitrite+nitrate, and induced more neuronal death. These data demonstrate that the expression of mSOD1 G93A results in activated and neurotoxic microglia, and suggests that the lack of mSOD1 G93A expression in microglia may contribute to motoneuron protection. This study confirms the importance of microglia as a double-edged sword, and focuses on the importance of targeting microglia to minimize cytotoxicity and maximize neuroprotection in neurodegenerative diseases.
Determination of myriocin-like long-chain bases (MLBs) is important for physiological and pharmacological studies of Cordyceps. Herein, a simple and sensitive reversed-phase liquid chromatographic method, based on the pre-column derivatization with O-phthalaldehyde, was developed for the simultaneous determination of four MLBs, namely myriocin, phytosphingosine, sphingosine and sphinganine in Cordyceps. The chromatographic and derivatization conditions were intensively optimized, and the structures of the derivatives were confirmed by mass spectra. The developed method was applied for the analysis of four MLBs in C. sinensis, C. militaris, C. cicadae and C. gunnii and cultured C. cicadae, which also could be used for the fast determination of the MLBs in pharmaceutical products and biological fluids.
The eradication of chronic hepatitis B (CHB) caused by hepatitis B virus (HBV) infection is a crucial goal in clinical practice. Enhancing the anti-HBV activity of interferon type I (IFNI) is a key strategy for achieving a functional cure for CHB. In this study, we investigated the effect of combined treatment with IFNα and Desmethoxycurcumin (DMC) on HBV replication in HepG2 cells and explored the underlying mechanism. Our results indicated IFNα alone was ineffective in completely inhibiting HBV replication, which was attributed to the virus-induced down-regulation of IFNI receptor 1 (IFNAR1) protein. However, the addition of a low dose of DMC significantly synergized with IFNα, leading to notable enhancement of IFNα anti-HBV activity. This effect was achieved by stabilising the IFNAR1 protein. Further investigation revealed that low dose DMC effectively blocked the ubiquitination-mediated degradation of IFNAR1, which was accomplished by rescuing the protein levels of alphaB-crystallin (CRYAB) and orchestrating the interaction between CRYAB and the E3 ubiquitin ligase, β-Trcp. Importantly, over-expression of CRYAB was found to favour the antiviral activity of IFNα against HBV replication. In conclusion, our study demonstrates that low-dose DMC enhanced the anti-HBV activity of IFNα by counteracting the reduction of CRYAB and stabilising the IFNAR1 protein.
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