Synthesis of quinoline-fatty acid conjugates and characterization of their immunomodulatory properties

The anti-malarial chloroquine (CQ) and derivatives are useful anti-inflammatory agents which have been useful in treating patients with rheumatoid arthritis and systemic lupus erythromytosus. Nevertheless derivatives of CQ, such as hydroxychloroquine (HCQ) have been made to reduce the toxicity and increase the potency of the drug. We have approached this challenge by synthesizing 13 quinoline based compounds bearing a saturated or un-saturated fatty acid side chain (carbon chain length of 3 to 20). Examination of their immunomodulatory properties in vitro at concentrations up to 50μM showed these compounds to have no effect on phytohaemagglutinin- and antigen, tetanus toxoid- induced human lymphocyte proliferation and interferon-γ, interleukin(IL)-2, IL-10 and lymphotoxin production. Similarly, there was no effect on the responses induced by the B cell mitogen, Staphylococcus aureus. In contrast, at the same concentrations, CQ significantly inhibited lymphoproliferation and cytokine production induced by these agents. Using bacterial lipopolyssacharide (LPS) as a stimulus for monocytes in the peripheral blood mononuclear fraction, we found that cytokine production, tumour necrosis factor alpha (TNFα), IL-1β and IL-6 was inhibited by CQ but not the NT compounds. In contrast the data demonstrated that a number of the NT compounds were effective in inhibiting human neutrophil adherence induced by TNF. However, this activity was not related to either the carbon chain length or their saturated versus un-saturated state of the fatty acid side chain. In comparison, both CQ and HCQ had no effect on this response. The compound NT8 which had lauric acid on the side chain of the quinoline structure was the most active. Further studies with this compound revealed that it was particularly effective in inhibiting TNF-induced neutrophil cytokine (IL-1β and IL-8) production but not TNF-induced neutrophil migration inhibition or TNF-induced respiratory burst. CQ and HCQ had no effect on all of these responses. At the lower concentrations of NT8 which significantly inhibited neutrophil adherence and cytokine production, the compound had no effect on adherence induced by phorbol 12-myristate 13-acetate (PMA) and calcium ionophore (A23187). These agents are known to by-pass the surface receptors and act on protein kinase C and cause an increase in intracellular calcium levels respectively, suggesting that the effects of NT8 are upstream in the signalling cascade. Interestingly we found that NT8 caused a significant decrease in surface expression of TNF receptor II (TNFRII) but not TNFRI. This selective effect of NT8 on neutrophil functions such as adherence was lost with an increase in concentration, where the neutrophil responses to the agonists, complement fragment C5a, IL-8, granulocyte macrophage-colony stimulating factor, formyl-Met-Leu-Phe, PMA, A23187 and arachidonic acid were also inhibited. A similar selectivity was seen for neutrophil responses to leukotriene B4. The anti-inflammatory effects of NT8 were confirmed in vivo in a mouse model of LPS-induced peritonitis, where both TNF and neutrophils play an important role. The research in this thesis has enabled the development and characterization of a new class of quinoline based compounds with anti-inflammation properties distinguishable from those of CQ and HCQ, thus, providing a new avenue for the development of anti-inflammatory agents.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

A Point Cloud Alignment Algorithm Based on Stereo Vision Using Random Pattern Projection

This paper proposes a point cloud alignment algorithm based on stereo vision using Random Pattern Projection (RPP). In the application of stereo vision, it is rather difficult to find correspondences between stereo images of texture-less objects. To overcome this issue, RPP is used to enhance the object’s features, thus increasing the accuracy of the identified correspondences of the stereo images. In the 3D alignment algorithm, the down sample technique is used to filter out the outliers of the point cloud data to improve system efficiency. Furthermore, the extracted features of the down sample point cloud data were applied in the matching process. Finally, the object’s pose was estimated by the alignment algorithm based on object features. In experiments, the maximum error and standard deviation of rotation are respectively about 0.031°and 0.199°, while the maximum error and standard deviation of translation are respectively about 0.565 mm and 0.902 mm . The execution time for pose estimation is about 230ms

CFEVER: A Chinese Fact Extraction and VERification Dataset

We present CFEVER, a Chinese dataset designed for Fact Extraction and VERification. CFEVER comprises 30,012 manually created claims based on content in Chinese Wikipedia. Each claim in CFEVER is labeled as "Supports", "Refutes", or "Not Enough Info" to depict its degree of factualness. Similar to the FEVER dataset, claims in the "Supports" and "Refutes" categories are also annotated with corresponding evidence sentences sourced from single or multiple pages in Chinese Wikipedia. Our labeled dataset holds a Fleiss' kappa value of 0.7934 for five-way inter-annotator agreement. In addition, through the experiments with the state-of-the-art approaches developed on the FEVER dataset and a simple baseline for CFEVER, we demonstrate that our dataset is a new rigorous benchmark for factual extraction and verification, which can be further used for developing automated systems to alleviate human fact-checking efforts. CFEVER is available at https://ikmlab.github.io/CFEVER.Comment: AAAI-2

Identifying early decline of daily function and its association with physical function in chronic kidney disease: performance-based and self-reported measures

Objective To verify self-reported basic and instrumental activities of daily living (IADL) with a disability and the results of performance-based tests (namely the Taiwan performance-based IADL (TPIADL), the 2-minute step test (2MST), the 30-second chair-stand test (30-s CST), and handgrip dynamometer measurement) to identify disability early and assess the associations with functional fitness in patients with advanced chronic kidney disease (CKD). Methods A cross-sectional study of 99 patients with stage 4–5 CKD and 57 healthy elderly adults were recruited. Self-reported measures were used to collect information on basic (Barthel Index) and IADL (Lawton–Brody scale). Objective measures of the TPIADL and functional fitness (2MST, 30-s CST, handgrip dynamometer) were also assessed. Results Only IADL, as detected by the TPIADL, were impaired to a greater extent in the CKD patients than those of healthy elderly adults. Among all the patients with CKD, a greater impairment in the TPIADL remained statistically associated with a lower ability in the 2MST. A one step increase in the 2MST score was significantly associated with an improvement of 0.2 s in the total performance time of the TPIADL. Conclusion Performance-based measures, such as the TPIADL, may detect a functional limitation before it becomes measurable by traditional self-reported basic and IADL scales; functional limitation is mainly associated with cardiac endurance for advanced CKD

Therapeutic Effect of Yi-Chi-Tsung-Ming-Tang on Amyloid β

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by amyloid accumulation, neuronal death, and cognitive impairments. Yi-Chi-Tsung-Ming-Tang (YCTMT) is a traditional Chinese medicine and has never been used to enhance cognitive function and treat neurodegenerative disorders such as senile dementia. Whether YCTMT has a beneficial role in improving learning and memory in AD patients remains unclear. The present study showed that oral administration of YCTMT ameliorated amyloid-β- (Aβ1−40) injection-induced learning and memory impairments in rats, examined using passive avoidance and Morris water-maze tests. Immunostaining and Western Blot results showed that continuous Aβ1−40 infusion caused amyloid accumulation and decreased acetylcholine level in hippocampus. Oral administration of medium and high dose of YCTMT 7 days after the Aβ1−40 infusion decreased amyloid accumulation area and reversed acetylcholine decline in the Aβ1−40-injected hippocampus, suggesting that YCTMT might inhibit Aβ plague accumulation and rescue reduced acetylcholine expression. This study has provided evidence on the beneficial role of YCTMT in ameliorating amyloid-induced AD-like symptom, indicating that YCTMT may offer an alternative strategy for treating AD

Detection of the inferred interaction network in hepatocellular carcinoma from EHCO (Encyclopedia of Hepatocellular Carcinoma genes Online)

BACKGROUND: The significant advances in microarray and proteomics analyses have resulted in an exponential increase in potential new targets and have promised to shed light on the identification of disease markers and cellular pathways. We aim to collect and decipher the HCC-related genes at the systems level. RESULTS: Here, we build an integrative platform, the Encyclopedia of Hepatocellular Carcinoma genes Online, dubbed EHCO , to systematically collect, organize and compare the pileup of unsorted HCC-related studies by using natural language processing and softbots. Among the eight gene set collections, ranging across PubMed, SAGE, microarray, and proteomics data, there are 2,906 genes in total; however, more than 77% genes are only included once, suggesting that tremendous efforts need to be exerted to characterize the relationship between HCC and these genes. Of these HCC inventories, protein binding represents the largest proportion (~25%) from Gene Ontology analysis. In fact, many differentially expressed gene sets in EHCO could form interaction networks (e.g. HBV-associated HCC network) by using available human protein-protein interaction datasets. To further highlight the potential new targets in the inferred network from EHCO, we combine comparative genomics and interactomics approaches to analyze 120 evolutionary conserved and overexpressed genes in HCC. 47 out of 120 queries can form a highly interactive network with 18 queries serving as hubs. CONCLUSION: This architectural map may represent the first step toward the attempt to decipher the hepatocarcinogenesis at the systems level. Targeting hubs and/or disruption of the network formation might reveal novel strategy for HCC treatment

Women Under Kuomintang R ule Variations on the Feminine Mystique

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68360/2/10.1177_009770047500100101.pd

Women's preference for cesarean delivery and differences between Taiwanese women undergoing different modes of delivery

<p>Abstract</p> <p>Background</p> <p>The rate of cesarean delivery was 35% in 2007 in Taiwan. It is unclear how many of the cesarean deliveries were without medical indications. Women's preference for cesarean delivery during their course of pregnancy has rarely been studied and therefore our objectives were to examine rate of cesarean deliveries without medical indications, to explore women's preference for cesarean delivery as their gestation advances, and to compare background and perinatal factors among women who underwent different modes of delivery in Taiwan.</p> <p>Methods</p> <p>This prospective study applied a longitudinal design. The study participants were 473 women who received prenatal care at four hospitals in Taipei and answered structured questionnaires at 20 to 24 weeks of pregnancy, 34 to 36 weeks of pregnancy, and 5 to 7 weeks after delivery.</p> <p>Results</p> <p>Of the 151 women (31.9%) who had cesarean deliveries, 19.9% were without medical indication. Three indications: malpresentation, prior cesarean section, and dysfunctional labor together accounted for 82.6% of cesarean section with medical indications. The prevalence of maternal preference for cesarean delivery was found to be 12.5% and 17.5% during the second and third trimester, respectively. Of the women who preferred cesarean delivery during the second trimester, 93.2% eventually had a cesarean delivery. Women who were older, with older spouses, and who had health problems before or during pregnancy were more likely to have cesarean deliveries.</p> <p>Conclusions</p> <p>About 20% of cesarean deliveries were without medical indications. Women's preference for cesarean delivery during the second trimester predicts subsequent cesarean delivery. Counseling regarding mode of delivery should be offered early in pregnancy, especially for women who are older or with older spouses, have health problems, or had a prior cesarean section.</p