Correlation of Copper Interaction, Copper-Driven Aggregation, and Copper-Driven H2O2 Formation with Aβ40 Conformation

The neurotoxicity of Aβ is associated with the formation of free radical by interacting with redox active metals such as Cu2+. However, the relationship between ion-interaction, ion-driven free radical formation, and Aβ conformation remains to be further elucidated. In the present study, we investigated the correlation of Cu2+ interaction and Cu2+-driven free radical formation with Aβ40 conformation. The Cu2+-binding affinity for Aβ40 in random coiled form is 3-fold higher than that in stable helical form. Unexpectedly but interestingly, we demonstrate in the first time that the stable helical form of Aβ40 can induce the formation of H2O2 by interacting with Cu2+. On the other hand, the H2O2 generation is repressed at Aβ/Cu2+ molar ratio ≥1 when Aβ40 adopts random coiled structure. Taken together, our result demonstrates that Aβ40 adopted a helical structure that may play a key factor for the formation of free radical with Cu2+ ions

A Secure and Stable Multicast Overlay Network with Load Balancing for Scalable IPTV Services

The emerging multimedia Internet application IPTV over P2P network preserves significant advantages in scalability. IPTV media content delivered in P2P networks over public Internet still preserves the issues of privacy and intellectual property rights. In this paper, we use SIP protocol to construct a secure application-layer multicast overlay network for IPTV, called SIPTVMON. SIPTVMON can secure all the IPTV media delivery paths against eavesdroppers via elliptic-curve Diffie-Hellman (ECDH) key exchange on SIP signaling and AES encryption. Its load-balancing overlay tree is also optimized from peer heterogeneity and churn of peer joining and leaving to minimize both service degradation and latency. The performance results from large-scale simulations and experiments on different optimization criteria demonstrate SIPTVMON's cost effectiveness in quality of privacy protection, stability from user churn, and good perceptual quality of objective PSNR values for scalable IPTV services over Internet

Serum total antioxidant capacity reflects severity of illness in patients with severe sepsis

INTRODUCTION: We conducted the present study to evaluate the changes in serum total antioxidant capacity (TAC) in patients with severe sepsis and to investigate the association between serum TAC and clinical severity. METHOD: This was a prospective observational study involving a sample of patients who met established criteria for severe sepsis and were admitted to the emergency department of a university teaching hospital. Serum TAC was determined using the total radical-trapping antioxidant parameter method. The levels of TAC, uric acid, albumin, and bilirubin in sera were obtained in the emergency department and evaluated to determine whether there were any correlations between the major antioxidant biomarkers and clinical severity of sepsis. The Acute Physiology and Chronic Health Evaluation (APACHE) II score was used for clinical evaluation of the severity of sepsis. RESULTS: A total of 73 patients with sepsis, with a mean (± standard deviation) APACHE II score of 23.2 ± 8.2 and a mortality rate of 26.0%, were included. Seventy-six healthy individuals served as control individuals. Among the patients, serum TAC levels correlated significantly with APACHE II scores. Patients who died also had higher TAC than did those who survived. Serum uric acid levels correlated significantly with serum TAC and APACHE II scores in patients with severe sepsis. CONCLUSION: Elevated serum TAC level may reflect clinical severity of sepsis. In addition, serum uric acid levels appear to contribute importantly to the higher TAC levels observed in patients with severe sepsis

Differential Presentations of Arterial Thromboembolic Events Between Venous Thromboembolism and Atrial Fibrillation Patients

Objective: Atrial fibrillation (AF) and venous thromboembolism (VTE) share several risk factors related to arterial thromboembolism. No study has reported the differential contribution to arterial thromboembolic events and mortality between these two conditions in the same population. We therefore assessed the differential arterial thromboembolic events between AF and VTE. Methods: We included AF and VTE national cohorts derived from Taiwan National Health Insurance Research Database between 2001 and 2013. The eligible population was 314,861 patients in the AF cohort and 41,102 patients in the VTE cohort. The primary outcome was arterial thromboembolic events, including ischemic stroke, extracranial arterial thromboembolism (ECATE) and myocardial infarction (MI). Secondary outcomes were all-cause mortality and cardiovascular death. Results: After a 1:1 propensity matching, 32,688 patients in either group were analyzed. The risk of arterial thromboembolic events was lower in the VTE cohort than that in the AF cohort (subdistribution hazard ratio [SHR], 0.60; 95% confidence interval [CI], 0.57–0.62). The risk of ischemic stroke (SHR, 0.44; 95% CI, 0.42–0.46) and MI (SHR, 0.80; 95% CI, 0.72–0.89) were lower in the VTE cohort, while the risk of ECATE (SHR, 1.23; 95% CI, 1.14–1.33; particularly lower extremities) was higher in the VTE cohort. All-cause mortality rate was higher in the VTE cohort (HR, 1.18; 95% CI, 1.15–1.21) while the risk of cardiovascular death was lower in the VTE cohort (HR, 0.96; 95% CI, 0.93–0.995). Conclusions: Patients with AF had higher risks of arterial thromboembolic events compared to patients with VTE, despite having risk factors in common. The VTE cohort had higher risks of all-cause mortality and ECATE, particularly lower extremity events, compared to AF patients. The differential manifestations of thromboembolism sequelae and mortality between AF and VTE patients merit further investigation

Tumor-Associated Macrophage-Induced Invasion and Angiogenesis of Human Basal Cell Carcinoma Cells by Cyclooxygenase-2 Induction

Tumor-associated macrophages (TAMs) and cyclooxygenase-2 (COX-2) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human basal cell carcinoma (BCC) remains elusive. We found that the number of TAMs infiltrating the tumor is correlated with the depth of invasion, microvessel density, and COX-2 expression in human BCC cells. TAMs also aggregate near COX-2 expressing BCC tumor nests. We hypothesize that TAMs might activate COX-2 in BCC cells and subsequently increase their invasion and angiogenesis. TAMs are a kind of M2 macrophage derived from macrophages exposed to Th2 cytokines. M2-polarized macrophages derived from peripheral blood monocytes were cocultured with BCC cells without direct contact. Coculture with the M2 macrophages induced COX-2-dependent invasion and angiogenesis of BCC cells. Human THP-1 cell line cells, after treated with phorbol myristate acetate (PMA), differentiated to macrophages with M2 functional profiles. Coculture with PMA-treated THP-1 macrophages induced COX-2-dependent release of matrix metalloproteinase-9 and subsequent increased invasion of BCC cells. Macrophages also induced COX-2-dependent secretion of basic fibroblast growth factor and vascular endothelial growth factor-A, and increased angiogenesis in BCC cells

Mortality associated with the use of non-vitamin K antagonist oral anticoagulants in cancer patients:Dabigatran versus rivaroxaban

Abstract Objective This study assesses the mortality outcomes of non‐vitamin K antagonist oral anticoagulants (NOACs) in cancer patients with venous thromboembolism (VTE) and atrial fibrillation (AF). Methods Medical records of cancer patients receiving NOACs for VTE or AF between January 1, 2011, and December 31, 2016, were retrieved from Taiwan's National Health Institute Research Database. NOACs were compared using the inverse probability of treatment weighting (IPTW) method. The primary outcome was cancer‐related death. Secondary outcomes were all‐cause mortality, major bleeding, and gastrointestinal (GI) bleeding. Results Among 202,754 patients who received anticoagulants, 3591 patients (dabigatran: 907; rivaroxaban: 2684) with active cancers were studied. Patients who received dabigatran were associated with lower risks of cancer‐related death at one year (HR = 0.71, 95% CI = 0.54–0.93) and at the end of follow‐ups (HR = 0.79, 95% CI = 0.64–0.98) compared with rivaroxaban. Patients who received dabigatran were also associated with lower risks of all‐cause mortality (HR = 0.81, 95% CI = 0.67–0.97), major bleeding (HR = 0.64, 95% CI = 0.47–0.88), and GI bleeding (HR = 0.57, 95% CI = 0.39–0.84) at the end of follow‐ups compared with rivaroxaban. Conclusion Compared with rivaroxaban, the use of dabigatran may be associated with a lower risk of cancer‐related death and all‐cause mortality

Fibrate and the risk of cardiovascular disease among moderate chronic kidney disease patients with primary hypertriglyceridemia

IntroductionHypertriglyceridemia is the most prevalent dyslipidemia in patients with chronic kidney disease (CKD). However, research about fibrate treatment in CKD patients is limited, and assessing its benefits becomes challenging due to the frequent concurrent use of statins. Thus, this study is aimed to investigate the role of fibrate in CKD stage 3 patients with hypertriglyceridemia who did not receive other lipid-lowering agents.MethodsThis study enrolled patients newly diagnosed CKD3 with LDL-C<100mg/dL and had never received statin or other lipid-lowering agents from Chang Gung Research Database. The participants were categorized into 2 groups based on the use of fibrate: fibrate group and non-fibrate group (triglyceride >200mg/dL but not receiving fibrate treatment). The inverse probability of treatment weighting was performed to balance baseline characteristics.ResultsCompared with the non-fibrate group (n=2020), the fibrate group (n=705) exhibited significantly lower risks of major adverse cardiac and cerebrovascular events (MACCEs) (10.4% vs. 12.8%, hazard ratios [HRs]: 0.69, 95% confidence interval [CI]: 0.50 to 0.95), AMI (2.3% vs. 3.9%, HR: 0.52, 95% CI: 0.37 to 0.73), and ischemic stroke (6.3% vs. 8.0%, HR: 0.67, 95% CI: 0.52 to 0.85). The risk of all-cause mortality (5.1% vs. 4.5%, HR: 1.09, 95% CI: 0.67 to 1.79) and death from CV (2.8% vs. 2.3%, HR: 1.07, 95% CI: 0.29 to 2.33) did not significantly differ between the 2 groups.ConclusionThis study suggests that, in moderate CKD patients with hypertriglyceridemia but LDL-C < 100mg/dL who did not take other lipid-lowering agents, fibrates may be beneficial in reducing cardiovascular events

The Adhesion G Protein-Coupled Receptor GPR97/ADGRG3 Is Expressed in Human Granulocytes and Triggers Antimicrobial Effector Functions

The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in human, several of which are distinctly expressed and functionally involved in polymorphonuclear cells (PMNs). As former work indicated the possible presence of the aGPCR GPR97 in granulocytes, we studied its cellular distribution, molecular structure, signal transduction, and biological function in PMNs. RNA sequencing and mass-spectrometry revealed abundant RNA and protein expression of ADGRG3/GPR97 in granulocyte precursors and terminally differentiated neutrophilic, eosinophilic, and basophilic granulocytes. Using a newly generated GPR97-specific monoclonal antibody, we confirmed that endogenous GPR97 is a proteolytically processed, dichotomous, N-glycosylated receptor. GPR97 was detected in tissue-infiltrating PMNs and upregulated during systemic inflammation. Antibody ligation of GPR97 increased neutrophil reactive oxygen species production and proteolytic enzyme activity, which is accompanied by an increase in mitogen-activated protein kinases and IκBα phosphorylation. In-depth analysis of the GPR97 signaling cascade revealed a possible switch from basal Gαs/cAMP-mediated signal transduction to a Gαi-induced reduction in cAMP levels upon mutation-induced activation of the receptor, in combination with an increase in downstream effectors of Gβγ, such as SRE and NF-κB. Finally, ligation of GPR97 increased the bacteria uptake and killing activity of neutrophils. We conclude that the specific presence of GPR97 regulates antimicrobial activity in human granulocytes

KinasePhos 2.0: a web server for identifying protein kinase-specific phosphorylation sites based on sequences and coupling patterns

Due to the importance of protein phosphorylation in cellular control, many researches are undertaken to predict the kinase-specific phosphorylation sites. Referred to our previous work, KinasePhos 1.0, incorporated profile hidden Markov model (HMM) with flanking residues of the kinase-specific phosphorylation sites. Herein, a new web server, KinasePhos 2.0, incorporates support vector machines (SVM) with the protein sequence profile and protein coupling pattern, which is a novel feature used for identifying phosphorylation sites. The coupling pattern [XdZ] denotes the amino acid coupling-pattern of amino acid types X and Z that are separated by d amino acids. The differences or quotients of coupling strength CXdZ between the positive set of phosphorylation sites and the background set of whole protein sequences from Swiss-Prot are computed to determine the number of coupling patterns for training SVM models. After the evaluation based on k-fold cross-validation and Jackknife cross-validation, the average predictive accuracy of phosphorylated serine, threonine, tyrosine and histidine are 90, 93, 88 and 93%, respectively. KinasePhos 2.0 performs better than other tools previously developed. The proposed web server is freely available at http://KinasePhos2.mbc.nctu.edu.tw/

The Yuan-Tseh Lee Array for Microwave Background Anisotropy

The Yuan-Tseh Lee Array for Microwave Background Anisotropy (AMiBA) is the first interferometer dedicated to studying the cosmic microwave background (CMB) radiation at 3mm wavelength. The choice of 3mm was made to minimize the contributions from foreground synchrotron radiation and Galactic dust emission. The initial configuration of seven 0.6m telescopes mounted on a 6-m hexapod platform was dedicated in October 2006 on Mauna Loa, Hawaii. Scientific operations began with the detection of a number of clusters of galaxies via the thermal Sunyaev-Zel'dovich effect. We compare our data with Subaru weak lensing data in order to study the structure of dark matter. We also compare our data with X-ray data in order to derive the Hubble constant.Comment: accepted for publication in ApJ (13 pages, 7 figures); a version with high resolution figures available at http://www.asiaa.sinica.edu.tw/~keiichi/upfiles/AMiBA7/pho_highreso.pd