Comparative analysis of heparin affecting the biochemical properties of chicken and murine prion proteins.

The conversion of cellular prion protein (PrPC) to disease-provoking conformer (PrPSc) is crucial in the pathogenesis of prion diseases. Heparin has been shown to enhance mammalian prion protein misfolding. As spontaneous prion disease has not been reported in non-mammalian species, such as chicken, it is interesting to explore the influence of heparin on the conversion of chicken prion protein (ChPrP). Herein, we investigated the influences of heparin on biochemical properties of full-length recombinant ChPrP, with murine prion protein (MoPrP) as control. The results showed that at low heparin concentration (10 µg/mL), a great loss of solubility was observed for both MoPrP and ChPrP using solubility assays. In contrast, when the concentration of heparin was high (30 µg/mL), the solubility of MoPrP and ChPrP both decreased slightly. Using circular dichroism, PK digestion and transmission electron microscopy, significantly increased ß-sheet content, PK resistance and size of aggregates were observed for MoPrP interacted with 30 µg/mL heparin, whereas 30 µg/mL heparin-treated ChPrP showed less PK resistance and slight increase of ß-sheet structure. Therefore, heparin can induce conformational changes in both MoPrP and ChPrP and the biochemical properties of the aggregates induced by heparin could be modified by heparin concentration. These results highlight the importance of concentration of cofactors affecting PrP misfolding.

Different effects of lipid on conformational conversion of chicken and murine prion proteins.

Prion diseases are characterized by the conformational conversion of the cellular prion protein (PrPC) to the pathogenic isoform (PrPSc). Lipids have been found to interact with PrPC and contribute to the efficient formation of PrPSc. Non-mammalian PrPs are not readily to undergo the conversion process into an infectious isoform, yet the effect of lipid on the conformational conversion of non-mammalian PrPC remains to be explored. Herein, the effects of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) on full-length recombinant chicken PrP (ChPrP) 24-249 and murine PrP (MoPrP) 23-230 were investigated. Firstly, it was found that in the presence of chemical denaturant, POPG remarkably inhibited MoPrP amyloid fibril growth, while had slight effect on that of ChPrP as estimated by amyloid fibril growth and transmissible electronic microscope assays. Secondly, under physiological condition, POPG induced conformation changes in both MoPrP and ChPrP using Thioflavin T (ThT) fluorescence, circular dichroism, proteinase K digestion and transmission electron microscopy assays. With a POPG:PrP molar ratio of 30:1, the ThT fluorescence of MoPrP was found to be lower than that of ChPrP, however, the POPG-induced MoPrP had higher ß-sheet content and was more proteinase K-resistant than POPG-induced ChPrP. In summary, the present results suggested that the effects of POPG on conformational conversion of MoPrP and ChPrP were different under both denaturation and physiological conditions.

Detecting the genetic link between Alzheimer's disease and obesity using bioinformatics analysis of GWAS data.

Alzheimer's disease (AD) represents the major form of dementia in the elderly. In recent years, accumulating evidence indicate that obesity may act as a risk factor for AD, while the genetic link between the two conditions remains unclear. This bioinformatics analysis aimed to detect the genetic link between AD and obesity on single nucleotide polymorphisms (SNPs), gene, and pathway levels based on genome-wide association studies data. A total of 31 SNPs were found to be shared by AD and obesity, which were linked to 7 genes. These genes included PSMC3, CELF1, MYBPC3, SPI1, APOE, MTCH2 and RAPSN. Further functional enrichment analysis of these genes revealed the following biological pathways, including proteasome, osteoclast differentiation, hypertrophic cardiomyopathy, dilated cardiomyopathy, Epstein-Barr virus and TLV-I infection, as well as several cancer associated pathways, to be common among AD and obesity. The findings deepened our understanding on the genetic basis linking obesity and AD and may help shape possible prevention and treatment strategies.

Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through crosstalk with the NF-κB pathway.

Dishevelled (Dvl) not only links the canonical Wnt and non-canonical Wnt pathways but can also crosstalk with other pathways. As there is no systematic study to date on Dvl in rheumatoid arthritis (RA), we explored the impact of Dvl2 on proliferation and inflammatory cytokine secretion in RA fibroblast-like synoviocytes (FLSs). Expression of Dvl2 in RA synovial tissue and RA-FLSs was measured. Dvl2 was overexpressed in collagen-induced arthritis rats and human RA-FLSs,. the apoptosis and secretion of inflammatory cytokines were observed. Genetic changes and corresponding mechanisms caused by overexpressing Dvl2 in RA-FLSs were assessed. Dvl2 was found to be overexpressed in RA synovial tissue and RA-FLSs. Overexpression of Dvl2 increased apoptosis and inhibited inflammatory cytokine secretion by RA-FLSs in vivo and in vitro, and Dvl2 inhibited expression of anti-apoptotic and inflammatory genes. One possible mechanism is that Dvl2 decreases the nuclear translocation of P65 and inhibits its ability to bind to the promoters of NF-κB target genes. Our findings reveal an underappreciated role of Dvl2 in regulating inflammation and RA-FLS apoptosis and provide insight into crosstalk between the Wnt and nuclear factor-κB (NF-κB) pathways.

One-Year Outcomes of Emergency Department Patients With Atrial Fibrillation: A Prospective, Multicenter Registry in China.

There is lack of data about patient characteristics, practice patterns, and long-term adverse outcomes in patients with atrial fibrillation (AF) attending emergency departments (EDs) in China. A total of 2016 patients from 20 representative EDs were included. During 1 year, all-cause mortality was 291 (14.6%) cases, stroke/noncentral nervous system systemic embolism rate was 159 (8.0%) cases, and major bleeding was 26 (1.3%) cases. Heart failure, the major cause of mortality, accounted for 43.0% of deaths. Of 375 (18.6%) patients who used warfarin at baseline, only 217 (57.9%) patients were still on anticoagulation therapy during 1-year follow-up. Compared with the patients who continued on warfarin, the mortality rate was higher in those who did not continue (15.9% vs 5.5%, P < .001). Patients seen in ED with AF appear to have a high incidence rate of long-term all-cause mortality and inadequate anticoagulation rate.

Comparison of the clinical features and outcomes in two age-groups of elderly patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) disproportionately affects older adults. However, direct comparison of clinical features, medical therapy, and outcomes in AF patients aged 65-74 and ≥ 75 years is rare. The objective of the present study was to evaluate the differences in clinical characteristics and prognosis in these two age-groups of geriatric patients with AF. MATERIALS AND METHODS: A total of 1,336 individuals aged ≥ 65 years from a Chinese AF registry were assessed in the present study: 570 were in the 65- to 74-year group, and 766 were in the ≥ 75-year group. Multivariable Cox hazards regression was performed to analyze the major adverse cardiac events (MACEs) between groups. RESULTS: In our population, the older group were more likely to have coronary artery disease, hypertension, previous stroke, cognitive disorder, or chronic obstructive pulmonary disease, and the 65- to 74-year group were more likely to have valvular heart disease, left ventricular systolic dysfunction, or sleep apnea. The older patients had 1.2-fold higher mean CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes, stroke) scores, but less probability of being prescribed drugs. Compared with those aged 65-74 years, the older group had a higher risk of death (hazard ratio 2.881, 95% confidence interval 1.981-4.189; P<0.001) or MACE (hazard ratio 2.202, 95% confidence interval 1.646-2.945; P<0.001) at the 1-year follow-up. In multivariable Cox analyses, secondary AF diagnosis, a history of chronic obstructive pulmonary disease, and left ventricular systolic dysfunction were independent predictors of MACE in the older group. CONCLUSION: Patients aged ≥ 75 years had a worse prognosis than those aged 65-74 years, and were associated with a higher risk of both death and MACE.

Risk factors and incidence of stroke and MACE in Chinese atrial fibrillation patients presenting to emergency departments: a national wide database analysis.

BACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism in patients with atrial fibrillation (AF) are largely derived from western cohorts. The purpose of the present study is to assess the potential risk factors for stroke and major adverse cardiac events (MACE) in a large population of Chinese AF patients presenting to emergency department. METHODS: The Chinese AF registry is a multicenter, prospective, observational study with 1 year follow up. Patients who presented to an emergency department with atrial fibrillation or atrial flutter were recruited from November 2008 to October 2011. The MACE included all cause mortality, stroke, non-central nervous system systemic embolism and major bleed. RESULTS: A total of 2016 AF patients (1104 women) were included in the final analysis. Multivariate Cox regression analysis showed that the risk factors for stroke were female gender (1.419 (1.003-2.008), p=0.048), age ≥ 75 (2.576 (1.111-4.268), p<0.001), previous stroke/TIA (2.039 (1.415-2.939), p<0.001), LVSD (1.700 (1.015-2.848), p=0.044) and previous major bleeding (2.481 (1.141-5.397), p=0.022). For MACE, age ≥ 75 (3.042 (2.274-4.071), p<0.001), heart failure (1.371 (1.088-1.728), p=0.008), previous stroke/TIA (1.560 (1.244-1.957), p<0.001), LVSD (1.424 (1.089-1.862), p=0.010) and COPD (1.393 (1.080-1.798), p=0.011) were independent risk factors. History of hypertension and diabetes was not associated with the events, neither stroke nor MACE. For non-anticoagulation patients, the c-statistic for predicting stroke was 0.685 (0.637-0.732) and for MACE was 0.717 (0.687-0.746), respectively. CONCLUSIONS: We demonstrated that, except for the traditional risk factors, clinicians should pay more attention to patients with prior major bleeding or COPD in Chinese AF patients presenting to emergency department.