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1.  Constitutive α- and β-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines 
Neurobiology of disease  2012;49:137-147.
Proteolytic cleavage of the amyloid precursor protein (APP) by the two proteases α- and β-secretases controls the generation of the amyloid β peptide (Aβ), a key player in Alzheimer’s disease pathogenesis. The α-secretase ADAM10 and the β-secretase BACE1 have opposite effects on Aβ generation and are assumed to compete for APP as a substrate, such that their cleavages are inversely coupled. This concept was mainly demonstrated in studies using activation or overexpression of α- and β-secretases. Here, we report that this inverse coupling is not seen to the same extent upon inhibition of the endogenous proteases. Genetic and pharmacological inhibition of ADAM10 and BACE1 revealed that the endogenous, constitutive α-secretase cleavage of APP is largely uncoupled from β-secretase cleavage and Aβ generation in neuroglioma H4 cells and in neuronally differentiated SH-SY5Y cells. In contrast, inverse coupling was observed in primary cortical neurons. However, this coupling was not bidirectional. Inhibition of BACE1 increased ADAM10 cleavage of APP, but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP in the neurons. Our analysis shows that the inverse coupling of the endogenous α- and β-secretase cleavages depends on the cellular model and suggests that a reduction of ADAM10 activity is unlikely to increase the AD risk through increased β-secretase cleavage.
PMCID: PMC4310234  PMID: 22940630
Alzheimer’s disease; Alpha-secretase; Beta-secretase; Amyloid precursor protein
2.  Emission of Metals from Pelletized and Uncompressed Biomass Fuels Combustion in Rural Household Stoves in China 
Scientific Reports  2014;4:5611.
Effort of reducing CO2 emissions in developing countries may require an increasing utilization of biomass fuels. Biomass pellets seem well-suited for residential biomass markets. However, there is limited quantitative information on pollutant emissions from biomass pellets burning, especially those measured in real applications. In this study, biomass pellets and raw biomass fuels were burned in a pellet burner and a conventional stove respectively, in rural households, and metal emissions were determined. Results showed that the emission factors (EFs) ranged 3.20–5.57 (Pb), 5.20–7.58 (Cu), 0.11–0.23 (Cd), 12.67–39.00 (As), 0.59–1.31 mg/kg (Ni) for pellets, and 0.73–1.34 (Pb), 0.92–4.48 (Cu), 0.08–0.14 (Cd), 7.29–13.22 (As), 0.28–0.62 (Ni) mg/kg for raw biomass. For unit energy delivered to cooking vessels, the EFs ranged 0.42–0.77 (Pb), 0.79–1.16 (Cu), 0.01–0.03 (Cd), 1.93–5.09 (As), 0.08–0.19 mg/MJ (Ni) for pellets, and 0.30–0.56 (Pb), 0.41–1.86 (Cu), 0.04–0.06 (Cd), 3.25–5.49 (As), 0.12–0.26 (Ni) mg/MJ for raw biomass. This study found that moisture, volatile matter and modified combustion efficiency were the important factors affecting metal emissions. Comparisons of the mass-based and task-based EFs found that biomass pellets produced higher metal emissions than the same amount of raw biomass. However, metal emissions from pellets were not higher in terms of unit energy delivered.
PMCID: PMC4085603  PMID: 25002204
3.  Mosaic VSGs and the Scale of Trypanosoma brucei Antigenic Variation 
PLoS Pathogens  2013;9(7):e1003502.
A main determinant of prolonged Trypanosoma brucei infection and transmission and success of the parasite is the interplay between host acquired immunity and antigenic variation of the parasite variant surface glycoprotein (VSG) coat. About 0.1% of trypanosome divisions produce a switch to a different VSG through differential expression of an archive of hundreds of silent VSG genes and pseudogenes, but the patterns and extent of the trypanosome diversity phenotype, particularly in chronic infection, are unclear. We applied longitudinal VSG cDNA sequencing to estimate variant richness and test whether pseudogenes contribute to antigenic variation. We show that individual growth peaks can contain at least 15 distinct variants, are estimated computationally to comprise many more, and that antigenically distinct ‘mosaic’ VSGs arise from segmental gene conversion between donor VSG genes or pseudogenes. The potential for trypanosome antigenic variation is probably much greater than VSG archive size; mosaic VSGs are core to antigenic variation and chronic infection.
Author Summary
Trypanosoma brucei—a deadly parasite of humans and animals—owes its success to its ability to cope with host immunity, and the mechanism it uses to do so is a remarkable example of biological variation. Immune responses that develop against the parasite surface coat are only partially effective against the parasite population; some individual parasites will have already switched to a different variant of the coat antigen, and thus survive to prolong infection. Little is known about how the pattern of antigen variation unfolds, particularly after the early stage of infection. Here, we examined different antigen variants that appeared over the course of infection, to estimate their diversity and to see whether the parasites are able to generate new antigen variants by combination. We found antigen diversity was much greater than expected, and that ‘mosaic’ variants—produced by combining bits of more than one antigen gene—played a central role in the later stages of infection. These results provide important evidence for the robustness of this key survival strategy, provide clues about its evolution, and allow us to identify patterns in common with other antigenically variable pathogens.
PMCID: PMC3708902  PMID: 23853603
4.  Human Parainfluenza Virus-Associated Respiratory Tract Infection among Children and Genetic Analysis of HPIV-3 Strains in Beijing, China 
PLoS ONE  2012;7(8):e43893.
The relevance of human parainfluenza viruses (HPIVs) to the epidemiology of acute respiratory infections (ARI) in China is unclear. From May 2008 to September 2010, 443 nasopharyngeal aspirates (NPAs) from hospitalized pediatric patients (age from 1 to 93 months) in Beijing were collected and screened for HPIVs and other common respiratory viruses by real-time RT-PCR. Sixty-two of 443 samples were positive for HPIVs with 4 positive for HPIV-2 and 58 positive for HPIV-3, indicating that HPIV-3 was the predominant virus present during the study period. A phylogenetic tree based on all the available HN (hemagglutinin-neuraminidase) sequences of HPIV-3 indicated that three distinct clusters (A,B, and C) were circulating with some temporal and regional clustering. Cluster C was further divided into sub-clusters, C1, C2, C3 and C4. HPIV-3 from Beijing isolates belonged to sub-cluster C3, and were grouped with the isolates from two Provinces of China and the neighboring country of Japan. Genetic analysis based on entire HN gene revealed that the HPIV-3 isolates from Beijing were highly similar with 97.2%–100% identity at the nucleotide level and these could be divided into two closely related lineages, C3a and C3b. These findings suggested that there was co-circulation of multiple lineages of HPIV-3 in the Beijing region during the study period. This is the first study to describe the epidemiology and molecular characterization of HPIVs in China.
PMCID: PMC3429441  PMID: 22937119
5.  Emergence and Continuous Evolution of Genotype 1E Rubella Viruses in China 
Journal of Clinical Microbiology  2012;50(2):353-363.
In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.
PMCID: PMC3264136  PMID: 22162559

Results 1-5 (5)