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31.
The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence
Tan EK Zhao Y Skipper L Tan MG Di Fonzo A Sun L Fook-Chong S Tang S Chua E Yuen Y Tan L Pavanni R Wong MC Kolatkar P Lu CS Bonifati V Liu JJ 《Human genetics》2007,120(6):857-863
Evidence of LRRK2 haplotypes associated with Parkinson’s disease (PD) risk was recently found in the Chinese population from
Singapore, and a common LRRK2 missense variant, Gly2385Arg, was independently detected as a putative risk factor for PD in
the Chinese population from Taiwan. To test the association between the Gly2385Arg variant in a large case-control sample
of Chinese ethnicity from Singapore, and to perform functional studies of the wild type and Gly2385Arg LRRK2 protein in human
cell lines. In a case-control study involving 989 Chinese subjects, the frequency of the heterozygous Gly2385Arg genotype
was higher in PD compared to controls (7.3 vs. 3.6%, odds ratio = 2.1, 95% CI: 1.1–3.9, P = 0.014); these values yield an estimated population attributable risk (PAR) of ∼4%. In a multivariate logistic regression
analysis with the disease group (PD vs. controls) as the dependent variable and the genotype as an independent factor with
adjustments made for the effect of age and gender, the heterozygous Gly2385Arg genotype remained associated with an increased
risk of PD compared to wild type genotype (odds ratio = 2.67, 95% CI: 1.43–4.99, P = 0.002). The glycine at position 2385 is a candidate site for N-myristoylation, and the Gly2385Arg variant replaces the
hydrophobic glycine with the hydrophilic arginine, and increases the net positive charge of the LRRK2 WD40 domain. In transfection
studies, we demonstrated that both the wild type and Gly2385Arg variant LRRK2 protein localize to the cytoplasm and form aggregates.
However, under condition of oxidative stress, the Gly2385Arg variant was more toxic and associated with a higher rate of apoptosis.
Our study lends support to the contention that the Gly2385Arg is a common risk factor for PD in the Chinese population. Our
bioinformatics and in-vitro studies also suggest that the Gly2385Arg variant is biologically relevant and it might act through
pro-apoptotic mechanisms. 相似文献
32.
Christof J Majoor Marianne A van de Pol Pieter Willem Kamphuisen Joost CM Meijers Richard Molenkamp Katja C Wolthers Tom van der Poll Rienk Nieuwland Sebastian L Johnston Peter J Sterk Elisabeth HD Bel Rene Lutter Koenraad F van der Sluijs 《Respiratory research》2014,15(1):14
Background
Asthma exacerbations are frequently triggered by rhinovirus infections. Both asthma and respiratory tract infection can activate haemostasis. Therefore we hypothesized that experimental rhinovirus-16 infection and asthmatic airway inflammation act in synergy on the haemostatic balance.Methods
28 patients (14 patients with mild allergic asthma and 14 healthy non-allergic controls) were infected with low-dose rhinovirus type 16. Venous plasma and bronchoalveolar lavage fluid (BAL fluid) were obtained before and 6 days after infection to evaluate markers of coagulation activation, thrombin-antithrombin complexes, von Willebrand factor, plasmin-antiplasmin complexes, plasminogen activator inhibitor type-1, endogenous thrombin potential and tissue factor-exposing microparticles by fibrin generation test, in plasma and/or BAL fluid. Data were analysed by nonparametric tests (Wilcoxon, Mann Whitney and Spearman correlation).Results
13 patients with mild asthma (6 females, 19-29 y) and 11 healthy controls (10 females, 19-31 y) had a documented Rhinovirus-16 infection. Rhinovirus-16 challenge resulted in a shortening of the fibrin generation test in BAL fluid of asthma patients (t = -1: 706 s vs. t = 6: 498 s; p = 0.02), but not of controls (t = -1: 693 s vs. t = 6: 636 s; p = 0.65). The fold change in tissue factor-exposing microparticles in BAL fluid inversely correlated with the fold changes in eosinophil cationic protein and myeloperoxidase in BAL fluid after virus infection (r = -0.517 and -0.528 resp., both p = 0.01).Rhinovirus-16 challenge led to increased plasminogen activator inhibitor type-1 levels in plasma in patients with asthma (26.0 ng/mL vs. 11.5 ng/mL in healthy controls, p = 0.04). Rhinovirus-16 load in BAL showed a linear correlation with the fold change in endogenous thrombin potential, plasmin-antiplasmin complexes and plasminogen activator inhibitor type-1.Conclusions
Experimental rhinovirus infection induces procoagulant changes in the airways of patients with asthma through increased activity of tissue factor-exposing microparticles. These microparticle-associated procoagulant changes are associated with both neutrophilic and eosinophilic inflammation. Systemic activation of haemostasis increases with Rhinoviral load.Trial registration
This trial was registered at the Dutch trial registry (http://www.trialregister.nl): NTR1677. 相似文献33.
Laura C. Green David A. Wagner Joseph Glogowski Paul L. Skipper John S. Wishnok Steven R. Tannenbaum 《Analytical biochemistry》1982,126(1):131-138
A new automated system for the analysis of nitrate via reduction with a high-pressure cadmium column is described. Samples of urine, saliva, deproteinized plasma, gastric juice, and milk can be analyzed for nitrate, nitrite, or both with a lower limit of detection of 1.0 nmol NO3? or NO2?/ml. The system allows quantitative reduction of nitrate and automatically eliminates interference from other compounds normally present in urine and other biological fluids. Analysis rate is 30 samples per hour, with preparation for most samples limited to simple dilution with distilled water. The application of gas chromatography/mass spectrometry for the analysis of 15NO3? in urine after derivatization to 15NO2-benzene is also described. 相似文献
34.
The origin of and relationships among multiple forms of the estrogen receptor from rat uteri were investigated using electrophoretic and conventional hydrodynamic methods of analysis. Evidence is presented that the molybdate-stabilized, multimeric receptor (Stokes radius approximately 70A; S20,w approximately 9.5 S; Mr approximately 290,000) corresponds to an acidic form of the receptor that has relatively high electrophoretic mobility. This discrete form, which appears to represent the untransformed state that does not bind to DNA, was converted to a number of derived forms by exposure to conditions that result in receptor transformation and/or subunit dissociation. In crude cytosol, transformation always generated receptor forms that were excluded from polyacrylamide gels, and it was shown that these are large heterogeneous aggregates. This explains previous failed attempts to analyze the receptor by polyacrylamide gel electrophoresis. Transformation of partially purified, molybdate-stabilized receptor never led to aggregate formation, but resulted instead in the generation of two relatively basic estrogen-binding species of low electrophoretic mobility. These components may represent the free or dissociated estrogen-binding subunits. Together, the results suggest a model for the molybdate-stabilized receptor wherein at least one of its components is an acidic, nonestrogen-binding subunit. 相似文献
35.
Aim: To develop a novel assay technique for the botulinum neurotoxin family (BoNTs) which is dependent on both the endopeptidase and receptor‐binding activities of the BoNTs and which is insensitive to antigenic variation with the toxin family. Methods and Results: An endopeptidase activity, receptor‐binding assay (EARB assay) has been developed which captures biologically active toxin from media using brain synaptosomes. After capture, the bound toxin can be incubated with its substrate, and cleavage detected using serotype‐specific antibodies raised against the cleaved product of each toxin serotype. The EARB assay was assessed using a range of BoNT serotypes and subtypes. For BoNT/A, detection limits for subtypes A1, A2 and A3 were 0·5, 3 and 10 MLD50 ml?1, respectively. The limit of detection for BoNT/B1 was 5 MLD50 ml?1 and a novel antibody‐based endopeptidase assay for BoNT/F detected toxin at 0·5 MLD50 ml?1. All these BoNTs can be captured from media containing up to 10% serum without loss of sensitivity. BoNT/A1 could also be detected in dilutions of a lactose‐ containing formulation similar to that used for clinical preparations of the toxin. Different serotypes were found to possess different optimal cleavage pHs (pH 6·5 for A1, pH 7·4 for B1). Conclusions: The EARB assay has been shown to be able to detect a broad range of BoNT serotypes and subtypes from various media. Significance and Impact of the Study: The EARB assay system described is the first convenient in vitro assay system described which is requires multiple functional biological activities with the BoNTs. The assay will have applications in instances where it is essential or desirable to distinguish biologically active from inactive neurotoxin. 相似文献
36.
Sigl Tanja Schlamberger Gregor Kienberger Hermine Wiedemann Steffi Meyer Heinrich HD Kaske Martin 《Acta veterinaria Scandinavica》2010,52(1):1-8
After 27 years with no detected cases, an outbreak of anthrax occurred in a beef cattle herd in the south of Sweden. The outbreak was unusual as it occurred in winter, in animals not exposed to meat-and-bone meal, in a non-endemic country. The affected herd consisted of 90 animals, including calves and young stock. The animals were kept in a barn on deep straw bedding and fed only roughage. Seven animals died during 10 days, with no typical previous clinical signs except fever. The carcasses were reportedly normal in appearance, particularly as regards rigor mortis, bleeding and coagulation of the blood. Subsequently, three more animals died and anthrax was suspected at necropsy and confirmed by culture and PCR on blood samples. The isolated strain was susceptible to tetracycline, ciprofloxacin and ampicillin. Subtyping by MLVA showed the strain to cluster with isolates in the A lineage of Bacillus anthracis. Environmental samples from the holding were all negative except for two soil samples taken from a spot where infected carcasses had been kept until they were picked up for transport. The most likely source of the infection was concluded to be contaminated roughage, although this could not be substantiated by laboratory analysis. The suspected feed was mixed with soil and dust and originated from fields where flooding occurred the previous year, followed by a dry summer with a very low water level in the river allowing for the harvesting on soil usually not exposed. In the early 1900s, animal carcasses are said to have been dumped in this river during anthrax outbreaks and it is most likely that some anthrax spores could remain in the area. The case indicates that untypical cases in non-endemic areas may be missed to a larger extent than previously thought. Field tests allowing a preliminary risk assessment of animal carcasses would be helpful for increased sensitivity of detection and prevention of further exposure to the causative agent. 相似文献
37.
Srinivas Gadipelli Christopher A. Howard Jian Guo Neal T. Skipper Hong Zhang Paul R. Shearing Dan J. L. Brett 《Liver Transplantation》2020,10(9)
Nanoporous carbons (NPCs) with engineered specific pore sizes and sufficiently high porosities (both specific surface area and pore volume) are necessary for storing energy in the form of electric charges and molecules. Herein, NPCs, derived from biomass pine‐cones, coffee‐grounds, graphene‐oxide and metal‐organic frameworks, with systematically increased pore width (<1.0 nm to a few nm), micropore volume (0.2–0.9 cm3 g?1) and specific surface area (800–2800 m2 g?1) are presented. Superior CO2, H2, and H2O uptakes of 35.0 wt% (≈7.9 mmol g?1 at 273 K), 3.0 wt% (at 77 K) and 85.0 wt% (at 298 K), respectively at 1 bar, are achieved. At controlled microporosity, supercapacitors deliver impressive performance with a capacity of 320 and 230 F g?1 at 500 mA g?1, in aqueous and organic electrolytes, respectively. Excellent areal capacitance and energy density (>50 Wh kg?1 at high power density, 1000 W kg?1) are achieved to form the highest reported values among the range of carbons in the literature. The noteworthy energy storage performance of the NPCs for all five cases (CO2, H2, H2O, and capacitance in aqueous and organic electrolytes) is highlighted by direct comparison to numerous existing porous solids. A further analysis on the specific pore type governed physisorption capacities is presented. 相似文献
38.
Kristian Alsbjerg Skipper Peter Refsing Andersen Nynne Sharma Jacob Giehm Mikkelsen 《Journal of biomedical science》2013,20(1):92
DNA transposons are primitive genetic elements which have colonized living organisms from plants to bacteria and mammals. Through evolution such parasitic elements have shaped their host genomes by replicating and relocating between chromosomal loci in processes catalyzed by the transposase proteins encoded by the elements themselves. DNA transposable elements are constantly adapting to life in the genome, and self-suppressive regulation as well as defensive host mechanisms may assist in buffering ‘cut-and-paste’ DNA mobilization until accumulating mutations will eventually restrict events of transposition. With the reconstructed Sleeping Beauty DNA transposon as a powerful engine, a growing list of transposable elements with activity in human cells have moved into biomedical experimentation and preclinical therapy as versatile vehicles for delivery and genomic insertion of transgenes. In this review, we aim to link the mechanisms that drive transposon evolution with the realities and potential challenges we are facing when adapting DNA transposons for gene transfer. We argue that DNA transposon-derived vectors may carry inherent, and potentially limiting, traits of their mother elements. By understanding in detail the evolutionary journey of transposons, from host colonization to element multiplication and inactivation, we may better exploit the potential of distinct transposable elements. Hence, parallel efforts to investigate and develop distinct, but potent, transposon-based vector systems will benefit the broad applications of gene transfer. Insight and clever optimization have shaped new DNA transposon vectors, which recently debuted in the first DNA transposon-based clinical trial. Learning from an evolutionary drive may help us create gene vehicles that are safer, more efficient, and less prone for suppression and inactivation. 相似文献
39.
Epizootic outbreaks of sylvatic plague have dramatically influenced prairie dog (Cynomys sp.) populations across North America. While a great deal of debate surrounds the cause and persistence of plague, flea control can stop the spread of plague epizootic outbreaks and even increase prairie dog survival under non‐epizootic conditions. We investigated a newly‐developed imidacloprid‐treated grain bait that could potentially reduce flea infestations and mitigate the effects of plague on black‐tailed prairie dogs (C. ludovicianus). We used a study design involving randomly assigned experimental and control study plots to assess the effectiveness of the systemic flea control product. We observed a significant difference in flea prevalence and abundance between experimental and control sites on three of the four sites treated with a single application of imidacloprid‐treated grain bait for up to 90 days post‐treatment. We observed an even greater reduction in flea infestations following the double application of treatment bait on two of three additional experimental sites. While we were unable to reduce flea infestations to the extent reported for more commonly used topical insecticides containing deltamethrin, imidacloprid might still be effective at reducing the risk of plague and halting epizootics. In addition, this systemic product can be more rapidly applied than topical insecticides, providing managers with a tool to quickly reduce flea infestations. Future research is needed to evaluate the effectiveness of different application timing and rates, the utility of the product in limiting plague, and the potential effects on non‐target species that might also consume the treated bait. 相似文献
40.
Robert HS Kraus Hindrik HD Kerstens Pim Van Hooft Richard PMA Crooijmans Jan J Van Der Poel Johan Elmberg Alain Vignal Yinhua Huang Ning Li Herbert HT Prins Martien AM Groenen 《BMC genomics》2011,12(1):150