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  • 1
    In: Biometrika, 2006, Vol.93(4), pp.827-841
    Description: We consider parameter-driven models of time series of counts, where the observations are assumed to arise from a Poisson distribution with a mean changing over time according to a latent process. Estimation of these models is carried out within a Bayesian framework using data augmentation and Markov chain Monte Carlo methods. We suggest a new auxiliary mixture sampler, which possesses a Gibbsian transition kernel, where we draw from full conditional distributions belonging to standard distribution families only. Emphasis lies on application to state space modelling of time series of counts, but we show that auxiliary mixture sampling may be applied to a wider range of parameter-driven models, including random-effects models and panel data models based on the Poisson distribution.
    Keywords: Count Data; Data Augmentation; Finite Mixture Approximation; Gibbs Sampling; Partially Gaussian State Space Model.
    ISSN: 0006-3444
    E-ISSN: 1464-3510
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e32568
    Description: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. ; In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different co-incubation experiments were performed with competing ligands of the respective receptor. ; This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.
    Keywords: Research Article ; Biology ; Materials Science ; Medicine ; Biotechnology ; Pharmacology ; Biochemistry
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, 2010, Vol.5(12), p.e14213
    Description: Due to the use of organophosphates (OP) as pesticides and the availability of OP-type nerve agents, an effective medical treatment for OP poisonings is still a challenging problem. The acute toxicity of an OP poisoning is mainly due to the inhibition of acetylcholinesterase (AChE) in the peripheral and central nervous systems (CNS). This results in an increase in the synaptic concentration of the neurotransmitter acetylcholine, overstimulation of cholinergic receptors and disorder of numerous body functions up to death. The standard treatment of OP poisoning includes a combination of a muscarinic antagonist and an AChE reactivator (oxime). However, these oximes can not cross the blood-brain barrier (BBB) sufficiently. Therefore, new strategies are needed to transport oximes over the BBB. ; In this study, we combined different oximes (obidoxime dichloride and two different HI 6 salts, HI 6 dichloride monohydrate and HI 6 dimethanesulfonate) with human serum albumin nanoparticles and could show an oxime transport over an BBB model. In general, the nanoparticulate transported oximes achieved a better reactivation of OP-inhibited AChE than free oximes. ; With these nanoparticles, for the first time, a tool exists that could enable a transport of oximes over the BBB. This is very important for survival after severe OP intoxication. Therefore, these nanoparticulate formulations are promising formulations for the treatment of the peripheral and the CNS after OP poisoning.
    Keywords: Research Article ; Biotechnology ; Neurological Disorders ; Pharmacology -- Drug Development
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(3), p.e92068
    Description: This study was performed to explore the feasibility of tracing nanoparticles for drug transport in the healthy rat brain with a clinical MRI scanner. Phantom studies were performed to assess the R1 ( =  1/T1) relaxivity of different magnetically labeled nanoparticle (MLNP) formulations that were based on biodegradable human serum albumin and that were labeled with magnetite of different size. In vivo MRI measurements in 26 rats were done at 3T to study the effect and dynamics of MLNP uptake in the rat brain and body. In the brain, MLNPs induced T1 changes were quantitatively assessed by T1 relaxation time mapping in vivo and compared to post-mortem results from fluorescence imaging. Following intravenous injection of MLNPs, a visible MLNP uptake was seen in the liver and spleen while no visual effect was seen in the brain. However a histogram analysis of T1 changes in the brain demonstrated global and diffuse presence of MLNPs. The magnitude of these T1 changes scaled with post-mortem fluorescence intensity. This study demonstrates the feasibility of tracking even small amounts of magnetite labeled NPs with a sensitive histogram technique in the brain of a living rodent.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis
    Description: In accordance with the 3 Rs to reduce testing, more advanced models, moving from 2D monolayer to 3D cultures, should be developed for prediction of human toxicity of industrial chemicals and environmental pollutants. In this study we compared cytotoxic and genotoxic responses induced by chemicals in 2D and 3D spheroidal cultures of the human liver cancer cell line HepG2. HepG2 spheroids were prepared by hanging drop technology. Both 3D spheroids and 2D monolayer cultures were exposed to different chemicals (colchicine, chlorpromazine hydrochloride or methyl methanesulfonate) for geno- and cytotoxicity studies. Cytotoxicity was investigated by alamarBlue assay, flow cytometry and confocal imaging. DNA damage was investigated by the comet assay with and without Fpg enzyme for detection of DNA strand breaks and oxidized or alkylated base lesions. The results from the cyto- and genotoxicity tests showed differences in sensitivity comparing the 2D and 3D HepG2 models. This study shows that human 3D spheroidal hepatocellular cultures can be successfully applied for genotoxicity testing by the comet assay and represent a promising advanced model for toxicity testing.
    Keywords: Liver Spheroids ; Advanced in Vitro Model ; Genotoxicity ; Comet Assay ; 2d and 3d Culture ; Biology ; Public Health
    ISSN: 1383-5718
    E-ISSN: 1879-3592
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  • 6
    Language: English
    In: The Journal of Infectious Diseases, 1 September 1946, Vol.79(2), pp.159-167
    Description: The general question of immunity to Asiatic cholera is discussed. I t is concluded that present evidence is consistent with the view that a low grade immunity is produced by prophylactic inoculation with vaccine. I t is pointed out that either or both an antitoxic and an antibacterial immunity may be functional in effective immunity to the disease and that the latter is difficult to reconcile with the enteric character of the infection in the absence of leakage of humoral antibody into the lumen of the bowel. The 71 strains of vibrios available for this investigation, 51 strains of Vibrio cholerae, 14 strains of E1 Tor vibrios, and 6 strains of water vibrios, are described. There was a considerable degree of biochemical heterogeneity in the group; of the 51 cholera strains, only 15 were found to be "typical." It is concluded that the cholera vibrios do not make up a biochemically homogeneous group and cannot be sharply characterized by cultural reactions alone. The general question of immunity to Asiatic cholera is discussed. I t is concluded that present evidence is consistent with the view that a low grade immunity is
    Keywords: Biological sciences -- Biology -- Microbiology ; Health sciences -- Medical conditions -- Infections ; Health sciences -- Medical treatment -- Biological therapy ; Health sciences -- Medical sciences -- Immunology ; Education -- Formal education -- Educational institutions ; Health sciences -- Medical sciences -- Immunology ; Health sciences -- Health and wellness -- Public health ; Biological sciences -- Biochemistry -- Biochemical phenomena ; Health sciences -- Medical treatment -- Biological therapy ; Health sciences -- Medical conditions -- Diseases
    ISSN: 00221899
    E-ISSN: 15376613
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  • 7
    Language: English
    In: The Journal of Infectious Diseases, 1 September 1946, Vol.79(2), pp.168-197
    Keywords: Biological sciences -- Biology -- Microbiology -- Polyclonal antibodies ; Health sciences -- Medical sciences -- Immunology -- Bacterial antigens ; Health sciences -- Medical conditions -- Infections -- Bacterial antigens ; Health sciences -- Medical sciences -- Immunology -- Bacterial antigens ; Health sciences -- Medical sciences -- Immunology -- Bacterial antigens ; Health sciences -- Medical sciences -- Immunology -- Bacterial antigens ; Physical sciences -- Chemistry -- Chemical compounds -- Bacterial antigens ; Health sciences -- Medical sciences -- Immunology -- Bacterial antigens ; Health sciences -- Health and wellness -- Public health -- Bacterial antigens ; Health sciences -- Medical sciences -- Immunology -- Bacterial antigens
    ISSN: 00221899
    E-ISSN: 15376613
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  • 8
    Language: English
    In: Virology, 2006, Vol.352(2), pp.295-305
    Description: We have previously shown that Rev-dependent expression of HIV-1 Gag from CMV immediate early promoter critically depends on the AU-rich codon bias of the gag gene. Here, we demonstrate that adaptation of the green fluorescent protein (GFP) reporter gene to HIV codon bias is sufficient to turn this hivGFP RNA into a quasi-lentiviral message following the rules of late lentiviral gene expression. Accordingly, GFP expression was significantly decreased in transfected cells strictly correlating with reduced RNA levels. In the presence of the HIV 5′ major splice donor, the hivGFP RNAs were stabilized in the nucleus and efficiently exported to the cytoplasm following fusion of the 3′ Rev-responsive element (RRE) and coexpression of HIV-1 Rev. This Rev-dependent translocation was specifically inhibited by leptomycin B suggesting export via the CRM1-dependent pathway used by late lentiviral transcripts. In conclusion, this quasi-lentiviral reporter system may provide a new platform for developing sensitive Rev screening assays.
    Keywords: HIV-1 ; Gfp ; Codon Usage ; Rev ; Rre ; RNA Export ; Cte ; Crm1 ; Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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  • 9
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e37839
    Description: The regenerative potential declines upon aging. This might be due to cell-intrinsic changes in stem and progenitor cells or to influences by the microenvironment. Mesenchymal stem cells (MSC) raise high hopes in regenerative medicine. They are usually culture expanded in media with fetal calf serum (FCS) or other serum supplements such as human platelet lysate (HPL). In this study, we have analyzed the impact of HPL-donor age on culture expansion. 31 single donor derived HPLs (25 to 57 years old) were simultaneously compared for culture of MSC. Proliferation of MSC did not reveal a clear association with platelet counts of HPL donors or growth factors concentrations (PDGF-AB, TGF-β1, bFGF, or IGF-1), but it was significantly higher with HPLs from younger donors (〈35 years) as compared to older donors (〉45 years). Furthermore, HPLs from older donors increased activity of senescence-associated beta-galactosidase (SA-βgal). HPL-donor age did not affect the fibroblastoid colony-forming unit (CFU-f) frequency, immunophenotype or induction of adipogenic differentiation, whereas osteogenic differentiation was significantly lower with HPLs from older donors. Concentrations of various growth factors (PDGF-AB, TGF-β1, bFGF, IGF-1) or hormones (estradiol, parathormone, leptin, 1,25 vitamin D3) were not associated with HPL-donor age or MSC growth. Taken together, our data support the notion that aging is associated with systemic feedback mechanisms acting on stem and progenitor cells, and this is also relevant for serum supplements in cell culture: HPLs derived from younger donors facilitate enhanced expansion and more pronounced osteogenic differentiation.
    Keywords: Research Article ; Biology ; Medicine ; Biotechnology ; Physiology ; Hematology ; Developmental Biology
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: PLoS ONE, 2011, Vol.6(2), p.e16679
    Description: Epigenetic modifications of cytosine residues in the DNA play a critical role for cellular differentiation and potentially also for aging. In mesenchymal stromal cells (MSC) from human bone marrow we have previously demonstrated age-associated methylation changes at specific CpG-sites of developmental genes. In continuation of this work, we have now isolated human dermal fibroblasts from young (〈23 years) and elderly donors (〉60 years) for comparison of their DNA methylation profiles using the Infinium HumanMethylation27 assay. In contrast to MSC, fibroblasts could not be induced towards adipogenic, osteogenic and chondrogenic lineage and this is reflected by highly significant differences between the two cell types: 766 CpG sites were hyper-methylated and 752 CpG sites were hypo-methylated in fibroblasts in comparison to MSC. Strikingly, global DNA methylation profiles of fibroblasts from the same dermal region clustered closely together indicating that fibroblasts maintain positional memory even after in vitro culture. 75 CpG sites were more than 15% differentially methylated in fibroblasts upon aging. Very high hyper-methylation was observed in the aged group within the INK4A/ARF/INK4b locus and this was validated by pyrosequencing. Age-associated DNA methylation changes were related in fibroblasts and MSC but they were often regulated in opposite directions between the two cell types. In contrast, long-term culture associated changes were very consistent in fibroblasts and MSC. Epigenetic modifications at specific CpG sites support the notion that aging represents a coordinated developmental mechanism that seems to be regulated in a cell type specific manner.
    Keywords: Research Article ; Biology ; Genetics And Genomics ; Public Health And Epidemiology ; Molecular Biology ; Cell Biology ; Developmental Biology
    E-ISSN: 1932-6203
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