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1.
Br J Pharmacol ; 171(7): 1758-71, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24417347

ABSTRACT

BACKGROUND AND PURPOSE: The prevalence of smoking in schizophrenia patients is exceptionally high; it is not known why but many researchers suggest that smoking constitutes a form of self-medication. Among the symptoms of schizophrenia that may be improved by nicotine are cognitive deficits. Hence, we studied the effects of long-term nicotine administration on cognition in a genetic animal model of schizophrenia susceptibility, G72-transgenic (G72Tg) mice. EXPERIMENTAL APPROACH: The effect of long-term nicotine or saline, administered by osmotic minipumps, on different cognitive domains was assessed in G72Tg mice and controls using a battery of behavioural tests. To investigate the mechanism underlying phenotypic differences, quantitative autoradiographic mapping of nACh receptor subtypes was performed in forebrain structures to explore effects of chronic nicotine exposure on nACh receptor density in wild-type (WT) and G72Tg mice. KEY RESULTS: Genotype significantly affected the cognitive effects of chronic nicotine administration. Whereas chronic nicotine disrupted cognitive performance in WT mice, it was effective at restoring impaired prepulse inhibition, working memory and social recognition in G72Tg mice. However, long-term spatial learning was further impaired by nicotine in transgenic animals. In contrast, associative learning was protected by G72-expression against the adverse nicotine effects seen in WT animals. G72-expression did not decisively influence nicotine-induced up-regulation of the α4ß2*subtype, whereas α7nACh receptor density was differentially altered by genotype or by a genotype·treatment interaction in specific brain areas, most notably hippocampal subregions. CONCLUSIONS AND IMPLICATIONS: Our data support the hypothesis that nicotine self-medication of schizophrenics improves cognitive symptoms, possibly by facilitating nicotine-induced α7nACh receptor activation in the hippocampus.


Subject(s)
Behavior, Animal/drug effects , Memory, Short-Term/drug effects , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Nootropic Agents/administration & dosage , Schizophrenia/drug therapy , Schizophrenic Psychology , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cognition/drug effects , Disease Models, Animal , Drug Administration Schedule , Genotype , Humans , Intracellular Signaling Peptides and Proteins , Mice , Mice, Transgenic , Neural Inhibition/drug effects , Phenotype , Prosencephalon/drug effects , Prosencephalon/metabolism , Recognition, Psychology/drug effects , Schizophrenia/diagnosis , Schizophrenia/genetics , Social Behavior , Time Factors , alpha7 Nicotinic Acetylcholine Receptor/agonists , alpha7 Nicotinic Acetylcholine Receptor/metabolism
2.
Water Sci Technol ; 66(6): 1195-202, 2012.
Article in English | MEDLINE | ID: mdl-22828295

ABSTRACT

To determine the removal efficiency of ultrafiltration (UF) membranes for nano-particles in the size range of viruses the state of the art uses challenge tests with virus-spiked water. This work focuses on bench-scale and semi-technical scale experiments. Different experimental parameters influencing the removal efficiency of the tested UF membrane modules were analyzed and evaluated for bench- and semi-technical scale experiments. Organic matter in the water matrix highly influenced the removal of the tested bacteriophages MS2 and phiX174. Less membrane fouling (low ΔTMP) led to a reduced phage reduction. Increased flux positively affected phage removal in natural waters. The tested bacteriophages MS2 and phiX174 revealed different removal properties. MS2, which is widely used as a model organism to determine virus removal efficiencies of membranes, mostly showed a better removal than phiX174 for the natural water qualities tested. It seems that MS2 is possibly a less conservative surrogate for human enteric virus removal than phiX174. In bench-scale experiments log removal values (LRV) for MS2 of 2.5-6.0 and of 2.5-4.5 for phiX174 were obtained for the examined range of parameters. Phage removal obtained with differently fabricated semi-technical modules was quite variable for comparable parameter settings, indicating that module fabrication can lead to differing results. Potting temperature and module size were identified as influencing factors. In conclusion, careful attention has to be paid to the choice of experimental settings and module potting when using bench-scale or semi-technical scale experiments for UF membrane challenge tests.


Subject(s)
Bacteriophages , Membranes, Artificial , Ultrafiltration/instrumentation , Water Microbiology
3.
Water Sci Technol ; 66(1): 151-7, 2012.
Article in English | MEDLINE | ID: mdl-22678212

ABSTRACT

This study examines mechanisms for removal of bacteriophages (MS2 and phiX174) by ceramic membranes without application of flocculants. The ceramic membranes considered included ultra- and microfiltration membranes of different materials. Phages were spiked into the feed water in pilot scale tests in a waterworks. The membranes with pore sizes of 10 nm provided a 2.5-4.0 log removal of the phages. For pore sizes of 50 nm, the log removal dropped to 0.96-1.8. The membrane with a pore size of 200 nm did not remove phages. So, the removal of both MS2- and phiX174-phages depended on the pore size of the membranes. But apart from pore size also other factors influence the removal of phages. Removal was 0.5-0.9 log higher for MS2-phages compared with phiX174-phages. Size exclusion seems to be the major but not the only mechanism which influences the efficiency of phage removal by ceramic membranes.


Subject(s)
Bacteriophages/chemistry , Ceramics/chemistry , Membranes, Artificial , Water Microbiology , Water Purification/instrumentation , Pilot Projects , Water Purification/methods
4.
Mol Psychiatry ; 15(7): 702-11, 2010 Jul.
Article in English | MEDLINE | ID: mdl-19139748

ABSTRACT

In our biomarker identification efforts, we have reported earlier on a protein that differs in its electrophoretic mobility between mouse lines bred either for high or low trait anxiety. The altered electrophoretic behavior of enolase phosphatase (EP) is now identified to be caused by two single-nucleotide polymorphisms. In both cases, the genetic polymorphism introduces an amino acid change in the protein's sequence resulting in differential mobility on SDS gels. This was shown by recombinantly expressing the two EP isoforms. Functional studies indicate that the EP isoform from the high anxiety mouse line has a lower enzymatic activity than does its low anxiety mouse counterpart. EP is a member of the methionine salvage pathway that is responsible for the synthesis of S-adenosyl-L-methionine, a natural compound with potential antidepressant activities. In addition, it is linked to the polyamine pathway whose members have functions in anxiety/depression-related behaviors. In a freely-segregating F2 panel, both single-nucleotide polymorphisms were significantly associated with locomotion-independent trait anxiety, further supporting a functional role of EP for this phenotype. The study shows that proteomic analysis can reveal genotypic differences relevant for the phenotype. The identified protein alterations, in turn, can expose metabolic pathways pertinent to the behavioral phenotype.


Subject(s)
Anxiety/metabolism , Disease Models, Animal , Genotype , Isoenzymes/metabolism , Multienzyme Complexes/genetics , Phosphoric Monoester Hydrolases/genetics , Proteomics/methods , Animals , Brain/metabolism , Humans , Isoenzymes/genetics , Male , Mice , Mice, Inbred Strains , Models, Genetic , Multienzyme Complexes/metabolism , Phosphoric Monoester Hydrolases/metabolism , Polyamines/metabolism , Polymorphism, Single Nucleotide
5.
J Biol Chem ; 276(36): 33923-9, 2001 Sep 07.
Article in English | MEDLINE | ID: mdl-11438549

ABSTRACT

We reported previously that the carbohydrate domain of the amyloid precursor protein is involved in amyloid precursor protein (APP)-APP interactions. Functional in vitro studies suggested that this interaction occurs through the collagen binding site of APP. The physiological significance remained unknown, because it is not understood whether and how APP dimerization occurs in vivo. Here we report that cellular APP exists as homodimers matching best with a two-site model. Consistent with our published crystallographic data, we show that a deletion of the entire sequence after the kunitz protease inhibitor domain did not abolish APP homodimerization, suggesting that two domains are critically involved but that neither is essential for homodimerization. Finally, we generated stabilized dimers by expressing mutant APP with a single cysteine in the ectodomain juxtamembrane region. Mutation of Lys(624) to cysteine produced approximately 6-8-fold more A beta than cells expressing normal APP. Our results suggest that amyloid A beta production can in principle be positively regulated by dimerization in vivo. We suggest that dimerization could be a physiologically important mechanism for regulating the proposed signal activity of APP.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/chemistry , Animals , Binding Sites , Blotting, Western , COS Cells , Cell Membrane/metabolism , Chromatography, Gel , Collagen/metabolism , Cross-Linking Reagents/pharmacology , Cysteine/chemistry , Dimerization , Disulfides , Humans , Immunoblotting , Lysine/chemistry , Mutagenesis, Site-Directed , Mutation , Protein Binding , Protein Structure, Tertiary , Recombinant Proteins/metabolism , Signal Transduction , Transfection , Tumor Cells, Cultured
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