The effect of clozapine on mRNA expression for genes encoding G protein-coupled receptors and the protein components of clathrin-mediated endocytosis.

Clathrin-mediated endocytosis (CME) is an intracellular trafficking mechanism for packaging cargo, including G protein-coupled receptors (GPCRs), into clathrin-coated vesicles (CCVs). The antipsychotic chlorpromazine inhibits CCV assembly of adaptor protein AP2 whereas clozapine increases serotonin2A receptor internalization. We hypothesized that clozapine alters the expression of CME genes modulating vesicle turnover and GPCR internalization

Luminescence Dating of Medieval and Early Modern Brickwork

Essex is a county rich in significant historic brickwork spanning the medieval period. A great deal of earlier archaeological study has focused on the development and use of brick during this period, providing a framework of understanding as to how this material was employed in Essex through the medieval period. However, the common approaches adopted to date historic brick have several caveats that can potentially limit the amount of information they can provide. This presented an opportunity to apply the scientific dating technique of optically stimulated luminescence in order to derive absolute dates for important medieval brick sites in Essex. This in turn would allow this framework of understanding surrounding medieval brick to be critically examined and revised where necessary. A series of important brick buildings that spanned the 11th through to the 16th century were selected for inclusion in this thesis. The buildings were studied from an archaeological perspective, deriving likely dates for their erection and development, before samples of the brickwork were taken. These were subsequently dated by luminescence. In light of the luminescence dates, the archaeological evaluations of the buildings were reviewed and revised where necessary. The results have shown that medieval brick was introduced much earlier than had previously been suspected. This has refuted the long held notion that the Cistercians were responsible for introducing brick in the 12th century and has led to suggestions of a small scale, late Saxon brick industry. It was also apparent that, whilst being manufactured, brick was also being re-used to a large extent throughout the medieval period, especially in the 16th century. Whilst this is likely to be largely due to practical motivational factors, other esoteric social aspects are also likely to have played a role, such as the Great Rebuilding

Alcohol-related expectancies are associated with the D2 dopamine receptor and GABAa receptor B3 subunit genes

Molecular genetic research has identified promising markers of alcohol dependence, including alleles of the D2 dopamine receptor (DRD2) and the GABAA receptor ￢3 subunit (GABRB3) genes. Whether such genetic risk manifests itself in stronger alcohol-related outcome expectancies, or in difficulty resisting alcohol, is unknown. In the present study, A1+ (A1A1 and A1A2 genotypes) and A1- (A2A2 genotype) alleles of the DRD2 and G1+ (G1G1 and G1 non-G1 genotypes) and G1- (non-G1 non-G1 genotype) alleles of the GABRB3 were determined in a group of 56 medically-ill patients diagnosed with alcohol dependence. Mood-related Alcohol Expectancy (AE) and Drinking Refusal Self-Efficacy (DRSE) were assessed using the Drinking Expectancy Profile (Young and Oei, 1996). Patients with the DRD2 A1+ allele, compared to those with the DRD2 A1- allele, reported lower DRSE in situations of social pressure (p=. 009). Similarly, lower DRSE was reported under social pressure by patients with the GABRB3 G1+ allele when compared to those with the GABRB3 G1- allele (p=.027). Patients with the GABRB3 G1+ allele also revealed reduced DRSE in situations characterized by negative affect than patients with the GABRB3 G1- alleles (p=. 037). Patients carrying the GABRB3 G1+ allele showed stronger AE relating to negative affective change (for example, increased depression) than their GABRB3 G1- counterparts (p=. 006). Biological influence in the development of some classes of cognitions is hypothesized. The clinical implications, particularly with regard to patient-treatment matching and the development of an integrated psychological and pharmacogenetic approach are discussed

Genetic and social influences on starting to smoke: a study of Dutch adolescent twins and their parents

In a study of 1600 Dutch adolescent twin pairs we found that 59% of the inter‐individual variation in smoking behaviour could be attributed to shared environmental influences and 31% to genetic factors. The magnitude of the genetic and environmental effects did not differ between boys and girls. However, environmental effects shared by male twins and environmental effects shared by female twins were imperfectly correlated in twins from opposite‐sex pairs, indicating that different environmental factors influence smoking in adolescent boys and girls. In the parents of these twins, the correlation between husband and wife for‘currently smoking’(r = 0.43) was larger than for‘ever smoked’(r = 0.18). There was no evidence that smoking of parents (at present or in the past) encouraged smoking in their offspring. Resemblance between parents and offspring was significant but rather low and could be accounted for completely by their genetic relatedness. Moreover, the association between‘currently smoking’in the parents and smoking behaviour in their children was not larger than the association between‘ever smoking’in parents and smoking in their children. Copyright © 1994, Wiley Blackwell. All rights reserve

Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the γ-aminobutyric acidA receptor (GABAAR) β1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse

Safety evaluations of the cry1Ia1 protein found in the transgenic potato \u27SpuntaG2\u27

The transgenic potato \u27SpuntaG2\u27 (Solanum tuberosum), which is resistant to potato tuber moth (Phthorimaea operculella), was subjected to protein safety evaluations including protein equivalency tests for the Cry1Ia1 protein from \u27SpuntaG2\u27 and bacterially produced Cry1Ia1, toxicity and allergenicity evaluations of Cry1Ia1 protein, and compositional equivalency of \u27SpuntaG2\u27 compared with non-transgenic \u27Spunta\u27. Western blot analysis and biological activity assays showed molecular and functional equivalency between \u27SpuntaG2\u27-derived Cry1Ia1 protein and bacteria-derived Cry1Ia1 protein. Comparison of the Cry1Ia1 amino acid sequence to known amino acid sequences revealed no significant homology to known toxins or known allergens. Acute toxicity studies using rodents were used to calculate an acceptable daily intake (ADI) value of 20 mg·kg-1 body weight per day. The ADI value was then used to calculate a margin of exposure (MOE) of 2,222,222, which is more than 22,000 times greater than the commonly used target MOE of 100. Digestibility and thermostability assays determined that Cry1Ia1 was fully digested within 30 s of exposure to pepsin and inactive after 3 to 4 minutes at 100°C, indicating that it would not be a potential allergen. Compositional analyses revealed no difference between \u27SpuntaG2\u27 and non-transgenic \u27Spunta\u27. These results strongly indicate that the Cry1Ia protein and the transgenic potato \u27SpuntaG2\u27 is not a human health risk

A census of handicapped children in South Australia : factors related to dental care

Thesis (M.D.S.) -- University of Adelaide, Dept. of Dental Health, 197