Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer

Deficiencies in DNA repair have been hypothesized to increase cancer risk and excess cancer incidence is a feature of inherited diseases caused by defects in DNA damage recognition and repair. We investigated, using a case-control design, whether the double-strand break repair gene polymorphisms RAD51 5' untranslated region -135 G > C, XRCC2 R188H G > A, and XRCC3 T241M C > T were associated with risk of breast or ovarian cancer in Australian women. Sample sets included 1,456 breast cancer cases and 793 age-matched controls ages under 60 years of age, 549 incident ovarian cancer cases, and 335 controls of similar age distribution. For the total sample and the subsample of Caucasian women, there were no significant differences in genotype distribution between breast cancer cases and controls or between ovarian cancer cases and combined control groups. The crude odds ratios (OR) and 95% confidence intervals (95% CI) associated with the RAD51 GC/CC genotype frequency was OR, 1.10; 95% CI, 0.80-1.41 for breast cancer and OR, 1.22; 95% CI, 0.92-1.62 for ovarian cancer. Similarly, there were no increased risks associated with the XRCC2 GA/AA genotype (OR, 0.98; 95% CI, 0.76-1.26 for breast cancer and OR, 0.93; 95% CI, 0.69-1.25 for ovarian cancer) or the XRCC3 CT/TT genotype (OR, 0.92; 95% Cl, 0.77-1.10 for breast cancer and OR, 0.87; 95% CI, 0.71-1.08 for ovarian cancer). Results were little changed after adjustment for age and other measured risk factors. Although there was little statistical power to detect modest increases in risk for the homozygote variant genotypes, particularly for the rare RAD51 and XRCC2 variants, the data suggest that none of these variants play a major role in the etiology of breast or ovarian cancer.

Observation of crack initiation during hot tearing

While the general mechanisms of hot tearing are understood, i.e. the inability of liquid to feed imposed strain on the mushy material, work continues on improving the understanding of the mechanisms at play. A hot tear test rig that measures the temperature and load imposed on the mushy zone during solidification has been successfully used to study hot tearing. The mould has now been modified to incorporate a window above the hot spot region to allow observation of hot tear formation and growth. Combining information from visual observation with load and temperature data has led to a better understanding of the mechanism of hot tearing. Tests were carried out on an Al-0.5 wt-% Cu alloy. It was found that load development began at about 90% solid and a hot tear formed a short time later, at between 93% and 96% solid. Hot tearing started at a very low load.

The implications of simultaneous smoking initiation for inferences about the genetics of smoking behavior from twin data

We examined early social influences across stages of smoking within the context of a twin study using an environmental exposure specific to smoking: whether twins started smoking at the same time (simultaneous smoking initiation: SSI). We expected that SSI would be a good index of shared social influences on smoking initiation. Rates of SSI were indeed significantly higher in MZ twins and in twins who shared peers and classes, as well as in male twins. With the exception of regular smoking in females, we found no significant difference in estimates of genetic and environmental parameters between SSI and non-SSI pairs for any of the smoking measures that we examined (DSM-IV and Fagerstrom HSI measures of nicotine dependence; DSM-IV nicotine withdrawal; heavy smoking; and in males, regular smoking). For regular smoking in females, allowing for additional shared environmental influences associated with SSI only modestly reduced our estimates of additive genetic variance (56% vs. 68%). These results indicate the important social influences that may occur for smoking initiation do not appear to seriously bias estimates of genetic effects on later stages of smoking.

Changes in the initiation of heroin use after a reduction in heroin supply

Increasing heroin use in Australia over the past 30 years has been associated with a decline in the age of initiation to heroin use. The 2001 Australian heroin shortage was used to assess the effects of a reduction in heroin supply on age of initiation into heroin injecting. Data collected from regular injecting drug users (IDU) over the period 1996-2004 as part of the Australian Illicit Drug Reporting System were examined for changes in self- reported age of first heroin use after the onset of the heroin shortage. Estimates were also made of the number of young people who may not have commenced injecting heroin during the heroin shortage. The proportion of IDU interviewed in the IDRS who were aged

Genetic and Cultural Transmission of Smoking Initiation: An Extended Twin Kinship Model

Background Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a significant role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent–offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. Methods We examined the role of genetic and environmental factors for smoking initiation using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission. A dichotomous lifetime smoking measure was obtained from twins and relatives in the Virginia 30,000 sample. Results Results demonstrate that both genetic and environmental factors play a significant role in the liability to smoking initiation. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission and resulting genotype–environment covariance. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent–offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (i) age × gene interaction, and (ii) social homogamy. Neither mechanism provided a significantly better explanation of the data, although age regression was significant. Conclusions This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on smoking initiation.

A longitudinal controlled study of factors associated with mutans streptococci infection and caries lesion initiation in children 21 to 72 months old

Purpose: The purpose of this longitudinal study was to determine factors associated with mutans streptococci (MS) infection and development of caries lesions in a group of children 21 to 72 months old. Methods: The 63 caries-free children, recruited since birth, were divided into: (1) a study group of 24 children who were colonized with MS; and (2) a control group of 39 children without MS. The children were recalled every 3 months for approximately 24 months, and their social, medical, and dental histories were updated. At each recall, the teeth were checked for presence or absence of plaque, enamel hypoplasia, and caries lesions, and their MS status was assessed using a commercial test kit. Results: MS infection was associated with: (1) visible plaque (P < .01); (2) enamel hypoplasia (P < .05); (3) commencement of tooth-brushing after 12 months of age (P < .05); (4) lack of parental assistance with tooth-brushing (P < .025); and (5) increased hours of child care/school (P < .05). Four children (20%) were colonized at an age range of 21 to 36 months, 9 (45%) at 37 to 48 months, and 7 (35%) at 49 to 72 months (P < .001). Eight children who developed caries lesions: (1) had more hypoplastic teeth (P < .001); (2) ate sugar-containing snacks (P < .05); and (3) did not brush regularly with chlorhexidine gel (P < .01) compared to those who remained free of caries lesions. Conclusions: Lack of oral hygiene, consumption of sugar-containing snacks, and enamel hypoplasia are significant factors for both MS infection and caries lesion initiation.

A strand of vermicelli:Dr Darwin's part in the creation of Frankenstein's monster

Although much has been written about Mary Shelley's Frankenstein, the part played by Erasmus Darwin (1731-1802) has been almost entirely neglected. This is odd as, apart from some ghost stories, Dr Darwin is the one influence mentioned in both the 1816 and 1831 prefaces to the book. The present contribution aims to redress that omission. It aims to show that Darwin's ideas about spontaneous generation, his anti-establishment ideas, and his literary genius played a significant role in forming the 'dark and shapeless substance' surging in Mary Shelley's mind during the summer of 1816 and from which her tale of Gothic horror emerged. It is, however, ultimately ironic that Frankenstein, which warns against a too enthusiastic use of scientific knowledge, should have been partly inspired by one of the most optimistically forward-looking of all late eighteenth-century thinkers. © 2007 Institute of Materials, Minerals and Mining.

Improper organization of the actin cytoskeleton affects protein synthesis at initiation

Although the actin cytoskeleton and the translation machinery are considered to be separate cellular complexes, growing evidence supports overlapping regulation of the two systems. Because of its interaction with actin, the eukaryotic translation elongation factor 1A (eEF1A) is proposed to be a regulator or link between these processes. Using a genetic approach with the yeast Saccharomyces cerevisiae, specific regions of eEF1A responsible for actin interactions and bundling were identified. Five new mutations were identified along one face of eEF1A. Dramatic changes in cell growth, cell morphology, and actin cable and patch formation as well as a unique effect on total translation in strains expressing the F308L or S405P eEF1A mutant form were observed. The translation effects do not correlate with reduced translation elongation but instead include an initiation defect. Biochemical analysis of the eEF1A mutant forms demonstrated reduced actin-bundling activity in vitro. Reduced total translation and/or the accumulation of 80S ribosomes in strains with either a mutation or a null allele of genes encoding actin itself or actin-regulating proteins Tpm1p, Mdm20p, and Bnirp/Bni1p was observed. Our data demonstrate that eEF1A, other actin binding proteins, and actin mutants affect translation initiation through the actin cytoskeleton.

Flexibility of short-strand RNA in aqueous solution as revealed by molecular dynamics simulation:are A′-RNA and A-RNA distinct conformational structures?

We use molecular dynamics simulations to compare the conformational structure and dynamics of a 21-base pair RNA sequence initially constructed according to the canonical A-RNA and A'-RNA forms in the presence of counterions and explicit water. Our study aims to add a dynamical perspective to the solid-state structural information that has been derived from X-ray data for these two characteristic forms of RNA. Analysis of the three main structural descriptors commonly used to differentiate between the two forms of RNA namely major groove width, inclination and the number of base pairs in a helical twist over a 30 ns simulation period reveals a flexible structure in aqueous solution with fluctuations in the values of these structural parameters encompassing the range between the two crystal forms and more. This provides evidence to suggest that the identification of distinct A-RNA and A'-RNA structures, while relevant in the crystalline form, may not be generally relevant in the context of RNA in the aqueous phase. The apparent structural flexibility observed in our simulations is likely to bear ramifications for the interactions of RNA with biological molecules (e.g. proteins) and non-biological molecules (e.g. non-viral gene delivery vectors). © CSIRO 2009.