hSSB1 (NABP2/ OBFC2B) is required for the repair of 8-oxo-guanine by the hOGG1-mediated base excision repair pathway

The maintenance of genome stability is essential to prevent loss of genetic information and the development of diseases such as cancer. One of the most common forms of damage to the genetic code is the oxidation of DNA by reactive oxygen species (ROS), of which 8-oxo-7,8-dihydro-guanine (8-oxoG) is the most frequent modification. Previous studies have established that human single-stranded DNA-binding protein 1 (hSSB1) is essential for the repair of double-stranded DNA breaks by the process of homologous recombination. Here we show that hSSB1 is also required following oxidative damage. Cells lacking hSSB1 are sensitive to oxidizing agents, have deficient ATM and p53 activation and cannot effectively repair 8-oxoGs. Furthermore, we demonstrate that hSSB1 forms a complex with the human oxo-guanine glycosylase 1 (hOGG1) and is important for hOGG1 localization to the damaged chromatin. In vitro, hSSB1 binds directly to DNA containing 8-oxoguanines and enhances hOGG1 activity. These results underpin the crucial role hSSB1 plays as a guardian of the genome.

Tumor-associated mutations inO6-methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality

MGMT is the primary vehicle for cellular removal of alkyl lesions from the O-6 position of guanine and the O-4 position of thymine. While key to the maintenance of genomic integrity, MGMT also removes damage induced by alkylating chemotherapies, inhibiting the efficacy of cancer treatment. Germline variants of human MGMT are well-characterized, but somatic variants found in tumors were, prior to this work, uncharacterized. We found that MGMT G132R, from a human esophageal tumor, and MGMT G156C, from a human colorectal cancer cell line, are unable to rescue methyltransferase-deficient Escherichia coli as well as wild type (WT) human MGMT after treatment with a methylating agent. Using pre-steady state kinetics, we biochemically characterized these variants as having a reduced rate constant. G132R binds DNA containing an O6-methylguanine lesion half as tightly as WT MGMT, while G156C has a 40-fold decrease in binding affinity for the same damaged DNA versus WT. Mammalian cells expressing either G132R or G156C are more sensitive to methylating agents than mammalian cells expressing WT MGMT. G132R is slightly resistant to O6-benzylguanine, an inhibitor of MGMT in clinical trials, while G156C is almost completely resistant to this inhibitor. The impared functionality of expressed variants G132R and G156C suggests that the presence of somatic variants of MGMT in a tumor could impact chemotherapeutic outcomes.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin. © 2011 Nature America, Inc. All rights reserved.

The relationship between parents' and their adolescent children's mental health and mental illness

Depression and anxiety disorders are high-prevalence disorders with a significant impact globally and high social and economic costs. Promotion of mental health and the prevention of depression and anxiety disorders are key health priorities internationally. It is now understood that mental health and mental illness are not two ends of one spectrum but two separate, related spectrums. The relationship between mental illness in parents and the development of mental illness in their children has been well documented however this relationship has not yet been examined from a mental health perspective. A number of mental health protective factors (also known as flourishing factors) have been shown to have a preventative effect on the development of depression and anxiety disorders, however whether parents’ mental health protective factors may have any effect on children’s depression and anxiety disorder outcomes remains unknown.

Cloning and gastrointestinal expression of rat hephaestin: Relationship to other iron transport proteins

The membrane-bound ceruloplasmin homolog hephaestin plays a critical role in intestinal iron absorption. The aims of this study were to clone the rat hephaestin gene and to examine its expression in the gastrointestinal tract in relation to other genes encoding iron transport proteins. The rat hephaestin gene was isolated from intestinal mRNA and was found to encode a protein 96% identical to mouse hephaestin. Analysis by ribonuclease protection assay and Western blotting showed that hephaestin was expressed at high levels throughout the small intestine and colon. Immunofluorescence localized the hephaestin protein to the mature villus enterocytes with little or no expression in the crypts. Variations in iron status had a small but nonsignificant effect on hephaestin expression in the duodenum. The high sequence conservation between rat and mouse hephaestin is consistent with this protein playing a central role in intestinal iron absorption, although its precise function remains to be determined.

Crowdfunding and independent screen content production in Australia: A direct economic relationship between producer and audience

This thesis examines the significance of crowdfunding for Australian filmmakers and provides an empirical basis to current claims about the role of crowdfunding in the film production and policy sectors. It has found that crowdfunding is a small but growing source of supplementary finance which is opening up new possibilities for Australian independent screen content producers. This project also highlights the discussion within Australian film policy circles that is opening the way for crowdfunding to potentially become a larger and more formalised component of current and emerging policy initiatives.

Development of a cultured tissue substitute to repair the ageing retina

This project provides a foundation for the use of silk membranes in a tissue engineered therapy for the treatment of devastating retinal diseases such as age-related macular degeneration. The three-dimensional tissue model described in this thesis has great potential for use in basic research of retinal pathologies, and the potential to be implemented into clinical approaches after appropriate refinement.

Family violence in culturally and linguistically diverse communities: An evaluation of a family relationship centre

Federal legislative changes in Australia have sought to improve how family relationship centres (FRCs) can be more responsive to culturally and linguistically diverse (CALD) communities when addressing family disputes and family violence. Research on the prevalence of family violence against women from CALD backgrounds is sparse. This article seeks to contribute to the understanding of this issue by describing findings of an evaluation of the FRC at Broadmeadows conducted by the authors. The findings focus on family violence and the appropriateness of the services offered to three CALD community groups, namely Iraqi, Lebanese and Turkish. The final section provides reflections on these findings and offers suggestions about how FRC services might better cater to the family violence needs of CALD communities by developing more extensive partnerships with community groups and by expanding the range of processes they offer beyond mediation.

Exploring methods of preparing functional cartilage-bone xenografts for joint repair

This thesis explores the feasibility of donor-receiver concept for joint replacement where cartilage-bone tissues can be taken from either human or other mammals and prepared scientifically for repairing focal joint defects in knees, hips and shoulders. The manufactured construct is immunologically inert and is capable of acting as a scaffold for engineering new cartilage-bone laminates when placed in the joint. Innovative manufacturing procedures and assessment techniques were developed for appraising this tissue-based scaffold. This research has demonstrated that tissue replacement technology can be applied in situations where blood vessels are absent such as in articular cartilage.

Is there a relationship between screening for diabetes related foot complications and limb amputation?

Background From the conservative estimates of registrants with the National Diabetes Supply Scheme, we will be soon passing 1.1 Million Australians affected by all types of diabetes. The diabetes complications of foot ulceration and amputation are costly to all. These costs can be reduced with appropriate prevention strategies, starting with identifying people at risk through primary care diabetic foot screening. Yet levels of diabetic foot screening in Australia are difficult to quantify. This presentation aims to report on foot screening rates as recorded in existing academic literature, national health surveys and national database reports. Methods Literature searches included diabetic foot screening that occurred in the primary care setting for populations over 2000 people from 2002 to 2014. Searches were performed using Medline and CINAHL as well as internet searches of Organisations for Economic Co-operation and Development (OECD) countries health databases. The focus is on type 1 and type 2 diabetes in adults, and not gestational diabetes or children. The two primary outcome measures were foot -screening rates as a percentage of adult diabetic population and major lower limb amputation incidence rates from standardised OECD data. Results The most recent and accurate level for Australian population review was in the AUSDIAB (Australian Diabetes and lifestyle survey) from 2004. This survey reported screening in primary care to be as low as 50%. Countries such as the United Kingdom and United States of America have much higher reported rates of foot screening (67-86%) recorded using national databases and web based initiatives that involve patients and clinicians. By comparison major amputation rates for Australia were similar to the United Kingdom at 6.5 versus 5.1 per 100,000 population, but dis-similar to the United States of America at 17 per 100,000 population. Conclusions Australian rates of diabetic foot screening in primary care centres is ambiguous. There is no direct relationship between foot screening levels in a primary care environment and major lower limb amputation, based on national health survey's and OECD data. Uptake of national registers, incentives and web-based systems improve levels of diabetic foot assessment, which are the first steps to a healthier diabetic population.

Relationship between malnutrition and selected risk factors in two hospitals in Vietnam

Aim: The purpose of this study was to determine the percentage of patients assessed as malnourished using the Subjective Global Assessment in two hospitals in Ho Chi Minh City and Can Tho across multiple wards; and to investigate the association with factors including gender, age, days since admission, medical diagnosis and number of medications used. Methods: This cross-sectional study involved 205 inpatients from a hospital in Ho Chi Minh City and 78 inpatients and 89 outpatients from a hospital in Can Tho. Malnutrition status was assessed using Subjective Global Assessment. Ward, gender, age, medical diagnosis, time since admission and medication number were extracted from medical records. Results: 35.6% of inpatients and 9.0% of outpatients were malnourished. Multivariate analysis revealed factors predicting malnutrition status within inpatients (OR (95%CI)) were: age (OR = 1.03 (1.01-1.06)); cancer diagnosis (OR = 34.25 (3.16-370.89)); respiratory ward (11.49 (1.05-125.92)); or general medicine ward (20.34 (2.10-196.88)). Conclusions: Results indicate that malnutrition is a common problem in hospitals in Vietnam. Further research is needed to confirm this finding across a wider range of hospitals and to investigate the feasibility and efficacy of implementation of nutrition interventions in hospital settings.

The Relationship Between University Culture and Climate and Research Scientists’ Spin-off Intentions

Over the past decades, universities have increasingly become involved in entrepreneurial activities. Despite efforts to embrace their 'third mission', universities still demonstrate great heterogeneity in terms of their involvement in academic entrepreneurship. This chapter adopts an institutional perspective to understand how organizational characteristics affect research scientists' entrepreneurial intentions. We study the impact of university culture and climate on entrepreneurial intentions, thereby specifically focusing on intentions to spin off a company. Using a sample of 437 research scientists from Swedish and German universities, our results reveal that the extent to which universities articulate entrepreneurship as a fundamental element of their mission fosters research scientists' spin-off intentions. Furthermore, the presence of university role models positively affects research scientists' propensity to engage in entrepreneurial activities, both directly and indirectly through entrepreneurial self-efficacy. Finally, research scientists working at universities which explicitly reward people for 'third mission' related output show higher levels of spin-off intentions. This study has implications for both academics and practitioners, including university managers and policy makers.

The development and inter-relationship of metacognitive components among primary school children

Much interest has been expressed in the construct metacognition, the individual's knowledge and control of his own cognitive processes. Recent educational proposals have suggested the training of general metacognitive principles in schools. The exact nature of the construct has, however, remained vague. The aim of the present study was to provide some clarity. In a study of the metacognitive responses of 144 primary school children (aged 7‐11 years) four measures commonly used to assess metacognitive function were examined. First, the content of each measure was examined. Secondly, in an attempt to identify a metacognitive factor, commonality among the measures, both of developmental patterns and statistical relationship, was sought. Whilst a common pattern of development in the children's responses to the four measures was identified, factor analysis failed to provide evidence for a common metacognitive factor and unified construct.

The relationship between the determinants of rental housing satisfaction and considering moving in Finland

Purpose The purpose of this paper is to discuss the relation between dissatisfaction with housing conditions and considering moving among residents of Finnish rental multifamily buildings. The paper examines physical attributes, socioeconomic factors, and subjective opinions related to housing conditions and satisfaction with housing. Design/methodology/approach Logistic regression analysis is used to examine survey data to analyse which factors contribute to dissatisfaction with the housing unit and the apartment building and whether dissatisfaction is related to consideration of moving. Findings The findings indicate that dissatisfaction with the building and individual housing unit are associated with greater probability of considering moving. Satisfaction with kitchen, living room, storage, and building age are the most important indicators of satisfaction with the housing unit, and satisfaction with living room, bathroom, storage, and building age are associated with satisfaction with the apartment building. These are the areas in which landlords could invest in renovations to increase satisfaction in an attempt to reduce turnover. Research limitations/implications The study is conducted with Finnish data only. The sample is not a representative sample of the Finnish population. A longitudinal study would be needed to determine whether dissatisfied residents indending to move actually change residence. Originality/value This study is the first of its kind in the Finnish housing market. It tests a general model that has been suggested to be customized to local conditions. In addition, much of the research on this topic is more than 20 years old. Examination of the model under current housing and socioeconomic conditions is necessary to determine if relationships have changed over time.

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 +/- 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 +/- 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 +/- 0.06 s.e.), and ADHD and major depressive disorder (0.32 +/- 0.07 s.e.), low between schizophrenia and ASD (0.16 +/- 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.