Association of immunoproteasomes with the endoplasmic reticulum

Proteasomes are complex multisubunit proteases which play a critical role in intracellular proteolysis. Immunoproteasomes, which contain three c-interferon-inducible subunits, are a subset of proteasomes which have a specialized function in antigen processing for presentation by the MHC class I pathway. Two of the c-interferon inducible subunits, LMP2 and LMP7, are encoded within the MHC class II region adjacent to the two TAP (transporter associated with antigen presentation) genes. We have investigated the localization of immunoproteasomes using monoclonal antibodies to LMP2 and LMP7. Immunoproteasomes were strongly enriched around the endoplasmic reticulum as judged by double-immuno¯uorescence experiments with anticalreticulin antibodies, but were also present in the nucleus and throughout the cytosol. In contrast, proteasome subunit C2, which is present in all proteasomes, was found to be evenly distributed throughout the cytoplasm and in the nucleus, as was the delta subunit, which is replaced by LMP2 in immunoproteasomes. c-Interferon increased the level of immunoproteasomes, but had no effect on their distribution. Our results provide the ®rst direct evidence that immunoproteasomes are strongly enriched at the endoplasmic reticulum, where they may be located close to the TAP transporter to provide efficient transport of peptides into the lumen of the endoplasmic recticulum for association with MHC class I molecules.

Impact of physical, psychological, and sexual violence on social adjustment of school children in India

and sexual violence on the social adjustment of Grade 8 and 9 school children in the state of Tripura, India. The study participants, 160 boys and 160 girls, were randomly selected from classes in eight English and Bengali medium schools in Agartala city, Tripura. Data were collected using a self-administered Semi-structured Questionnaire for Children/Students and a Social Adjustment Inventory which were custom-made for the study based on measures in the extant research adapted for the Indian context. Findings revealed that students experienced physical (21.9%), psychological (20.9%), and sexual (18.1%) violence at home, and 29.7% of the children had witnessed family violence. Boys were more often victims of physical and psychological violence while girls were more often victims of sexual violence. The social adjustment scores of school children who experienced violence, regardless of the nature of the violence, was significantly lower when compared with scores of those who had not experienced violence (p<0.001). Social adjustment was poorer for girls than boys (p<0.001). The study speaks in favour of early detection and intervention for all child maltreatment subtypes and for children exposed to interparental violence, and highlights the crucial role of schools and school psychology in addressing the problem.

Injury prevention among friends : the benefits of school connectedness

Background: Injury is a leading cause of adolescent death. Risk-taking behaviours, including unsafe road behaviours, violence and alcohol use, are primary contributors. Recent research suggests adolescents look out for their friends and engage in protective behaviour to reduce others’ involvement in risk-taking. A positive school environment, and particularly students’ school connectedness, is also associated with reduced injury-risks. Aim: This study aimed to understand the role of school connectedness in adolescents’ intentions to protect and prevent their friends from involvement in alcohol use, fights, drink driving and unlicensed driving. Method: Surveys were completed by 540 13-14 year old students (49% male). Four sequential logistic regression analyses were conducted to determine whether school connectedness statistically predicted intentions to protect friends from injury-risk behaviours. Gender and ethnicity were entered at step 1, students’ own risk behaviour at step 2, and school connectedness scores at step 3 for all analyses. Results: School connectedness significantly predicted intentions to protect friends from all four injury-risk behaviours, after accounting for the variance attributable to sex, ethnicity and adolescents’ own involvement in injury-risks. Significance: School connectedness is negatively associated with adolescents’ own injury-risk behaviours. This research extends our knowledge of this critical protective factor, as it shows that students who are connected to school are also more likely to protect their friends from alcohol use, violence and unsafe road behaviours. School connectedness may therefore be an important factor to target in school-based prevention programs, both to reduce adolescents’ own injury-risk behaviour and to increase injury prevention among friends.

Australia at the crossroads : a review of school science practical work

In Australia we are at a crossroad in science education. We have come from a long history of adopting international curricula, through to blending international and Australian developed materials, to the present which is a thoroughly unique Australian curriculum in science. This paper documents Australia’s journey over the past 200 years, as we prepare for the unveiling of our first truly Australian National Curriculum. One of the unique aspects of this curriculum is the emphasis on practical work and inquiry-based learning. This paper identifies seven forms of practical work currently used in Australian schools and the purposes aligned with each form by 138 pre-service and experienced in-service teachers. The paper explores the question “What does the impending national curriculum, with its emphasis on practical inquiry mean to the teachers now, are they ready?” The study suggests that practical work in Australian schools is multifaceted, and the teacher aligned purposes are dependent not only upon the age of the student, but also on the type of practical work being undertaken. It was found that most teachers are not ready to teach using inquiry-based pedagogy and cite lack of content knowledge, behaviour management, and lack of physical resources and availability of classroom space as key issues which will hinder their implementation of the inquiry component of Australia’s pending curriculum in science.

Epistemic beliefs and beliefs about teaching practices for moral learning in the early years of school : relationships and complexities

While investment in young children is recognised as important for the development of moral values for a cohesive society, little is known about early years teaching practices that promote learning of moral values. This paper reports on observations and interviews with 11 Australian teachers, focusing on their epistemic beliefs and beliefs about teaching practices for moral education with children aged 5 to 8 years. The analysis revealed three main patterns of thinking about moral education: following others, reflecting on points of view, and informing reflection for action. These patterns suggest a relationship between epistemic beliefs and beliefs about teaching practices for moral learning which have implications for teacher professional development concerning experiences in moral education.

Child sexual abuse prevention education : A review of school policy and curriculum provision in Australia

The past four decades have seen increasing public and professional awareness of child sexual abuse. Congruent with public health approaches to prevention, efforts to eliminate child sexual abuse have inspired the emergence of prevention initiatives which can be provided to all children as part of their standard school curriculum. However, relatively little is known about the scope and nature of child sexual abuse prevention efforts in government school systems internationally. This paper assesses and compares the policies and curriculum initiatives for child sexual abuse prevention education in primary (elementary) schools across state and territory Departments of Education in Australia. Using publicly available electronic data, a deductive qualitative content analysis of policy and curriculum documents was undertaken to examine the characteristics of child sexual abuse prevention education in these school systems. It was found that the system-level provision of child sexual abuse prevention education occurs unevenly across state and territory jurisdictions. This results in the potential for substantial inequity in Australian children’s access to learning opportunities in child abuse prevention education as a part of their standard school curriculum. In this research, we have developed a strategy for generating a set of theoretically-sound empirical criteria that may be more extensively applied in comparative research about prevention initiatives internationally.

Association of a Notch 3 gene polymorphism with migraine susceptibility

Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) shares common symptoms with migraine. Most CADASIL causative mutations occur in exons 3 and 4 of the Notch 3 gene. This study investigated the role of C381T (rs 3815188) and G684A (rs 1043994) single nucleotide polymorphisms (SNP) in exons 3 and 4, respectively, of the Notch 3 gene in migraine. Results The first part of the study, in a population of 275 migraineurs and 275 control individuals, found a significant association between the C381T variant and migraine, specifically in migraine without aura (MO) sufferers. The G684A variant was also found to be significantly associated with migraine, specifically in migraine with aura (MA) sufferers. A follow-up study in 300 migraineurs and 300 control individuals did not show replicated association of the C381T variant with migraineurs. However, the G684A variant was again shown to be significantly associated with migraine, specifically with MA. Conclusion Further investigation of the G684A variant and the Notch 3 gene is warranted to understand their role in migraine.

Association of the NuMA region on chromosome 11q13 with breast cancer susceptibility

The development of breast cancer is a complex process that involves multiple genes at many stages, from initial cell cycle dysregulation to disease progression. To identify genetic variations that influence this process, we conducted a large-scale association study using a collection of German cases and controls and >25,000 SNPs located within 16,000 genes. One of the loci identified was located on chromosome 11q13 [odds ratio (OR)=1.85, P=0.017]. The initial association was subsequently tested in two independent breast cancer collections. In both sample sets, the frequency of the susceptibility allele was increased in the cases (OR=1.6, P=0.01). The susceptibility allele was also associated with an increase in cancer family history (P=0.1). Fine mapping showed that the region of association extends approximately 300 kb and spans several genes, including the gene encoding the nuclear mitotic apparatus protein (NuMA). A nonsynonymous SNP (A794G) in NuMA was identified that showed a stronger association with breast cancer risk than the initial marker SNP (OR=2.8, P=0.005 initial sample; OR=2.1, P=0.002 combined). NuMA is a cell cycle-related protein essential for normal mitosis that is degraded in early apoptosis. NuMA-retinoic acid receptor alpha fusion proteins have been described in acute promyelocytic leukemia. Although the potential functional relevance of the A794G variation requires further biological validation, we conclude that variations in the NuMA gene are likely responsible for the observed increased breast cancer risk.

Association of estrogen receptor and glucocorticoid receptor gene polymorphisms with sporadic breast cancer

We have utilized a cross-sectional association approach to investigate sporadic breast cancer. Polymorphisms in 2 candidate genes, ESRalpha and GRL, were examined in an unrelated breast cancer-affected and age-matched control population. Several polymorphic regions within the ESRalpha gene have been identified, and some alleles of these polymorphisms have been found to occur at increased levels in breast-cancer patients. Additionally, variations in GRL have the potential to disrupt cell transcription and may be associated with cancer formation. We analyzed 3 polymorphisms, from codons 10 (TCT to TCC), 325 (CCC to CCG) and 594 (ACA to ACG) of ESRalpha, and a highly polymorphic dinucleotide repeat, D5S207, located within 200 kb of the GRL. When allelic frequencies of the codon 594 (exon 8) ESR polymorphism were compared between affected and unaffected populations, a significant difference was observed (p = 0.005). Results from the D5S207 dinucleotide repeat located near GRL also indicated a significant difference between the tested case and control populations (p = 0.001). Allelic frequencies of the codon 10 and codon 325 ESR polymorphisms were not significantly different between populations (p = 0.152 and 0.181, respectively). Our results indicate that specific alleles of the ESR gene (alpha subtype) and a marker for the GRL gene locus are associated with sporadic breast-cancer development in the tested Caucasian population and justify further investigation of the role of these and other nuclear steroid receptors in the etiology of breast cancer.

Association of a vitamin D receptor polymorphism with sporadic breast cancer development

Breast cancer is the leading cause of cancer death among Australian women and its incidence is annually increasing. Genetic factors are involved in the complex etiology of breast cancer. The seco-steroid hormone, 1.25 dihydroxy vitamin D3 can influence breast cancer cell growth in vitro. A number of studies have reported correlations between vitamin D receptor (VDR) gene polymorphisms and several diseases including prostate cancer and osteoporosis. In breast cancer, low vitamin D levels in serum are correlated with disease progression and bone metastases, a situation also noted in prostate cancer and suggesting the involvement of the VDR. In our study, 2 restriction fragment length polymorphisms (RFLP) in the 3' region (detected by Apa1 and Taq1) and an initiation codon variant in the 5' end of the VDR gene (detected by Fok1) were tested for association with breast cancer risk in 135 females with sporadic breast cancer and 110 cancer-free female controls. Allele frequencies of the 3' Apa1 polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI = 1.09-2.24) while the Taq1 RFLP showed a similar trend (p = 0.053; OR = 1.45, 95% CI = 1.00-2.00). Allele frequencies of the Fok1 polymorphism were not significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69-1.43) in the study population. Our results suggest that specific alleles of the VDR gene located near the 3' region may identify an increased risk for breast cancer and justify further investigation of the role of VDR in breast cancer.

Association of a polymorphism of the angiotensin I-converting enzyme gene with essential hypertension

A polymorphism of the angiotensin I converting enzyme (ACE) gene has recently been reported and analysis of this polymorphism has indicated that it is associated with several cardiovascular diseases. However, the results are still controversial and such association has not yet been established conclusively. To determine whether the ACE gene may be responsible for essential hypertension in a Japanese population, we also compared the distribution of genotypes and the allele frequency of this polymorphism in our findings of a Japanese population with these features in other countries. Eighty-seven hypertensive patients with a family history of essential hypertension and 95 normotensive patients whose parents had no such history were enrolled in the study. Polymorphism of the ACE gene was determined by using the polymerase chain reaction. Homozygotes for this polymorphism had either a 490-bp band (II) or a 190-bp band (DD) and heterozygotes had both bands (ID). In hypertensive subjects, the numbers and frequency of the ACE genotypes were: II, 44 (0.51); ID, 26 (0.30); DD, 17 (0.19). In normotensive subjects these were: II, 35 (0.37); ID, 43 (0.45); DD, 17 (0.18). There were no significant differences between the two groups in derived allele frequencies (chi 2 = 1.41). The difference between the overall allelic frequency in Japan and that reported in several other countries was significant. We did not find any association between ACE gene polymorphism and essential hypertension in Japan. However, there were significant differences in derived allele frequencies between our findings in a Japanese population and those reported from Europe and Australia.

Marked association of a RFLP for the low density lipoprotein receptor gene with obesity in essential hypertensives

RFLPs at the low density lipoprotein receptor locus (LDLR) display marked linkage disequilibrium between each other. Cross-sectional analysis of a bi-alleleic ApaLI RFLP of LDLR showed that the 9.4- and 6.6-kb alleles were present in similar frequency between a group of 84 Caucasian essential hypertensive (HT) and a group of 96 normotensive subjects whose parents each had a similar blood pressure status at age > or = 50. After subdividing HTs into lean and obese, however, the frequency of the 6.6-kb allele in the 27 HTs with BMI > or = 26 kg/m2 was 0.63, compared with 0.39 for HTs with BMI < 26 (chi 2 = 8.8; P = 0.004). The difference in genotype frequencies was even more striking (chi 2 = 23; P = 0.00008), with a virtual absence of 9.4-kb homozygotes in the obese HT group (1 vs 22). Genetic variation at LDLR (19p13.2) is thus associated with obesity in HT.