Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants

Background: The vast majority of BRCA1 missense sequence variants remain uncharacterised for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. Objective: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. Methods and Results: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. Conclusions: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

A Classification of Homogeneous Operators in the Cowen-Douglas Class

A complete list of homogeneous operators in the Cowen-Douglas class B-n(D) is given. This classification is obtained from an explicit realization of all the homogeneous Hermitian holomorphic vector bundles on the unit disc under the action of the universal covering group of the bi-holomorphic automorphism group of the unit disc.

Reliable stabilization using a multi-controller configuration

Given a plant P, we consider the problem of designing a pair of controllers C1 and C2 such that their sum stabilizes P, and in addition, each of them also stabilizes P should the other one fail. This is referred to as the reliable stabilization problem. It is shown that every strongly stabilizable plant can be reliably stabilized; moreover, one of the two controllers can be specified arbitrarily, subject only to the constraint that it should be stable. The stabilization technique is extended to reliable regulation.

The Effect of Post-Pubertal Castration on Behaviour in Beef Cattle

Castration of male beef cattle is advantageous for management, however pre-pubertal (early) castration results in comparative losses in growth rate (Jago et al., 1996). Post-pubertal (late) castration may maintain growth rate but lead to management problems. The behavioural differences between early castrates (9mo) and late castrates (18mo), which may have an effect on growth rate were studied.

First report of Tomato spotted wilt virus in chickpea (Cicer arietinum) in Australia

Tomato spotted wilt virus (genus Tospovirus) is recorded on chickpea (Cicer arietinum) in Australia for the first time. It caused shoot tip symptoms of wilting, necrosis, bunching and chlorosis, followed by premature death of plants.

Social skills, expectancies, and drinking in adolescents

Research in the field of teenage drinking behavior has shown relationships between both social skills and drinking and alcohol expectancies and drinking. The present research investigated the comparative power of both of these sets of variables in predicting teenage drinking behavior, as well as looking at the contribution of more global cognitive structures. It was hypothesised that adolescents with high alcohol involvement would be discriminated from those with low involvement on the basis of social skills, cognitive structures, and alcohol expectancies. Seven hundred thirty-two adolescents participated in the study. Results indicated that adolescent alcohol involvement was associated with social skills deficits, positive alcohol expectancies, and negative cognitive structures concerning parents and teachers. The results revealed that, although the bulk of the variance in drinking behavior was explained by the independent effects of social skills and expectancies, the interaction of the two constructs explained an additional and significant proportion of the variance. Implications for preventive and treatment programs are discussed.

Population genetic structure of the brown tiger prawn, Penaeus esculentus, in tropical northern Australia

Eight polymorphic microsatellite loci were analysed in six population samples from four locations of the Australian endemic brown tiger prawn, Penaeus esculentus. Tests of Hardy-Weinberg equilibrium were generally in accord with expectations, with only one locus, in two samples, showing significant deviations. Three samples were taken in different years from the Exmouth Gulf. These showed no significant heterogeneity, and it was concluded that they were from a single panmictic population. A sample from Shark Bay, also on the west coast of Australia, showed barely detectable differentiation from Exmouth Gulf (F (ST) = 0 to 0.0014). A northeast sample from the Gulf of Carpentaria showed low (F (ST) = 0.008) but significant differentiation from Moreton Bay, on the east coast. However, Exmouth Gulf/Shark Bay samples were well differentiated from the Gulf of Carpentaria/Moreton Bay (F (ST) = 0.047-0.063). The data do not fit a simple isolation by distance model. It is postulated that the east-west differentiation largely reflects the isolation of east and west coast populations that occurred at the last glacial maximum when there was a land bridge between north-eastern Australia and New Guinea.

Rapid and sensitive detection of Avibacterium paragallinarum in the presence of other bacteria using a 5' Taq nuclease assay: A new tool for diagnosing infectious coryza

A 5' Taq nuclease assay specific for Avibacterium paragallinarum was designed and optimized for use in diagnosing infectious coryza. The region chosen for assay design was one of known specificity for Av. paragallinarum. The assay detected Av. paragallinarum reference strains representing the three Page and the eight Kume serovars, and field isolates from diverse geographical locations. No cross-reactions were observed with other Avibacterium species, with other bacteria taxonomically related to Av. paragallinarum nor with bacteria and viruses likely to be present in swabs collected from suspected infectious coryza cases. The detection limit for the assay was 6 to 60 colony-forming units per reaction. Twenty-two out of 53 swabs collected from sick birds reacted in the 5' Taq nuclease assay, whereas Av. paragallinarum was not isolated from any of the swabs. All of the 22 swabs yielded other bacteria in culture. The presence of Av. paragallinarum in the swabs was also demonstrated by sequencing, thereby confirming the ability of the assay to detect Av. paragallinarum in the presence of other bacteria. The ability to quantify bacterial load in the swabs using the 5' Taq nuclease assay was demonstrated.

The Google Online Marketing Challenge: A Transnational Comparison of Classroom Learning with Real Clients, Real Money, and Real Advertising Campaigns

In 2008, a collaborative partnership between Google and academia launched the Google Online Marketing Challenge (hereinafter Google Challenge), perhaps the world’s largest in-class competition for higher education students. In just two years, almost 20,000 students from 58 countries participated in the Google Challenge. The Challenge gives undergraduate and graduate students hands-on experience with the world’s fastest growing advertising mechanism, search engine advertising. Funded by Google, students develop an advertising campaign for a small to medium sized enterprise and manage the campaign over three consecutive weeks using the Google AdWords platform. This article explores the Challenge as an innovative pedagogical tool for marketing educators. Based on the experiences of three instructors in Australia, Canada and the United States, this case study discusses the opportunities and challenges of integrating this dynamic problem-based learning approach into the classroom.

Taxonomy, distribution and ecology of Zoysia macrantha desv., an Australian native species with turf breeding potential

Only three of the 11 species in the genus Zoysia Willd. have thus far contributed to commercially available turfgrass varieties. One of the neglected taxa is Z. macrantha Desv., an Australian native species further divided into two subspecies. The coarser Z. macrantha subsp. macrantha occurs on sand dunes, headlands and tidal areas along eastern and southeastern coasts from about 23 to 38°S latitude. The shorter, denser-growing Z. macrantha subsp. walshii M.E. Nightingale is found on the southern mainland (South Australia and Victoria from longitude 137° to 148°E and at latitudes higher than 36°S), adjacent offshore islands, and northern, eastern and central Tasmania to 43°S growing on the edges of coastal, sub-coastal and even inland salt lakes, in riverine environments, and from moist grassy depressions (both coastal and inland) to rocky headlands. The latter subspecies has the more discontinuous and specialised distribution, largely determined by the need for an appropriate level of peat, clay or silt in the soil to maintain adequate moisture during the dry summers in southern Australia while at the same time avoiding anything more than temporary waterlogging. It grows on low fertility soils ranging from strongly acid to neutral or mildly alkaline, and is often very closely grazed by marsupials. Both subspecies are salt and drought tolerant, but not notably shade tolerant. Their potential to add greater drought tolerance in particular to the Asian Zoysia material in current use through future breeding programs is discussed.

On the transfer matrix for a uniform tube with a moving medium

Abstract is not available.

Comparison of the Radar and Seeker Modes of Pursuer Guidance

This paper compares closed-loop performance of seeker-based and radar-based estimators for surface-to-air interception through 6-degree-of-freedom simulation using proportional navigation guidance.Ground radar measurements are evader range, azimuth and elevation angles contaminated by Gaussian noise. Onboard seeker measurements are pursuer-evader relative range, range rate also contaminated by Gaussian noise. The gimbal angles and line-of-sight rates in the gimbal frame,contaminated by time-correlated non-Gaussian noise with realistic numerical values are also available as measurements. In both the applications, extended Kalman filter with Gaussian noise assumption are used for state estimation. For a typical engagement, it is found that,based on Monte Carlo studies, seeker estimator outperforms radar estimator in terms of autopilot demand and reduces the miss distance.Thus, a seeker estimator with white Gaussian assumption is found to be adequate to handle the measurements even in the presence of non-Gaussian correlated noise. This paper uses realistic numerical values of all noise parameters.

Synthetic arabinomannan glycolipids and their effects on growth and motility of the Mycobacterium smegmatis

Arabinomannan-containing glycolipids, relevant to the mycobacterial cell-wall component lipoarabinomannan, were synthesized by chemical methods. The glycolipids were presented with tri- and tetrasaccharide arabinomannans as the sugar portion and a double alkyl chain as the lyophilic portion. Following synthesis, systematic biological and biophysical studies were undertaken in order to identify the effects of the glycolipids during mycobacterium growth. The studies included mycobacterial growth, biofilm formation and motility assays. From the studies, it was observed that the synthetic glycolipid with higher arabinan residues inhibited the mycobacterial growth, lessened the biofilm formation and impaired the motility of mycobacteria. A surface plasmon resonance study involving the immobilized glycan surface and the mycobacterial crude lysates as analytes showed specificities of the interactions. Further, it was found that cell lysates from motile bacteria bound oligosaccharide with higher affinity than non-motile bacteria.

Cancer incidence, mortality, and pregnancy outcome among women treated for cervical intraepithelial neoplasia

Cervical cancer develops through precursor lesions, i.e. cervical intraepithelialneoplasms (CIN). These can be detected and treated before progression to invasive cancer. The major risk factor for developing cervical cancer or CIN is persistent or recurrent infection with high-risk human papilloma virus (hrHPV). Other associated risk factors include low socioeconomic status, smoking, sexually transmitted infections, and high number of sexual partners, and these risk factors can predispose to some other cancers, excess mortality, and reproductive health complications as well. The aim was to study long-term cancer incidence, mortality, and reproductive health outcomes among women treated for CIN. Based on the results, we could evaluate the efficacy and safety of CIN treatment practices and estimate the role of the risk factors of CIN patients for cancer incidence, mortality, and reproductive health. We collected a cohort of 7 599 women treated for CIN at Helsinki University Central Hospital from 1974 to 2001. Information about their cancer incidence, cause of death, birth of children and other reproductive endpoints, and socio-economic status were gathered through registerlinkages to the Finnish Cancer Registry, Finnish Population Registry, and Statistics Finland. Depending on the endpoints in question, the women treated were compared to the general population, to themselves, or to an age- and municipality-matched reference cohort. Cervical cancer incidence was increased after treatment of CIN for at least 20 years, regardless of the grade of histology at treatment. Compared to all of the colposcopically guided methods, cold knife conization (CKC) was the least effective method of treatment in terms of later CIN 3 or cervical cancer incidence. In addition to cervical cancer, incidence of other HPV-related anogenital cancers was increased among those treated, as was the incidence of lung cancer and other smoking-related cancers. Mortality from cervical cancer among the women treated was not statistically significantly elevated, and after adjustment for socio-economic status, the hazard ratio (HR) was 1.0. In fact, the excess mortality among those treated was mainly due to increased mortality from other cancers, especially from lung cancer. In terms of post-treatment fertility, the CIN treatments seem to be safe: The women had more deliveries, and their incidence of pregnancy was similar before and after treatment. Incidence of extra-uterine pregnancies and induced abortions was elevated among the treated both before and after treatment. Thus this elevation did not occur because they were treated rather to a great extent was due to the other known risk factors these women had in excess, i.e. sexually transmitted infections. The purpose of any cancer preventive activity is to reduce cancer incidence and mortality. In Finland, cervical cancer is a rare disease and death from it even rarer, mostly due to the effective screening program. Despite this, the women treated are at increased risk for cancer; not just for cervical cancer. They must be followed up carefully and for a long period of time; general health education, especially cessation of smoking, is crucial in the management process, as well as interventions towards proper use of birth control such as condoms.