Long terminal repeats act as androgen-responsive enhancers for the PSA-Kallikrein locus

The androgen receptor (AR) signaling pathway is a common therapeutic target for prostate cancer, because it is critical for the survival of both hormone-responsive and castrate-resistant tumor cells. Most of the detailed understanding that we have of AR transcriptional activation has been gained by studying classical target genes. For more than two decades, Kallikrein 3 (KLK3) (prostate-specific antigen) has been used as a prototypical AR target gene, because it is highly androgen responsive in prostate cancer cells. Three regions upstream of the KLK3 gene, including the distal enhancer, are known to contain consensus androgen-responsive elements required for AR-mediated transcriptional activation. Here, we show that KLK3 is one of a specific cluster of androgen-regulated genes at the centromeric end of the kallikrein locus with enhancers that evolved from the long terminal repeat (LTR) (LTR40a) of an endogenous retrovirus. Ligand-dependent recruitment of the AR to individual LTR-derived enhancers results in concurrent up-regulation of endogenous KLK2, KLK3, and KLKP1 expression in LNCaP prostate cancer cells. At the molecular level, a kallikrein-specific duplication within the LTR is required for maximal androgen responsiveness. Therefore, KLK3 represents a subset of target genes regulated by repetitive elements but is not typical of the whole spectrum of androgen-responsive transcripts. These data provide a novel and more detailed understanding of AR transcriptional activation and emphasize the importance of repetitive elements as functional regulatory units

Patients with terminal cancer who use alternative therapies: their beliefs and practices

This paper examines the extent to which patients who have been diagnosed as having terminal cancer choose to use non-medical therapies. In particular it is concerned with the illness behaviour of patients who are receiving conventional cytotoxic drug and radiation treatments, who also decide to use a wide range of ‘alternative’ medications and therapies. The paper discusses the findings of a study of 152 patients with metastatic cancer that examined the extent to which they used alternative cancer therapies, as well as the beliefs and attitudes they have about their cancer, its treatment, and the practitioners providing that treatment. Four groups of users of alternative therapies, who differ according to their commitment to and the type of therapies they use, were identified. Results of logistic regression analyses indicate that those using alternative therapies were different in range of social attitudes. These differences were primarily their greater reported ‘will to live’ and desire for control over treatment decisions, and the differing beliefs they hold about their disease.

A Kansei approach to passenger terminal design

Current approaches to passenger terminal design are based on a direct relationship between the number of travelers and the size of the passenger terminal building: as one increases, so does the other. Over the next several decades, it is believed that the number of travelers worldwide will increase significantly. It follows, therefore, that in order to process these additional passengers, airports will need to build larger terminal facilities. Unfortunately, this is not a viable option for many airports due to financial, economic, operational and general space constraints. In this paper, we explore a new way of approaching terminal design based on a passenger oriented perspective. In doing so, we extend an interpretation of the Kansei design concept and show how it may be applicable towards the creation of new design paradigms in aviation. Our results are based on data collected in-situ at a major international terminal during 2012.

A Sustainable Community for Older People : Case Studies of Green Retirement Villages in Australia

In Australia, the proportion of the population aged 65 years and over reached 13.5% in 2010 and is expected to increase steadily to around 20% by the year 2056 [Australia Bureau of Statistics (ABS), 2010], creating what has been regarded as a looming crisis in how to house and care for older people. As a viable accommodation option, the retirement village is widely accepted as a means of promoting and enhancing independence, choice and quality of life for older people. Recent research by Barker (2010) indicates that the current and potential residents of retirement villages are generally very conscious of resource consumption and would like their residences and community to be more sustainable. The aim of this study was to understand the perception of older people toward sustainability ideas and identify the sustainable practices involved in retirement villages to improve the wellbeing of residents. Multiple research methods, including content analysis, questionnaire survey, interviews and case studies were conducted for the research purpose. The results indicate that most retirement village residents understand and recognize the importance of sustainability in their lifestyle. However, their sustainability requirements need to be supported and enhanced by the provision of affordable sustainability features. Additionally, many retirement village developers and operators realize the importance of providing a sustainable retirement community for their residents, and that a sustainable retirement village (that is environmental-friendly, affordable, and improves social engagement) can be achieved through the consideration of project planning, design, construction, and operations throughout the project life cycle. The clear shift from healthcare to lifestyle-focused services in the recent development of retirement villages together with the increasing number of aged people moving into retirement villages (Simpson and Cheney, 2007) has raised awareness of the need for the retirement village industry to provide a sustainable community for older people to improve their life quality after retirement. This is the first critical study of sustainable development in the retirement village industry and its potential in addressing the housing needs of older people, providing a contribution towards improving the life quality of older people and with direct and immediate significance to the community as a whole.

Review of community facilities in Australian retirement villages : a content analysis

Aim Facilities in retirement villages form a supportive environment for older residents. The purpose of this paper is to investigate the provision of these facilities in retirement villages, which are regarded as a viable accommodation option for the ever-increasing ageing population in Australia. Method A content analysis of 124 retirement villages operated by 22 developers in Queensland and South Australia was conducted for the research purpose. Results The most widely provided facilities are community centres, libraries, barbeque facilities, hairdressers/salons and billiards/snooker/pool tables. Commercial operators provide more facilities than not-for-profit organisations and larger retirement villages normally have more facilities due to the economics of scale involved. Conclusions The results of the study provide a useful reference for providing facilities within retirement villages that may support the quality lifestyles for the older residents.

N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB

Protein N-terminal acetylation (Nt-acetylation) is an important mediator of protein function, stability, sorting, and localization. Although the responsible enzymes are thought to be fairly well characterized, the lack of identified in vivo substrates, the occurrence of Nt-acetylation substrates displaying yet uncharacterized N-terminal acetyltransferase (NAT) specificities, and emerging evidence of posttranslational Nt-acetylation, necessitate the use of genetic models and quantitative proteomics. NatB, which targets Met-Glu-, Met-Asp-, and Met-Asn-starting protein N termini, is presumed to Nt-acetylate 15% of all yeast and 18% of all human proteins. We here report on the evolutionary traits of NatB from yeast to human and demonstrate that ectopically expressed hNatB in a yNatB-Δ yeast strain partially complements the natB-Δ phenotypes and partially restores the yNatB Nt-acetylome. Overall, combining quantitative N-terminomics with yeast studies and knockdown of hNatB in human cell lines, led to the unambiguous identification of 180 human and 110 yeast NatB substrates. Interestingly, these substrates included Met-Gln- N-termini, which are thus now classified as in vivo NatB substrates. We also demonstrate the requirement of hNatB activity for maintaining the structure and function of actomyosin fibers and for proper cellular migration. In addition, expression of tropomyosin-1 restored the altered focal adhesions and cellular migration defects observed in hNatB-depleted HeLa cells, indicative for the conserved link between NatB, tropomyosin, and actin cable function from yeast to human.

Applying a validation framework to a working airport terminal model

Validation is an important issue in the development and application of Bayesian Belief Network (BBN) models, especially when the outcome of the model cannot be directly observed. Despite this, few frameworks for validating BBNs have been proposed and fewer have been applied to substantive real-world problems. In this paper we adopt the approach by Pitchforth and Mengersen (2013), which includes nine validation tests that each focus on the structure, discretisation, parameterisation and behaviour of the BBNs included in the case study. We describe the process and result of implementing a validation framework on a model of a real airport terminal system with particular reference to its effectiveness in producing a valid model that can be used and understood by operational decision makers. In applying the proposed validation framework we demonstrate the overall validity of the Inbound Passenger Facilitation Model as well as the effectiveness of the validity framework itself.

Role of the N-terminal region in G protein-coupled receptor functions : negative modulation revealed by 5-HT2B receptor polymorphisms

The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild-type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5-HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family

Re-evaluation of the effect of smoking on the methylation of N-terminal valine in haemoglobin

In view of the established extrapulmonary cancer sites targeted by smoking a multiplicity of compounds, and mechanisms might be involved. It has been debated that smoking caused increased incidence of N-methylvaline at the N-terminus of haemoglobin. Because this could indicate a relevance of methylating nitrosamines in tobacco smoke, data are presented from an industrial cohort of 35 smokers and 21 non-smokers repeatedly monitored between 1994 and 1999. In general, N-methylvaline adduct levels in haemoglobin of smokers were approximately 50% higher than those of non-smokers. The smoking-induced methylation of haemoglobin is likely to be caused by dimethylnitrosamine (N-nitroso-dimethylamine), a major nitrosamine in side-stream tobacco smoke. The biomonitoring data emphasise the potential value of N-methylvaline as a smoking-related biomarker and call for intensified research on tobacco smoke compounds that lead to macromolecular methylation process.

Circulating fragments of N-Terminal Pro-B-Type Natriuretic Peptides in plasma of heart failure patients

BACKGROUND: The use of nonstandardized N-terminal pro-B-type natriuretic peptide (NT-proBNP) assays can contribute to the misdiagnosis of heart failure (HF). Moreover, there is yet to be established a common consensus regarding the circulating forms of NT-proBNP being used in current assays. We aimed to characterize and quantify the various forms of NT-proBNP in the circulation of HF patients. METHODS: Plasma samples were collected from HF patients (n = 20) at rest and stored at -80 degrees C. NT-proBNP was enriched from HF patient plasma by use of immunoprecipitation followed by mass spectrometric analysis. Customized homogeneous sandwich AlphaLISA (R) immunoassays were developed and validated to quantify 6 fragments of NT-proBNP. RESULTS: Mass spectrometry identified the presence of several N- and C-terminally processed forms of circulating NT-proBNP, with physiological proteolysis between Pro2-Leu3, Leu3-Gly4, Pro6-Gly7, and Pro75-Arg76. Consistent with this result, AlphaLISA immunoassays demonstrated that antibodies targeting the extreme N or C termini measured a low apparent concentration of circulating NT-proBNP. The apparent circulating NT-proBNP concentration was increased with antibodies targeting nonglycosylated and nonterminal epitopes (P < 0.05). CONCLUSIONS: In plasma collected from HF patients, immunoreactive NT-proBNP was present as multiple N- and C-terminally truncated fragments of the full length NT-proBNP molecule. Immunodetection of NT-proBNP was significantly improved with the use of antibodies that did not target these terminal regions. These findings support the development of a next generation NT-proBNP assay targeting nonterminal epitopes as well as avoiding the central glycosylated region of this molecule. (c) 2013 American Association for Clinical Chemistry

Sustainability literacy of older people in retirement villages

With many developed countries experiencing the aging of the population, older people play a large role in contributing to environmental problems but also to environmental solutions. The purpose of this research is to understand the awareness and behavior of current older people living in retirement villages towards sustainability development. To achieve this, a sustainability literacy survey was conducted with 65 older residents of a private retirement village located 10 Km outside the Brisbane, Australia’s central business district (CBD). Most of residents recognized the importance of environment protection and would like to lead a more environmentally friendly lifestyle. In addition, the majority were willing to pay higher prices for a living environment with sustainable features. The importance of positive social communications was emphasized with most residents having established good relationships with others in the village. The findings provide an important insight into consumer perspectives regarding the sustainable features that should and can be incorporated into the village planning and development.