Realising the therapeutic potential of neuroactive steroid modulators of the GABA_A receptor

In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine "neurosteroid" messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABAAR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders

Development of systems and techniques for landing an aircraft using onboard television

A flight program was conducted to develop a landing technique with which a pilot could consistently and safely land a remotely piloted research vehicle (RPRV) without outside visual reference except through television. Otherwise, instrumentation was standard. Such factors as the selection of video parameters, the pilot's understanding of the television presentation, the pilot's ground cockpit environment, and the operational procedures for landing were considered. About 30 landings were necessary for a pilot to become sufficiently familiar and competent with the test aircraft to make powered approaches and landings with outside visual references only through television. When steep approaches and landings were made by remote control, the pilot's workload was extremely high. The test aircraft was used as a simulator for the F-15 RPRV, and as such was considered to be essential to the success of landing the F-15 RPRV

Flight test evaluation of a separate surface attitude command control system on a Beech 99 airplane

A joint NASA/university/industry program was conducted to flight evaluate a potentially low cost separate surface implementation of attitude command in a Beech 99 airplane. Saturation of the separate surfaces was the primary cause of many problems during development. Six experienced professional pilots who made simulated instrument flight evaluations experienced improvements in airplane handling qualities in the presence of turbulence and a reduction in pilot workload. For ride quality, quantitative data show that the attitude command control system results in all cases of airplane motion being removed from the uncomfortable ride region

Learning the game: Breakdowns, breakthroughs and player strategies

Digital games are rich learning environments that require players to engage with challenging situations in order to progress. Recent research indicates that game-play involves overcoming breakdowns and achieving breakthroughs in relation to player action, understanding and involvement. In particular, breakthroughs involve moments of insight where learning occurs which, in turn, can help increase involvement. However, little is known about how players actually achieve breakthroughs. We applied the breakdown/breakthrough “lens” to explore how players attempt to achieve breakthroughs in relation to two single player games. We identified a finite number of strategies that illustrate how players learn in games. These strategies are considered in relation to producing playable and engaging games

Tamoxifen, 17beta-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin.

Invasion through stromal extracellular matrix (ECM) is part of the complex, multistep process of tumour cell invasion and metastasis. Our group has previously demonstrated that calcium and calmodulin are important in another step in the metastatic cascade - that of attachment of cells to ECM. Interestingly, the non-steroidal anti-oestrogen tamoxifen (which also has calmodulin antagonist activity), used in the treatment of breast cancer and now in metastatic cutaneous melanoma, can inhibit the attachment of normal and neoplastic cells to ECM. In this study, we investigated whether such drugs, known to inhibit cell attachment, could also subsequently reduce their invasion through a layer of human fibronectin. We examined the ability of the specific calmodulin antagonist J8, tamoxifen and its two major metabolites, N-desmethyltamoxifen (N-des) and 4-hydroxytamoxifen (4-OH), as well as the pure anti-oestrogen ICI 182,780 and 17beta-oestradiol to inhibit invasion of the human cutaneous melanoma cell line, A375-SM, uveal melanoma cells and uveal melanocytes. A375-SM cells and uveal melanoma cells showed a high level of invasion (15.2% and 33.7% respectively) compared with melanocytes (around 5%) under the experimental conditions used. Submicromolar concentrations of N-des, tamoxifen, J8 and 17beta-oestradiol significantly reduced the invasiveness of the A375-SM cell line. The uveal melanoma cells also showed similar inhibition, although at higher concentrations of these agents. 4-OH and ICI 182, 780 had little or no effect on invasion of A375-SM cells (these were not tested on uveal melanoma cells). All cells used in this study were found to be negative for type I nuclear oestrogen receptors, reinforcing the possibility that tamoxifen and 17beta-oestradiol can act via mechanisms unrelated to binding to classical oestrogen receptors to inhibit tumour cell invasion

Effects of Sex and Hormonal Implant on Beef Carcass Characteristics and Palatability

A comparison of crossbred bulls, steers and heifers indicated that bulls have heavier carcasses, larger rib eyes and a more desirable yield grade. The USDA quality grade of the bulls was one-third of a grade lower than for the steers and heifers. The sensory and palatability characteristics showed no significant differences among axes. Implanted bulls as compared to non-implanted bulls showed more desirable taste panel scores for tenderness, juiciness and overall panel desirability

The Value of Literacy Practices

The concepts of literacy events and practices have received considerable attention in educational research and policy. In comparison, the question of value, that is, ‘which literacy practices do people most value?’ has been neglected. With the current trend of cross-cultural adult literacy assessment, it is increasingly important to recognise locally valued literacy practices. In this paper we argue that measuring preferences and weighting of literacy practices provides an empirical and democratic basis for decisions in literacy assessment and curriculum development and could inform rapid educational adaptation to changes in the literacy environment. The paper examines the methodological basis for investigating literacy values and its potential to inform cross-cultural literacy assessments. The argument is illustrated with primary data from Mozambique. The correlation between individual values and respondents’ socio-economic and demographic characteristics is explored

The Anti-Sigma Factor MucA of Pseudomonas aeruginosa: Dramatic Differences of a mucA22 vs. a ΔmucA Mutant in Anaerobic Acidified Nitrite Sensitivity of Planktonic and Biofilm Bacteria in vitro and During Chronic Murine Lung Infection

Mucoid mucA22 Pseudomonas aeruginosa (PA) is an opportunistic lung pathogen of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients that is highly sensitive to acidified nitrite (A-NO2-). In this study, we first screened PA mutant strains for sensitivity or resistance to 20 mM A-NO2- under anaerobic conditions that represent the chronic stages of the aforementioned diseases. Mutants found to be sensitive to A-NO2- included PA0964 (pmpR, PQS biosynthesis), PA4455 (probable ABC transporter permease), katA (major catalase, KatA) and rhlR (quorum sensing regulator). In contrast, mutants lacking PA0450 (a putative phosphate transporter) and PA1505 (moaA2) were A-NO2- resistant. However, we were puzzled when we discovered that mucA22 mutant bacteria, a frequently isolated mucA allele in CF and to a lesser extent COPD, were more sensitive to A-NO2- than a truncated ΔmucA deletion (Δ157–194) mutant in planktonic and biofilm culture, as well as during a chronic murine lung infection. Subsequent transcriptional profiling of anaerobic, A-NO2--treated bacteria revealed restoration of near wild-type transcript levels of protective NO2- and nitric oxide (NO) reductase (nirS and norCB, respectively) in the ΔmucA mutant in contrast to extremely low levels in the A-NO2--sensitive mucA22 mutant. Proteins that were S-nitrosylated by NO derived from A-NO2- reduction in the sensitive mucA22 strain were those involved in anaerobic respiration (NirQ, NirS), pyruvate fermentation (UspK), global gene regulation (Vfr), the TCA cycle (succinate dehydrogenase, SdhB) and several double mutants were even more sensitive to A-NO2-. Bioinformatic-based data point to future studies designed to elucidate potential cellular binding partners for MucA and MucA22. Given that A-NO2- is a potentially viable treatment strategy to combat PA and other infections, this study offers novel developments as to how clinicians might better treat problematic PA infections in COPD and CF airway diseases

Developing music teacher identities: an international multi-site study

This study investigates pre-service music teacher’s (PSMT) perceptions of their professional identities. University-level education students in the United States America (USA), Spain and Australia were all asked interview questions based on general themes relevant to teacher identity development, and their responses were subjected to content analysis. Similarities were found in their perceptions of the role of ‘music teacher’ and their pre-university experiences/influences. Across the sites it seems that there was a dynamic and shifting relationship between PSMTs’ understandings of themselves as ‘musicians’ or as ‘teachers’ during their university years. This study confirms previous research in the area and contributes to the field in its discovery that these themes are found across three international sites. Implications of the findings are discussed and recommendations made for future research and practice