Conformational selection of inhibitors and substrates by proteolytic enzymes: Implications for drug design and polypeptide processing

Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such as AIDS and viral infections, cancers, inflammatory disorders, and Alzheimer's disease. Generic approaches to the design of protease inhibitors are limited by the unpredictability of interactions between, and structural changes to, inhibitor and protease during binding. A computer analysis of superimposed crystal structures for 266 small molecule inhibitors bound to 48 proteases (16 aspartic, 17 serine, 8 cysteine, and 7 metallo) provides the first conclusive proof that inhibitors, including substrate analogues, commonly bind in an extended beta-strand conformation at the active sites of all these proteases. Representative superimposed structures are shown for (a) multiple inhibitors bound to a protease of each class, (b) single inhibitors each bound to multiple proteases, and (c) conformationally constrained inhibitors bound to proteases. Thus inhibitor/substrate conformation, rather than sequence/composition alone, influences protease recognition, and this has profound implications for inhibitor design. This conclusion is supported by NMR, CD, and binding studies for HIV-1 protease inhibitors/ substrates which, when preorganized in an extended conformation, have significantly higher protease affinity. Recognition is dependent upon conformational equilibria since helical and turn peptide conformations are not processed by proteases. Conformational selection explains the resistance of folded/structured regions of proteins to proteolytic degradation, the susceptibility of denatured proteins to processing, and the higher affinity of conformationally constrained 'extended' inhibitors/substrates for proteases. Other approaches to extended inhibitor conformations should similarly lead to high-affinity binding to a protease.

Teaching of medical ethics: Implications for an integrated curriculum

This paper reports on an investigation into the teaching of medical ethics and related areas in the medical undergraduate course at the University of Queensland. The project was designed in the context of a major curriculum change to replace the current 6 year course by an integrated, problem-based, 4 year graduate medical course, which began in 1997. A survey of clinical students, observations of clinical teaching sessions, and interviews with clinical teachers were conducted. Data obtained have contributed to curriculum development and will provide a baseline for comparison and evaluation of the graduate course in this field. A view of integrated ethics teaching is advanced in the light of the data obtained.

Beyond the middle: A report about literacy and numeracy development of target group students in the middle years of schooling: Volume 1

The report was commissioned by the Department of Education, Science and Training to investigate the perceived efficacy of middle years programmes in all States and Territories in improving the quality of teaching, learning and student outcomes, especially in literacy and numeracy and for student members of particular target groups. These target groups included students from lower socio-economic communities, Aboriginal and Torres Strait Islander communities, students with a language background other than English, rural and remote students, and students struggling with the transition from middle/upper primary to the junior secondary years. The project involved large scale national and international literature reviews on Australian and international middle years approaches as well as an analysis of key literacy and numeracy teaching and learning strategies being used. In the report, there is emergent evidence of the relative efficacy of a combination of explicit state policy, dedicated funding and curriculum and professional development frameworks that are focused on the improvement of classroom pedagogy in the middle years. The programs that evidenced the greatest current and potential value for target group students tended to have developed in state policy environments that encouraged a structural rather than adjunct approach to middle years innovations. The authors conclude that in order to translate the gains made into sustainable improvement of educational results in literacy and numeracy for target groups, there is a need for a second generation of middle years theorising, research, development and practice.

Beyond the middle: A report about literacy and numeracy development of target group students in the middle years of schooling: Volume 2 (Appendices)

This research project was commissioned by the Commonwealth Department of Education, Science and Training to investigate the perceived efficacy of middle years programs in all States and Territories in improving the quality of teaching, learning and student outcomes - especially in literacy and numeracy and for student members of particular target groups. The latter groups included students from lower socio-economic communities, Aboriginal and Torres Strait Islander (Indigenous) communities, students with a Language Background Other than English (hereafter LBOTE), rural and remote students, and students struggling with the transition from middle/upper primary to the junior secondary years.

Analysis of the gate capacitance measurement technique and its application for the evaluation of hot-carrier degradation in submicrometer MOSFETs

The use of gate-to-drain capacitance (C-gd) measurement as a tool to characterize hot-carrier-induced charge centers in submicron n- and p-MOSFET's has been reviewed and demonstrated. By analyzing the change in C-gd measured at room and cryogenic temperature before and after high gate-to-drain transverse field (high field) and maximum substrate current (I-bmax) stress, it is concluded that the degradation was found to be mostly due to trapping of majority carriers and generation of interface states. These interface states were found to be acceptor states at top half of band gap for n-MOSFETs and donor states at bottom half of band gap for p-MOSFETs. In general, hot electrons are more likely to be trapped in gate oxide as compared to hot holes while the presence of hot holes generates more interface states. Also, we have demonstrated a new method for extracting the spatial distribution of oxide trapped charge, Q(ot), through gate-to-substrate capacitance (C-gb) measurement. This method is simple to implement and does not require additional information from simulation or detailed knowledge of the device's structure. (C) 2001 Elsevier Science Ltd. All rights reserved.

Drug targets and mechanisms of resistance in the anaerobic protozoa

The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated ruing laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance.

Dopant extraction from scanning capacitance microscopy measurements of p-n junctions using combined inverse modeling and forward simulation

This article proposes a more accurate approach to dopant extraction using combined inverse modeling and forward simulation of scanning capacitance microscopy (SCM) measurements on p-n junctions. The approach takes into account the essential physics of minority carrier response to the SCM probe tip in the presence of lateral electric fields due to a p-n junction. The effects of oxide fixed charge and interface state densities in the grown oxide layer on the p-n junction samples were considered in the proposed method. The extracted metallurgical and electrical junctions were compared to the apparent electrical junction obtained from SCM measurements. (C) 2002 American Institute of Physics.

Development of the HIV/AIDS stress scale

Development of a self-report measure of stress specific to HIV/AIDS is needed to advance our understanding of the role of stress in adaptation to HIV/AIDS: hence, the aim of this study was the development of the HIV/AIDS Stress Scale. A total of 132 homosexual/bisexual men with HIV/AIDS v ere interviewed and completed the HIV/AIDS Stress Scale and measures of coping strategies, appraisal, social support and adjustment (global distress, depression, social adjustment, number of HIV symptoms, and subjective health status) at three time points. Thirty-nine primary caregivers were interviewed and completed measures of stress and adjustment. Exploratory factor analyses of the HIV/AIDS Stress Scale items revealed three factors: Social, Instrumental and Emotional/Existential Stress. Factors had adequate internal reliabilities and were stable over 12 months. Construct validation data are consistent with recent stress/coping research that links higher levels of stress with more HIV symptoms. reliance on emotion-focused coping, lower social support, poorer levels of adjustment and higher levels of caregiver stress. Results extend this research by revealing new differential relations between various stress dimensions and stress/coping variables. Convergent validation data suggest that the HIV/AIDS Stress Scale shares conceptual similarity with threat appraisal. and differs from control liability and challenge appraisals. The HIV/AIDS Stress Scale shows potential for the elucidation of the role of stress in coping and adaptation to HIV/AIDS and disease progression in both research and clinical applications.

Understanding sociocognitive space of written discourse: Implications for teaching business writing to Chinese students

Confronted with various issues in teaching business writing to Chinese students in New Zealand, this paper sees the need for bridging the gap between genre-based research and teaching in an intercultural context. Specifically, it develops an intercultural reflective model in the light of Bhatia's sociocognitive genre study as well as cross-cultural persuasion. As an important part of the model, New Zealand and Chinese experts' intracultural and intercultural reflections on business writing are solicited and compared and the theoretical implications for teaching and learning business writing are discussed. It has been found, through a case study of analysing English and Chinese business faxes, this model can offer an in-depth understanding about discursive competence across cultures, and provide a link between genre-based theory, teaching practice and professional expertise.

Student expectations of TESOL programs: Student and teacher perspectives

Most practitioners teaching English to speakers of other languages (TESOL) will agree that students come with some expectations about course content and teaching methodology and that these expectations play a vital role in student motivation and learning. However, the study of student expectations has been a surprising omission from Second Language Acquisition research. In the studies reported here, the authors develop a model of student expectations by adapting the Expectation Disconfirmation paradigm, widely used in consumer psychology. Student and teacher perspectives on student expectations were gathered by interviews. Responses shed light on the nature of expectations, factors causing expectations and effects of expectation fulfilment (or lack of it). The findings provide new avenues for research on affective factors as well as clarify some ambiguities in motivational research in second language acquisition. The model presented here can be used by teachers or institutions to conduct classroom-based research, thus optimising students' learning and performance, and enhancing student morale.

Balancing curriculum processes and content in a project centred curriculum - In pursuit of graduate attributes

Chemical engineering education is challenged around the world by demands and rapid changes encompassing a wide range of technical and social drivers. Graduates must be prepared for practice in increasingly diverse workplace environments in which generic or transferable attributes such as communication and teamwork together with technical excellence are mandated by prospective employers and society at large. If academe is to successfully deliver on these graduate attributes, effective curriculum design needs to include appropriate educational processes as well as course content. Conventional teacher centred approaches, stand-alone courses and retro-fitted remedial modules have not delivered the desired outcomes. Development of the broader spectrum of attributes is more likely when students are engaged with realistic and relevant experiences that demand the integration and practice of these attributes in contexts that the students find meaningful. This paper describes and evaluates The University of Queensland's Project Centred Curriculum in Chemical Engineering (PCC), a programme-wide approach to meeting these requirements. PCC strategically integrates project-based learning with more traditional instruction. Data collected shows improved levels of student attainment of generic skills with institutional and nationally benchmarked indicators showing significant increases in student perceptions of teaching quality, and overall satisfaction with the undergraduate experience. Endorsements from Australian academic, professional and industry bodies also support the approach as more effectively aligning engineering education with professional practice requirements.

The status and relevance of Vietnamese journalism education: An empirical analysis

Based primarily on data from indepth interviews with senior journalists and journalism educators as well as a content analysis of journalism curricula, this paper sets out to provide an overview of the demand, overall provision structure, teaching materials and methods of Vietnamese journalism education. It first shows that with a fast expansion in both size and substance, the Vietnamese media system is beginning to feel the urgent need for formal journalism education. However, the country's major journalism programs have been criticised for producing hundreds of unqualified journalism graduates a year. In general, the most deplorable aspects of Vietnamese journalism education include its body of outdated and awkward teaching material, its undue focus on theories and politics at the expense of practical training, its lack of qualified teaching staff and its inadequate teaching resources.

Teaching Australian cello music to Intermediate students: An exploratory study of motivation through repertoire

This paper explores the motivational aspects of repertoire for intermediate student cellists. Research into interest and intrinsic motivation related to the learning of instrumental music has been limited to date. As a cello teacher interested in including contemporary and Australian music in my students' studies I started to research availability of Australian repertoire for intermediate cellists and found that there was limited accessibility to such pedagogical material at this level. This study emerged as a way of providing useful information to composers. It investigates intrinsic motivation by questioning students and their teachers about which aspects of music repertoire are most likely to inspire students to practice more and strive for excellence. This paper presents the findings of the purpose-designed questionnaire distributed to cello teachers in Queensland. A similar set of questions has been prepared for student cellists and information gathering from students is still underway. Musical aspects investigated include technique and its development, style, harmony, tempo (speed), and rhythm. The questionnaire gathered information on the most frequently used teaching repertoire and teachers' experiences in teaching contemporary and Australian repertoire. This information was balanced with questions regarding the technical developmental requirements perceived necessary for intermediate students as well as other motivational aspects. It is hoped that information collated from this research will be of benefit in the selection of motivational repertoire for intermediate student cellists and especially in promoting the composition of Australian pieces for intermediate cellists.