Mastering the canonical loop of serine protease inhibitors : enhancing potency by optimising the internal hydrogen bond network

Background Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact β-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity. Methodology/Principal Findings In this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (Ki = 0.0386±0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion. Conclusion/Significance These findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors.

Mastering medical terminology : Australia and New Zealand

Mastering Medical Terminology: Australia and New Zealand is medical terminology book of relevance to an audience in Australia and New Zealand. Australian terminology, perspectives, examples and spelling have been included and Australian pronunciation specified. The textbook is accompanied by a self-help workbook, an online workbook and a Smartphone app. Throughout Mastering Medical Terminology, review of medical terminology as it is used in clinical practice is highlighted. Features of the textbook, workbook and electronic product include: • Simple, non-technical explanations of medical terms • Workbook format with ample spaces to write answers • Explanations of clinical procedures, laboratory tests and abbreviations used in Australian clinical practice, as they apply to each body system and speciality area • Pronunciation of terms and spaces to write meanings of terms • Practical applications sections • Exercises that test understanding of terminology as students work through the text chapter by chapter • Review activities that pull together terminology to help students study • Comprehensive glossary and appendices for reference • Links to other useful references, such as websites and textbooks.

Mastering medical terminology : Australia and New Zealand Workbook

Mastering Medical Terminology: Australia and New Zealand Workbook is the indispensable companion to Mastering Medical Terminology Textbook. Packed with a range of exercises and activities to accompany the main text, the Workbook provides an ideal resource for self-testing and revision in a fun, practical and accessible format, and forms a key part of the Mastering Medical Terminology suite of products which are all available for separate purchase enabling you to pick and choose the right package for your learning requirements. Featuring a variety of question types including crossword puzzles, anagrams, multiple-choice questions and label-the-diagram exercises, the Workbook uses entirely Australian spelling and aligns to the chapters of the main text. When used in combination with the main text and MedWords app, Mastering Medical Terminology: Australia and New Zealand Workbook will make the scholarship of medical terminology not only manageable, but fun!

Mastering medical terminology online workbook

Key Features: "Aligns to Mastering Medical Terminology: Australia and New Zealand. Self-test to practise and revise combining forms, word roots, prefixes and suffixes. Crossword puzzles, anagrams and label-the-diagram exercises Also available iOS/Android app featuring audio glossary, flashcards and MCQs."--publisher website

Mastering your destiny

Dance psychologist Gene Moyle explains how your attitude can help your career.

Expert Identity in Development of Core-Task-Oriented Working Practices for Mastering Demanding Situations

The point of departure in this dissertation was the practical safety problem of unanticipated, unfamiliar events and unexpected changes in the environment, the demanding situations which the operators should take care of in the complex socio-technical systems. The aim of this thesis was to increase the understanding of demanding situations and of the resources for coping with these situations by presenting a new construct, a conceptual model called Expert Identity (ExId) as a way to open up new solutions to the problem of demanding situations and by testing the model in empirical studies on operator work. The premises of the Core-Task Analysis (CTA) framework were adopted as a starting point: core-task oriented working practices promote the system efficiency (incl. safety, productivity and well-being targets) and that should be supported. The negative effects of stress were summarised and the possible countermeasures related to the operators' personal resources such as experience, expertise, sense of control, conceptions of work and self etc. were considered. ExId was proposed as a way to bring emotional-energetic depth into the work analysis and to supplement CTA-based practical methods to discover development challenges and to contribute to the development of complex socio-technical systems. The potential of ExId to promote understanding of operator work was demonstrated in the context of the six empirical studies on operator work. Each of these studies had its own practical objectives within the corresponding quite broad focuses of the studies. The concluding research questions were: 1) Are the assumptions made in ExId on the basis of the different theories and previous studies supported by the empirical findings? 2) Does the ExId construct promote understanding of the operator work in empirical studies? 3) What are the strengths and weaknesses of the ExId construct? The layers and the assumptions of the development of expert identity appeared to gain evidence. The new conceptual model worked as a part of an analysis of different kinds of data, as a part of different methods used for different purposes, in different work contexts. The results showed that the operators had problems in taking care of the core task resulting from the discrepancy between the demands and resources (either personal or external). The changes of work, the difficulties in reaching the real content of work in the organisation and the limits of the practical means of support had complicated the problem and limited the possibilities of the development actions within the case organisations. Personal resources seemed to be sensitive to the changes, adaptation is taking place, but not deeply or quickly enough. Furthermore, the results showed several characteristics of the studied contexts that complicated the operators' possibilities to grow into or with the demands and to develop practices, expertise and expert identity matching the core task. They were: discontinuation of the work demands, discrepancy between conceptions of work held in the other parts of organisation, visions and the reality faced by the operators, emphasis on the individual efforts and situational solutions. The potential of ExId to open up new paths to solving the problem of the demanding situations and its ability to enable studies on practices in the field was considered in the discussion. The results were interpreted as promising enough to encourage the conduction of further studies on ExId. This dissertation proposes especially contribution to supporting the workers in recognising the changing demands and their possibilities for growing with them when aiming to support human performance in complex socio-technical systems, both in designing the systems and solving the existing problems.

Case study: Mastering the governance of technology

Case study on how the Heart of Worcestershire College is leading a project with four other colleges to support college governors in making confident, effective and well-informed decisions on the investment, innovation and development of technology use to support learning.

Professionell mastering : Ett bra alternativ för oetablerade musiker?

Pre-mastering, populärt men något missvisande kallat mastering, är en process där slutmixen av en låt optimeras för att erbjuda en så pass njutbar lyssning som möjligt för de allra flesta som lyssnar på den aktuella musiken. I denna uppsats har jag föresatt mig att ta reda på om det är meningsfullt för oetablerade artister (demoartister) att anlita någon av de professionella masteringfirmor som finns för att utföra detta, eller om det går att göra med likvärdigt resultat på egen hand. Resultatet visar att de flesta lyssnare tycker att en professionellt mastrad slutmix låter bättre än en hemmagjord mastering. Även om de flesta skivbolagen enligt min undersökning tycker att det är en onödig investering för musiker som söker skivkontrakt så bör professionell mastering ändå anses som ett bra alternativ för oetablerade musiker.

Mastering : Hur påverkas den subjektiva musikuppfattningen av mastering?

Examensarbetet undersöker hur mastering påverkar den subjektiva musikuppfattningen. Detta har undersökts med hjälp av ett lyssningstest där testdeltagare i två grupper, ”vana lyssnare” och ”ovana lyssnare”, lyssnat till tre versioner av tre olika produktioner i olika genrer. De tre versionerna är en professionell, en semiprofessionell samt en omastradversion. Testdeltagarna har sedan fått betygsätta produktionen ur ett rent ljudkvalitetsmässigt perspektiv samt motivera varför de betygsatt som de gjort.Resultatet tyder på att musikuppfattningen påverkas beroende på om produktionen är mastrad eller ej för såväl ”vana lyssnare” som ”ovana lyssnare”. Resultatet tyder även på att musikuppfattningen påverkas av hur, och av vem, en produktion är mastrad.Examensarbetet behandlar även ”vana” och ”ovana lyssnares” syn på kvalitet när det gällermusik. Resultatet visar att det skiljer sig inte bara mellan de två grupperna utan äveninbördes. Ytterligare resultat tyder på att båda grupperna har lika uppfattning om vadljudteknisk kvalitet är.