In silico prediction of mutant HIV-1 proteases cleaving a target sequence

HIV-1 protease represents an appealing system for directed enzyme re-design, since it has various different endogenous targets, a relatively simple structure and it is well studied. Recently Chaudhury and Gray (Structure (2009) 17: 1636 -- 1648) published a computational algorithm to discern the specificity determining residues of HIV-1 protease. In this paper we present two computational tools aimed at re-designing HIV-1 protease, derived from the algorithm of Chaudhuri and Gray. First, we present an energy-only based methodology to discriminate cleavable and non cleavable peptides for HIV-1 proteases, both wild type and mutant. Secondly, we show an algorithm we developed to predict mutant HIV-1 proteases capable of cleaving a new target substrate peptide, different from the natural targets of HIV-1 protease. The obtained in silico mutant enzymes were analyzed in terms of cleavability and specificity towards the target peptide using the energy-only methodology. We found two mutant proteases as best candidates for specificity and cleavability towards the target sequence

Persuasive Technology for Learning and Teaching – The EuroPLOT Project

The concept of persuasive design has demonstrated its benefits by changing human behavior in certain situations, but in the area of education and learning, this approach has rarely been used. To change this and to study the feasibility of persuasive technology in teaching and learning, the EuroPLOT project (PLOT = Persuasive Learning Objects and Technologies) has been funded 2010-2013 by the Education, Audiovisual and Culture Executive Agency (EACEA) in the Life-long Learning (LLL) programme. In this program two tools have been developed (PLOTMaker and PLOTLearner) which allow to create learning objects with inherently persuasive concepts embedded. These tools and the learning objects have been evaluated in four case studies: language learning (Ancient Hebrew), museum learning (Kaj Munk Museum, Denmark), chemical handling, and academic Business Computing. These case studies cover a wide range of different learning styles and learning groups, and the results obtained through the evaluation of these case studies show the wide range of success of persuasive learning. They also indicate the limitations and areas where improvements are required

Demonstration of PLOTs from the EuroPLOT project

The EuroPLOT project (2010-2013) has been funded to explore the concept of persuasive design for learning and teaching. It has developed Persuasive Learn-ing Objects and Technologies (PLOTs), manifested in two tools and a set of learning objects that have been tested and evaluated in four different case studies. These PLOTs will be shown in this demonstration, and the participants can try them out and experience for themselves the impact of persuasive technology that is embedded in these PLOTs. This will be one authoring tool (PLOTMaker) and one delivery tool (PLOTLearner). Furthermore, there will be learning objects shown which have been developed for those four different case studies. All of these PLOTs have already been tested and evaluated during case studies with real learners

Weak lensing of large scale structure in the presence of screening

A number of alternatives to general relativity exhibit gravitational screening in the non-linear regime of structure formation. We describe a set of algorithms that can produce weak lensing maps of large scale structure in such theories and can be used to generate mock surveys for cosmological analysis. By analysing a few basic statistics we indicate how these alternatives can be distinguished from general relativity with future weak lensing surveys.Comment: 25 pages, 7 figures, accepted by JCAP. v2: references updat

Persuasive Technology for Learning in Business Context

"Persuasive Design is a relatively new concept which employs general principles of persuasion that can be implemented in persuasive technology. This concept has been introduced by BJ Fogg in 1998, who since then has further extended it to use computers for changing attitudes and behaviour. Such principles can be applied very well in learning and teaching: in traditional human-led learning, teachers always have employed persuasion as one of the elements of teaching. Persuasive technology moves these principles into the digital domain, by focusing on technology that inherently stimulates learners to learn more quickly and effectively. This is very relevant for the area of Business Management in several aspects: Consumer Behavior, Communications, Human Resource, Marketing & Advertising, Organisational Behavior & Leadership. The persuasive principles identified by BJ Fogg are: reduction, tunnelling, tailoring, suggestion, self-monitoring, surveillance, conditioning, simulation, social signals. Also relevant is the concept of KAIROS, which means the just-in-time, at the right place provision of information/stimulus. In the EuroPLOT project (2010-2013) we have developed persuasive learning objects and tools (PLOTs) in which we have applied persuasive designs and principles. In this context, we have developed a pedagogical framework for active engagement, based on persuasive design in which the principles of persuasive learning have been formalised in a 6-step guide for persuasive learning. These principles have been embedded in two tools – PLOTmaker and PLOTLearner – which have been developed for creating persuasive learning objects. The tools provide specific capability for implementing persuasive principles at the very beginning of the design of learning objects. The feasibility of employing persuasive learning concepts with these tools has been investigated in four different case studies with groups of teachers and learners from realms with distinctly different teaching and learning practices: Business Computing, language learning, museum learning, and chemical substance handling. These case studies have involved the following learner target groups: school children, university students, tertiary students, vocational learners and adult learners. With regards to the learning context, they address archive-based learning, industrial training, and academic teaching. Alltogether, these case studies include participants from Sweden, Africa (Madagascar), Denmark, Czech Republic, and UK. One of the outcomes of this investigation was that one cannot apply a common set of persuasive designs that would be valid for general use in all situations: on the contrary, the persuasive principles are very specific to learning contexts and therefore must be specifically tailored for each situation. Two of these case studies have a direct relevance to education in the realm of Business Management: Business Computing and language learning (for International Business). In this paper we will present the first results from the evaluation of persuasive technology driven learning in these two relevant areas.

Redox characteristics of the eukaryotic cytosol

AbstractThe eukaryotic cytoplasm has long been regarded as a cellular compartment in which the reduced state of protein cysteines is largely favored. Under normal conditions, the cytosolic low-molecular weight redox buffer, comprising primarily of glutathione, is highly reducing and reactive oxygen species (ROS) and glutathionylated proteins are maintained at very low levels. In the present review, recent progress in the understanding of the cytosolic thiol–disulfide redox metabolism and novel analytical approaches to studying cytosolic redox properties are discussed. We will focus on the yeast model organism, Saccharomyces cerevisiae, where the combination of genetic and biochemical approaches has brought us furthest in understanding the mechanisms underlying cellular redox regulation. It has been shown in yeast that, in addition to the enzyme glutathione reductase, other mechanisms may exist for restricting the cytosolic glutathione redox potential to a relatively narrow interval. Several mutations in genes involved in cellular redox regulation cause ROS accumulation but only moderate decreases in the cytosolic glutathione reducing power. The redox regulation in the cytosol depends not only on multiple cytosolic factors but also on the redox homeostasis of other compartments like the secretory pathway and the mitochondria. Possibly, the cytosol is not just a reducing compartment surrounding organelles with high oxidative activity but also a milieu for regulation of the redox status of more than one compartment. Although much has been learned about redox homeostasis and oxidative stress response several important aspects of the redox regulation in the yeast cytosol are still unexplained

Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.

Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions

Multivariate Hawkes process models of the occurrence of regulatory elements

<p>Abstract</p> <p>Background</p> <p>A central question in molecular biology is how transcriptional regulatory elements (TREs) act in combination. Recent high-throughput data provide us with the location of multiple regulatory regions for multiple regulators, and thus with the possibility of analyzing the multivariate distribution of the occurrences of these TREs along the genome.</p> <p>Results</p> <p>We present a model of TRE occurrences known as the Hawkes process. We illustrate the use of this model by analyzing two different publically available data sets. We are able to model, in detail, how the occurrence of one TRE is affected by the occurrences of others, and we can test a range of natural hypotheses about the dependencies among the TRE occurrences. In contrast to earlier efforts, pre-processing steps such as clustering or binning are not needed, and we thus retain information about the dependencies among the TREs that is otherwise lost. For each of the two data sets we provide two results: first, a qualitative description of the dependencies among the occurrences of the TREs, and second, quantitative results on the favored or avoided distances between the different TREs.</p> <p>Conclusions</p> <p>The Hawkes process is a novel way of modeling the joint occurrences of multiple TREs along the genome that is capable of providing new insights into dependencies among elements involved in transcriptional regulation. The method is available as an R package from <url>http://www.math.ku.dk/~richard/ppstat/</url>.</p