Application of genomics, proteomics and metabolomics in drug discovery, development and clinic

Genomics, proteomics and metabolomics are three areas that are routinely applied throughout the drug-development process as well as after a product enters the market. This review discusses all three 'omics, reporting on the key applications, techniques, recent advances and expectations of each. Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced areas of drug discovery and development through the comparative assessment of normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and the identification of biomarkers. Proteomics, through techniques including isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two-hybrid systems is utilized in multiple areas through the drug development pipeline including target and lead identification, compound optimization, throughout the clinical trials process and after market analysis. Metabolomics, although the most recent and least developed of the three 'omics considered in this review, provides a significant contribution to drug development through systems biology approaches. Already implemented to some degree in the drug-discovery industry and used in applications spanning target identification through to toxicological analysis, metabolic network understanding is essential in generating future discoveries.

Application of genomics, proteomics and metabolomics in drug discovery, development and clinic

Genomics, proteomics and metabolomics are three areas that are routinely applied throughout the drug-development process as well as after a product enters the market. This review discusses all three 'omics, reporting on the key applications, techniques, recent advances and expectations of each. Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced areas of drug discovery and development through the comparative assessment of normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and the identification of biomarkers. Proteomics, through techniques including isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two-hybrid systems is utilized in multiple areas through the drug development pipeline including target and lead identification, compound optimization, throughout the clinical trials process and after market analysis. Metabolomics, although the most recent and least developed of the three 'omics considered in this review, provides a significant contribution to drug development through systems biology approaches. Already implemented to some degree in the drug-discovery industry and used in applications spanning target identification through to toxicological analysis, metabolic network understanding is essential in generating future discoveries.

g-C3N4/NaTaO3 organic–inorganic hybrid nanocomposite:high-performance and recyclable visible light driven photocatalyst

Novel g-C3N4/NaTaO3 hybrid nanocomposites have been prepared by a facile ultrasonic dispersion method. Our results clearly show the formation of interface between NaTaO3 and g-C3N4 and further loading of g-C3N4 did not affect the crystal structure and morphology of NaTaO3. The g-C3N4/NaTaO3 nanocomposites exhibited enhanced photocatalytic performance for the degradation of Rhodamine B under UV–visible and visible light irradiation compared to pure NaTaO3 and Degussa P25. Interestingly, the visible light photocatalytic activity is generated due to the loading of g-C3N4. A mechanism is proposed to discuss the enhanced photocatalytic activity based on trapping experiments of photoinduced radicals and holes. Under visible light irradiation, electron excited from the valance band (VB) to conduction band (CB) of g-C3N4 could directly inject into the CB of NaTaO3, making g-C3N4/NaTaO3 visible light driven photocatalyst. Since the as-prepared hybrid nanocomposites possess high reusability therefore it can be promising photocatalyst for environmental applications.

Adult education directors' perceptions of performance indicators for adult education programs in the state of Florida

Current demands for accountability in education emphasize outcome-based program evaluation and tie program funding to individual student performance. As has been the case for elementary and secondary programs, demands for accountability have increased pressure on adult educators to show evidence of the benefits of their programs in order to justify their financial support. In Florida, recent legislation fundamentally changes the delivery of adult education in the state by establishing a performance-based funding system that is based on outcomes related to the retention, completion, and employment of program participants.^ A performance-based funding system requires an evaluation process that stresses outcome indicators over indicators that focus on program context or process. Although the state has adopted indicators of program quality to evaluate its adult education programs, these indicators focus mostly on program processes rather than student outcomes. In addition, the indicators are not specifically tied to workforce development outcomes, a priority to federal and local funding agents.^ Improving the accountability of adult education programs and defining the role of these programs in Florida's Workforce Development System has become a priority to policy makers across the state. Another priority has been to involve adult education practitioners in every step of this process.^ This study was conducted in order to determine what performance indicators, as judged by the directors and supervisors of adult education programs in the state of Florida, are important and feasible in measuring the quality and effectiveness of these programs. The results of the study indicated that, both statewide and by region, the respondents consistently gave the highest ratings on both importance and feasibility to the indicators of Program Context, which reflect the needs, composition, and structure of the programs, and to the indicators of Educational Gain, which reflect learner progress in the attainment of basic skills and competencies. In turn, the respondents gave the lowest ratings on both importance and feasibility to the indicators in the areas of Return on State's Investment, Efficiency, Retention, and Workforce Training. In general, the indicators that received high ratings for importance also received high ratings for feasibility. ^

Changing Parental Perceptions of Math and Science Curriculum Through Hands-on Workshops

Many parents hold negative perceptions of math and science because they have never been taught these domains from a hands-on, constructivist approach. Only 20 - 30% of adults have actually experienced activity-based science inquiry. Instead, these individuals were exposed to didactic science programs that emphasize drill, skill and memorization (Shymanksy, 2000). This has had a negative impact upon their content knowledge in these areas and their perceptions of math and science. Consequently, parents are hesitant to incorporate math and science into their home life. There is a dire need to determine if parental perceptions of math, science, and their content knowledge will be positively effected as a result of participation in hands-on science workshops.

Building bridges for future sustainability? Breaching the research-teaching nexus in engineering education

The relationship between research and learning and teaching represents what has been described as amongst the most intellectually tangled, managerially complex and politically contentious issues in mass higher education (Scott, 2005, p 53). Despite this, arguments that in order to achieve high quality scholarly outcomes, university teachers need to adopt an approach to teaching similar to that of research (founded upon academic rigour and evidence), has long been discussed in the literature. However, the practicalities of promoting an empirical and evidence-based approach to teaching in engineering education make dealing with the research / teaching nexus a somewhat challenging proposition. Using a phenomenographic approach, bringing together and applying the findings of a mixed methodological study, the workshop will adopt an activity based, interactive approach to encourage staff to consider the challenges and benefits of adopting an evidence-based approach to learning and teaching through the utilisation of research to inform their own practice. © 2009 Authors.

Reduction of salt in yeasted wheat bread: impact on bread quality and solutions using sourdough fermented by functional lactic acid bacteria strains

The dietary intake of sodium chloride has increased considerably over the last few decades due to changes in the human diet. This higher intake has been linked to a number of diseases including hypertension and other cardiovascular diseases. Numerous international health agencies, as well as the food industry, have now recommended a salt intake level of 5-6 g daily, approximately half of the average current daily intake level. Cereal products, and in particular bread, are a major source of salt in the Western diet. Therefore, any reduction in the level of salt in bread could have a major impact on global health. However, salt is a critical ingredient in bread production, and its reduction can have a deleterious effect on the production process as well as on the final bread quality characteristics such as shelf-life, bread volume and sensory characteristics, all deviating from the bakers’ and consumers’ expectations. This work addresses the feasibility of NaCl reduction in wheat bread focusing on options to compensate NaCl with the use of functional sourdoughs. Three strains were used for the application of low-salt bread; L. amylovorus DSM19280, W. cibaria MG1 and L. reuteri FF2hh2. The multifunctional strain L. reuteri FF2hh2 was tested the first time and its application could be demonstrated successfully. The functionalities were based on the production of exopolysaccharides as well as the production of antifungal compounds. While the exopolysaccharides, mainly high molecular dextrans, positively influenced mainly bread loaf volume, crumb structure and staling rate, the strains producing antifungal compounds prolonged the microbial shelf life significantly and compensated the lack of salt. The impact on the sensory characteristics of bread were evaluated by descriptive sensory evaluation. The increase in surface area as well as the presence of organic acids impacted significantly on the flavour profile of the sourdough bread samples. The flavour attribute “salt” could be enhanced by sourdough addition and increased the salty perception. Furthermore, a trained sensory panel evaluated for the first time the impact of yeast activity, based on different salt and yeast concentrations, on the volatile aroma profile of bread crumb samples. The analytical measurements using high resolution gas chromatography and proton-transfer-reaction mass spectrometry (PTR-MS) resulted in significantly different results based on different yeast activities. Nevertheless, the extent of the result could not be recognised by the sensory panel analysing the odour profile of the bread crumb samples. Hence, the consumer cannot recognised low-salt bread by its odour. The use of sourdough is a natural option to overcome the broad range of technological issues caused by salt reduction and also a more popular alternative compared to existing chemical salt replacers.

Extracellular cathepsin S and intracellular caspase 1 activation are surrogate biomarkers of particulate-induced lysosomal disruption in macrophages

BACKGROUND: Particulate matter has been shown to stimulate the innate immune system and induce acute inflammation. Therefore, while nanotechnology has the potential to provide therapeutic formulations with improved efficacy, there are concerns such pharmaceutical preparations could induce unwanted inflammatory side effects. Accordingly, we aim to examine the utility of using the proteolytic activity signatures of cysteine proteases, caspase 1 and cathepsin S (CTSS), as biomarkers to assess particulate-induced inflammation.

METHODS: Primary peritoneal macrophages and bone marrow-derived macrophages from C57BL/6 mice and ctss(-/-) mice were exposed to micro- and nanoparticulates and also the lysosomotropic agent, L-leucyl-L-leucine methyl ester (LLOME). ELISA and immunoblot analyses were used to measure the IL-1β response in cells, generated by lysosomal rupture. Affinity-binding probes (ABPs), which irreversibly bind to the active site thiol of cysteine proteases, were then used to detect active caspase 1 and CTSS following lysosomal rupture. Reporter substrates were also used to quantify the proteolytic activity of these enzymes, as measured by substrate turnover.

RESULTS: We demonstrate that exposure to silica, alum and polystyrene particulates induces IL-1β release from macrophages, through lysosomal destabilization. IL-1β secretion positively correlated with an increase in the proteolytic activity signatures of intracellular caspase 1 and extracellular CTSS, which were detected using ABPs and reporter substrates. Interestingly IL-1β release was significantly reduced in primary macrophages from ctss(-/-) mice.

CONCLUSIONS: This study supports the emerging significance of CTSS as a regulator of the innate immune response, highlighting its role in regulating IL-1β release. Crucially, the results demonstrate the utility of intracellular caspase 1 and extracellular CTSS proteolytic activities as surrogate biomarkers of lysosomal rupture and acute inflammation. In the future, activity-based detection of these enzymes may prove useful for the real-time assessment of particle-induced inflammation and toxicity assessment during the development of nanotherapeutics.

A Selective Irreversible Inhibitor of Furin Does Not Prevent Pseudomonas Aeruginosa Exotoxin A-Induced Airway Epithelial Cytotoxicity

Many bacterial and viral pathogens (or their toxins), including Pseudomonas aeruginosa exotoxin A, require processing by host pro-protein convertases such as furin to cause dis- ease. We report the development of a novel irreversible inhibitor of furin (QUB-F1) consist- ing of a diphenyl phosphonate electrophilic warhead coupled with a substrate-like peptide (RVKR), that also includes a biotin tag, to facilitate activity-based profiling/visualisation. QUB-F1 displays greater selectivity for furin, in comparison to a widely used exemplar com- pound (furin I) which has a chloromethylketone warhead coupled to RVKR, when tested against the serine trypsin-like proteases (trypsin, prostasin and matriptase), factor Xa and the cysteine protease cathepsin B. We demonstrate QUB-F1 does not prevent P. aerugi- nosa exotoxin A-induced airway epithelial cell toxicity; in contrast to furin I, despite inhibiting cell surface furin-like activity to a similar degree. This finding indicates additional proteases, which are sensitive to the more broad-spectrum furin I compound, may be involved in this process.

Toimintolaskennan hyödyntäminen prosessijohtamisen tukena julkisen sektorin terveydenhuolto-organisaatiossa

Tämän tutkielman tavoitteena on tutkia toimintolaskennan ja toimintojohtamisen käyttöä sekä hyödyntämistä prosessijohtamisen tukena. Työssä keskitytään tarkastelemaan ilmiötä julkisen sektorin terveydenhuoltoalalla. Tutkielmassa sovelletaan kvalitatiivista eli laadullista tutkimusmenetelmää. Tutkielma koostuu kahdesta osasta. Teoriaosassa käsitellään alan kirjallisuutta tieteellisten artikkelien valossa. Empiriaosassa selvitettiin tutkittavan organisaation kustannus- ja toimintolaskennan hyödyntämisestä prosessijohtamisen tukena. Aineistonkeruu empiirisen osion osalta toteutettiin avoimina ja strukturoimattomina haastatteluina. Tutkielman tuloksina muodostui ymmärrys organisaation kustannuslaskennan nykytilanteesta ja hyödyntämismahdollisuuksista prosessienkehittämisessä. Kustannus- ja toimintolaskentaa hyödynnetään nykyisin pääasiassa hinnoittelupäätöksiin. Kustannustietoja ei systemaattisesti hyödynnetä prosessienkehittämisessä eikä arvioitaessa potentiaalisia kehitys- ja parannuskohteita. Toimintolaskennan erityispiirteet tukevat kuitenkin sitä, että toimintolaskenta sopii terveydenhuolto-organisaatioon kustannuslaskentamalliksi. Voidaan todeta kustannuslaskennan tukevan Lean- kehitystyön kohdentamista ja tuloksien arviointia.

Real-time analytics on large dynamic graphs

In today's fast-paced and interconnected digital world, the data generated by an increasing number of applications is being modeled as dynamic graphs. The graph structure encodes relationships among data items, while the structural changes to the graphs as well as the continuous stream of information produced by the entities in these graphs make them dynamic in nature. Examples include social networks where users post status updates, images, videos, etc.; phone call networks where nodes may send text messages or place phone calls; road traffic networks where the traffic behavior of the road segments changes constantly, and so on. There is a tremendous value in storing, managing, and analyzing such dynamic graphs and deriving meaningful insights in real-time. However, a majority of the work in graph analytics assumes a static setting, and there is a lack of systematic study of the various dynamic scenarios, the complexity they impose on the analysis tasks, and the challenges in building efficient systems that can support such tasks at a large scale. In this dissertation, I design a unified streaming graph data management framework, and develop prototype systems to support increasingly complex tasks on dynamic graphs. In the first part, I focus on the management and querying of distributed graph data. I develop a hybrid replication policy that monitors the read-write frequencies of the nodes to decide dynamically what data to replicate, and whether to do eager or lazy replication in order to minimize network communication and support low-latency querying. In the second part, I study parallel execution of continuous neighborhood-driven aggregates, where each node aggregates the information generated in its neighborhoods. I build my system around the notion of an aggregation overlay graph, a pre-compiled data structure that enables sharing of partial aggregates across different queries, and also allows partial pre-computation of the aggregates to minimize the query latencies and increase throughput. Finally, I extend the framework to support continuous detection and analysis of activity-based subgraphs, where subgraphs could be specified using both graph structure as well as activity conditions on the nodes. The query specification tasks in my system are expressed using a set of active structural primitives, which allows the query evaluator to use a set of novel optimization techniques, thereby achieving high throughput. Overall, in this dissertation, I define and investigate a set of novel tasks on dynamic graphs, design scalable optimization techniques, build prototype systems, and show the effectiveness of the proposed techniques through extensive evaluation using large-scale real and synthetic datasets.

L'évaluation de l'autonomie fonctionnelle des personnes âgées : contribution de la didactique professionnelle à la formation des travailleuses et travailleurs sociaux au Québec

Résumé : Le vieillissement démographique est statistiquement indiscutable au Québec. Ce singulier trompeur masque les différentes manières de vieillir. Pour ceux qui ne parviennent pas à vieillir en santé, les solidarités familiales, comme les solidarités institutionnelles, c’est à dire publiques viennent en principe compenser ce qu’il est convenu de désigner de perte d’autonomie. Les politiques de santé publique au Québec organisent les services de soutien à domicile sous condition d’avoir estimé la situation de la personne avec l’outil d’évaluation multiclientèle (OEMC). Il est en usage dans l’ensemble du réseau de la santé et des services sociaux, et utilisé par les professionnels dont les travailleuses et les travailleurs sociaux (TS). Or, la gérontologie est peu soutenue dans la formation initiale des TS. Nous nous sommes interrogée sur les savoirs mobilisés par les TS quand ils évaluent. S’agissant des savoirs inscrits dans la pratique, nous avons orienté la recherche dans les théories de l’activité, la didactique professionnelle et le cadre conceptuel de la médiation. Nous avons étudié l’activité de professionnels en travail social expérimentés afin d’identifier certains des savoirs mobilisés pour les rendre disponibles à la formation des étudiant (e)s en travail social au Québec. Cent-cinquante heures d’observations et vingt-deux entretiens individuels et collectifs ont été réalisés avec des intervenants volontaires du service de soutien à domicile. Les résultats préliminaires de la recherche ont été présentés lors de groupes de discussion avec les TS ayant participé à la recherche, puis avec des enseignants en travail social. Nos résultats permettent de décrire les procédures de l’évaluation dans l’organisation du service d’aide à domicile et d’en différencier le processus de l’activité par laquelle le TS évalue l’autonomie fonctionnelle de la personne. Nous constatons que les savoirs mobilisés par les TS reposent premièrement sur une connaissance fine du territoire, de l’outil d’évaluation et des institutions. Un deuxième registre de savoir concerne la conceptualisation de l’autonomie fonctionnelle par l’outil OEMC comme objet et domaine d’intervention des TS. Enfin, un troisième registre se réfère aux savoirs mobilisés pour entrer en relation avec les personnes âgées, avec leur entourage. Or, ces trois registres de savoir n’apparaissent pas dans le discours des TS et résultent de notre propre analyse sur leur pratique. L’évaluation de l’autonomie fonctionnelle analysée par le concept de médiation est révélatrice du rapport aux savoirs du TS. S’agissant de savoirs de la pratique, nous constatons que leur classification entre les catégories usuelles de savoirs théoriques ou pratiques était inopérante. Nous empruntons le vocabulaire de la didactique professionnelle : celui des invariants opératoires reliés à l’autonomie fonctionnelle et celui des schèmes d’activité reliés à l’activité d’évaluation. C’est ainsi que nous avons identifié deux moments dans l’évaluation. Le premier assemble la collecte des informations et l’analyse des données. L’autonomie fonctionnelle se décline dans des conditions d’existence de la personne sur l’axe allant de la mobilité à la cognition avec comme balises d’intervention la sécurité et l’intégrité de la personne. Dans ce processus itératif, le TS identifie avec la personne ce qui nuit à son quotidien. L’évaluation formule comment résoudre cette incidence, comment la perte d’autonomie pourrait être compensée. La collecte d’information et le raisonnement du TS est alors un mouvement itératif, les deux éléments du processus sont liés et en continu. Le second moment de l’évaluation apparait si, dans le processus itératif, le TS perçoit une dissonance. Il est essentiel d’en identifier la nature pour la prendre en compte et maintenir la finalité de l’activité qui consiste à évaluer l’autonomie fonctionnelle à des fins compensatrices. Le TS doit identifier l’objet de la dissonance pour pouvoir cerner avec la personne le besoin inhérent à la perte d’autonomie et envisager d’y remédier. La prise en compte de cette dissonance vient ralentir le déroulement de l’activité. Le raisonnement qui, jusque-là, était relié à la collecte d’informations s’en dissocie pour analyser ce qui vient faire obstacle à l’activité d’évaluation à partir de la situation. Les composantes qui génèrent la dissonance paraissent reliées à la quotidienneté, aux conditions de vie à domicile de la personne (cohérence/incohérence, refus de services, autonégligence, maltraitance, agressivité). La dissonance génère une activité plus complexe pour évaluer la situation. L’autonomie fonctionnelle se décline toujours sur l’axe mobilité/cognition avec comme balises d’intervention la sécurité et l’intégrité de la personne. Or, pour ce faire, les TS raisonnent selon trois schèmes. Dans les situations où, pour décider de la suite du dossier, il faut en référer à une norme (de service, de profession, etc.) le raisonnement est déontologique. Il est aussi des situations où le TS agit au regard de valeurs et de représentations qui relèvent de sa sphère personnelle. Nous désignons ce raisonnement d’instinctuel. Enfin, le TS peut naviguer entre ces deux orientations et choisir la voie du raisonnement clinique que nous qualifions d’éthique et se rapproche alors des pratiques prudentielles qui sont marquées par l’incertitude.

O impacto das medidas da Troika no desempenho económico-financeiro das empresas portuguesas

Os efeitos despoletados com a crise financeira de 2008 marcaram uma mudança radical de pensamentos e políticas entre as várias economias mundiais. Esta crise ficou marcada pelo enorme esforço que as economias tiveram que suportar, obrigando todos mercados a moldarem-se em função das contingências implementadas. Após análise e leitura de diversa literatura é consensual a referência ao início da crise financeira nos Estados Unidos da América (EUA) com o chamado subprime, percebendo-se também que muito rapidamente atingiria a Europa e todo o mundo. Desta forma, a Europa e inevitavelmente Portugal, acabaria por ser atingido e sofrer diversas consequências resultantes desta crise financeira. Na verdade, fruto da enorme turbulência dos mercados mundiais e da globalização, Portugal (incapaz de por si só sair da crise em que se viu envolvido) vê-se na necessidade de recorrer a ajuda externa por parte da Troika. Neste sentido, a presente dissertação tem como objetivo relatar resumidamente o início da crise financeira mundial, analisando o impacto das políticas de combate à crise implementadas em Portugal, no desempenho económico-financeiro das empresas portuguesas. Este estudo recaiu sobre a análise e perceção de comportamento de alguns indicadores económico financeiros entre os anos de 2010 a 2014, período durante o qual a Troika esteve presente em Portugal, implementando uma serie de reformas e políticas de combate à crise. Assim, debruçamo-nos sobre quatro setores de atividade (Construção Civil, Restauração, Hotelaria e Indústria do Calçado), observando os dados financeiros extraídos da base de dados SABI (Sistema de análise de Balanços Ibéricos) sobre empresas inseridas nos respetivos setores de atividade. Com base nos resultados do estudo realizado podemos concluir que o desempenho dos indicadores económico financeiros foram mais penalizados nos setores da Construção Civil e da Hotelaria.

Self-regulated learning in higher education : strategies adopted by computer programming students

Trabalho apresentado em PAEE/ALE’2016, 8th International Symposium on Project Approaches in Engineering Education (PAEE) and 14th Active Learning in Engineering Education Workshop (ALE)

Innovative approaches of regional policy of rural tourism development

The present work intends to study Rural Tourism. More specifically: regional policy of Rural Tourism development. Purpose of this research is creation of innovative qualitative model of regional policy of Rural Tourism development for Ukraine. With this aim literature review was made, developed a research methodology and analysis made. It was established a way of creation of qualitative model, based on studied information and scientific papers. Research methodology was described in next part. Decided to do it in three stages: (1) justification of analytical research; (2) data sample collection and analysis; (3) creating of innovative model of regional policy of Rural Tourism development. Each of these stages have sub stages supported by results of previous. In accordance to methodology, analytical part was made in two steps: (1) analysis of statistical information about rural houses availability; (2) analysis of resources needed for successfully Rural Tourism activity. This part gave information about placement of rural houses by geographical regions and defined most attractive geographical regions for Rural Tourism development. The results showed that the highest rural houses availability is in Western geographical region. Other regions have low level of rural houses availability. However, analysis of resources needed for successful Rural Tourism development showed, that all geographical regions are attractive for organizing Rural Tourism activity. Based on this information an innovative qualitative model of Rural Tourism development was created.