Design and synthesis of novel quinolones directed to the Plasmodium falciparum bc1 protein complex

Tese de Doutoramento, Química, Especialização em Química Orgânica, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2016

Standardised tobacco packaging:a health policy case study of corporate conflict expansion and adaptation

Objectives: To investigate opposition to standardised tobacco packaging in the UK. To increase understanding of how transnational corporations are adapting to changes in their access to policymakers precipitated by Article 5.3 of the Framework Convention on Tobacco Control (FCTC). Design: Case study web-based documentary analysis, using NVivo V.10. Examination of relationships between opponents of standardised packaging and transnational tobacco companies (TTCs) and of the volume, nature, transparency and timing of their activities. Setting: UK standardised packaging policy debate 2011-2013. Participants: Organisations selected on basis of opposition to, or facilitation thereof, standardised tobacco packaging in the UK; 422 associated documents. Results: Excluding tobacco manufacturing and packaging companies (n=12), 109 organisations were involved in opposing standardised packaging, 82 (75%) of which had a financial relationship with 1 or more TTC. These 82 organisations (43 actively opposing the measure, 39 facilitating opposition) were responsible for 60% of the 404 activities identified, including the majority of public communications and research production. TTCs were directly responsible for 28% of total activities, predominantly direct lobbying, but also financially underwrote third party research, communication, mass recruitment and lobbying. Active organisations rarely reported any financial relationship with TTCs when undertaking opposition activities. Conclusions: The multifaceted opposition to standardised packaging was primarily undertaken by third parties with financial relationships with major tobacco manufacturers. Low levels of transparency regarding these links created a misleading impression of diverse and widespread opposition. Countries should strengthen implementation of Article 5.3 of the FCTC by systematically requiring conflict of interest declarations from all organisations participating in political or media debates on tobacco control.

Website content and design in SME: insights from Portugal

Although there is a vast amount of literature on website evaluation, relatively little has been written about the analysis of websites of small and medium-sized enterprises (SME). This paper examines a comprehensive set of content and design features of 915 websites of Portuguese SME, as well as the relationship between these features and enterprise size. The results indicate that the majority of the websites are used to convey information, rather than to make transactions, support networking and collaboration or to interact dynamically with users. Accessibility or privacy and security features are not common among websites. Web 2.0 features have a low presence in SME websites, but social media emerged as a construct. In contrast with existing literature, the study has found that website content and design features are positively related with enterprise size. The contributions and implications are discussed together with avenues for further research.

Determinants of the Design and Use of PMS in Portuguese Government Agencies: A Complementary Theoretical Approach

Performance measurement is seen as a main pillar of public management reforms. However, prior research did not mitigate the level of ambiguity on PMS development and use and many questions left unanswered. Our findings provide knowledge on the design and use of PMS in the public sector answer- ing to calls for a complementary approach among institutional and contingency factors. The authors find that the design of PMS and the use of performance information for external purposes are increased to legitimate the organizational’ work and to obtain external support. Moreover, structural variables such as type of agency and management autonomy are also determinants on the organizational responses. Finally, the authors find some coupling between the design of PMS and outcomes. So, both contingent and institutional approaches play an important role on the empirical model.

Data protection by design in the e-health care sector: theoretical and applied perspectives

In the digital age, e-health technologies play a pivotal role in the processing of medical information. As personal health data represents sensitive information concerning a data subject, enhancing data protection and security of systems and practices has become a primary concern. In recent years, there has been an increasing interest in the concept of Privacy by Design, which aims at developing a product or a service in a way that it supports privacy principles and rules. In the EU, Article 25 of the General Data Protection Regulation provides a binding obligation of implementing Data Protection by Design technical and organisational measures. This thesis explores how an e-health system could be developed and how data processing activities could be carried out to apply data protection principles and requirements from the design stage. The research attempts to bridge the gap between the legal and technical disciplines on DPbD by providing a set of guidelines for the implementation of the principle. The work is based on literature review, legal and comparative analysis, and investigation of the existing technical solutions and engineering methodologies. The work can be differentiated by theoretical and applied perspectives. First, it critically conducts a legal analysis on the principle of PbD and it studies the DPbD legal obligation and the related provisions. Later, the research contextualises the rule in the health care field by investigating the applicable legal framework for personal health data processing. Moreover, the research focuses on the US legal system by conducting a comparative analysis. Adopting an applied perspective, the research investigates the existing technical methodologies and tools to design data protection and it proposes a set of comprehensive DPbD organisational and technical guidelines for a crucial case study, that is an Electronic Health Record system.

Theoretical and experimental study of novel hybrid composite and metal-composites interfaces

The growing demand for lightweight solutions in every field of engineering is driving the industry to seek new technological solutions to exploit the full potential of different materials. The combination of dissimilar materials with distinct property ranges embodies a transparent allocation of component functions while allowing an optimal mix of their characteristics. From both technological and design perspectives, the interaction between dissimilar materials can lead to severe defects that compromise a multi-material hybrid component's performance and its structural integrity. This thesis aims to develop methodologies for designing, manufacturing, and monitoring of hybrid metal-composite joints and hybrid composite components. In Chapter 1, a methodology for designing and manufacturing hybrid aluminum/composite co-cured tubes is assessed. In Chapter 2, a full-field methodology for fiber misalignment detection and stiffness prediction for hybrid, long fiber reinforced composite systems is shown and demonstrated. Chapter 3 reports the development of a novel technology for joining short fiber systems and metals in a one-step co-curing process using lattice structures. Chapter 4 is dedicated to a novel analytical framework for the design optimization of two lattice architectures.

Smart tracking of composite parts: feasibility study and effect on mechanical behaviour

This research proposes a solution for integrating RFID - Radio Frequency Identification technology within a structure based on CFRPs - Carbon Fiber Reinforced Polymers. Therefore, the main objective is to use technology to monitor and track composite components during manufacturing and service life. The study can be divided into two macro-areas. The first portion of the research evaluates the impact of the composite materials used on transmitting the electromagnetic signal to and from the tag. RFID technology communicates through radio frequencies to to track and trace items associated with the tags. In the first instance, a feasibility study was carried out to assess using commercially available tags. Then, after evaluating different solutions, it was decided to incorporate the tags into coupons during production. The second portion of the research is focused on evaluating the impact on the composite material's resistance to tag embedding. It starts with designing tensile test specimens through the FEM model with different housing configurations. Subsequently, the best configuration was tested in the facilities of the In the Faculty of Aerospace Engineering at TU Delft, particularly in the Structure & Materials Laboratory, two tests were conducted: the first one based on ASTM D3039/D3039 - 14 - Standard Test Method for Tensile Properties of Polymer Matrix Composite Materials, the second one dividing the path to failure into failure intervals in a load-unload-reload. Both tests were accompanied by instruments such as DIC, AE, C-Scan and Optical Microscopes. The expected result of the inclusion of RFID tags in composite components is that it brings added value to the parts with which it is associated without affecting too much its mechanical properties. This comes first from the automatic identification of RFID during the production cycle and its useful life. As a result, improvements were made in the design of production facilities.

Kinase Inhibitor Profile For Human Nek1, Nek6, And Nek7 And Analysis Of The Structural Basis For Inhibitor Specificity.

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.

Nasopharyngeal Intubation in Robin Sequence: Technique and Management

Objective: To provide a detailed description of the nasopharyngeal intubation (NPI) technique and photographs, which should be helpful for those who may need to perform it for treating the airway obstruction in Robin sequence. Design: To describe and illustrate the NPI technique and the necessary considerations for its application. Setting: Hospital de Reabilitacao de Anomalias Craniofacial of University of Sao Paulo, Brazil. Result: The NPI procedure involves the use of a whitish, Portex, number 3.0 or 3.5, silicone tube, introduced 8 cm deep into the infant`s nostril and fixed with Micropore tape. The tube is to be removed at least twice a day for proper hygiene (with running water, detergent, and swabs) and should be changed every 7 days. This procedure is taught to the children`s parents or caretakers by the nurse during hospitalization. Conclusion: The technique is so simple that it can be performed by the parents themselves, allowing continuation of the treatment at home.

Modeling and analysis of laminate composite plates with embedded active-passive piezoelectric networks

The objective of this work is to present the finite element modeling of laminate composite plates with embedded piezoelectric patches or layers that are then connected to active-passive resonant shunt circuits, composed of resistance, inductance and voltage source. Applications to passive vibration control and active control authority enhancement are also presented and discussed. The finite element model is based on an equivalent single layer theory combined with a third-order shear deformation theory. A stress-voltage electromechanical model is considered for the piezoelectric materials fully coupled to the electrical circuits. To this end, the electrical circuit equations are also included in the variational formulation. Hence, conservation of charge and full electromechanical coupling are guaranteed. The formulation results in a coupled finite element model with mechanical (displacements) and electrical (charges at electrodes) degrees of freedom. For a Graphite-Epoxy (Carbon-Fibre Reinforced) laminate composite plate, a parametric analysis is performed to evaluate optimal locations along the plate plane (xy) and thickness (z) that maximize the effective modal electromechanical coupling coefficient. Then, the passive vibration control performance is evaluated for a network of optimally located shunted piezoelectric patches embedded in the plate, through the design of resistance and inductance values of each circuit, to reduce the vibration amplitude of the first four vibration modes. A vibration amplitude reduction of at least 10 dB for all vibration modes was observed. Then, an analysis of the control authority enhancement due to the resonant shunt circuit, when the piezoelectric patches are used as actuators, is performed. It is shown that the control authority can indeed be improved near a selected resonance even with multiple pairs of piezoelectric patches and active-passive circuits acting simultaneously. (C) 2010 Elsevier Ltd. All rights reserved.

Milk yield, milk composition, eating behavior, and lamb performance of ewes fed diets containing soybean hulls replacing coastcross (Cynodon species) hay

The objective of this experiment was to evaluate the effects of replacing coastcross hay NDF by soybean hull (SH) NDF on the lactation performance and eating behavior of ewes and also on the performance of their lambs. Fifty-six Santa Ines lactating ewes (56.1 +/- 6.8 kg of initial BW; mean +/- SD) were penned individually and used in a randomized complete block design with 14 blocks and 4 treatments. Diets were formulated to provide similar concentrations of NDF (56%) and CP (16%). The SH NDF replaced 33 (SH33), 67 (SH67), or 100% (SH100) of the NDF contributed by coastcross hay in a 70% forage-based diet (SH0), resulting in SH inclusion rates of 0, 25, 54, and 85% of the dietary DM. Once a week, from the second to the eighth week of lactation (weaning time), ewes were separated from their lambs, stimulated by a 6-IU i.v. oxytocin injection, and hand milked to empty the udder. After 3 h, milk production was obtained after the same procedure. Quadratic effect for milk production (142.4, 179.8, 212.6, and 202.9 g/3 h) and cubic effect for DMI (2.27, 2.69, 3.25, and 3.00 kg/d) were observed as SH inclusion increased from 0 to 85% of the dietary DM. Milk fat (7.59, 7.86, 7.59, and 7.74%), protein (4.53, 4.43, 4.40, and 4.55%), and total solids (18.24, 18.54, 18.39, and 18.64%) did not differ among the 70% forage-based diet and diets with SH NDF replacing 33, 67, or 100% of the NDF. A linear increase in lactose concentration was observed with SH inclusion. Ewe BW gain during the trial showed a cubic response (0.37, 0.03, 4.80, and 2.80 kg) with SH inclusion. The preweaning ADG of lambs increased linearly, and ADG of lambs after weaning decreased linearly with SH inclusion. Final BW of lambs (2 wk after weaning) did not differ among treatments. Eating behavior observations were conducted with 44 ewes. The same facilities, experimental design, dietary treatments, and feeding management were used. Observations were visually recorded every 5 min for a 24-h period when ewes were 46 +/- 6.8 d in milk. Eating time (min/d, min/g of DMI, and min/g of NDF intake) and time expended in rumination and chewing activities (min/g of DMI and min/g of NDF intake) decreased linearly with the addition of SH in the diets. The inclusion of SH improved DMI and milk production, also reflecting on the BW of lambs at weaning. Milk performance was not affected when SH NDF replaced 100% of hay NDF.

Satellite protection and drag reduction using a purging gas flow

We have used the DSMC method to determine contamination (impingement of atmospheric molecules) and the aerodynamic forces on a cold satellite when a protective “purge gas” is ejected from a sting protruding ahead of the satellite. Forward ejection of the purge gas provides the greatest protection for a given mass of purge gas and the aerodynamic drag can be significantly reduced, thus compensating for the backward reaction from the forward ejection. If the purge gas is ejected backward from the sting (towards the satellite) the ejection provides thrust and the net retarding force can be reduced to zero. Contamination can be reduced and the mass of purging gas is less than the mass of conventional rocket propellant required to maintain the orbit of an unprotected satellite.

Effect of coinfection with STDs and of STD treatment on HIV shedding in genital-tract secretions - Systematic review and data synthesis

Objective: To determine whether coinfection with sexually transmitted diseases (STD) increases HIV shedding in genital-tract secretions, and whether STD treatment reduces this shedding. Design: Systematic review and data synthesis of cross-sectional and cohort studies meeting. predefined quality criteria. Main Outcome Measures: Proportion of patients with and without a STD who had detectable HIV in genital secretions, HIV toad in genital secretions, or change following STD treatment. Results: Of 48 identified studies, three cross-sectional and three cohort studies were included. HIV was detected significantly more frequently in participants infected with Neisseria gonorrhoeae (125 of 309 participants, 41%) than in those without N gonorrhoeae infection (311 of 988 participants, 32%; P = 0.004). HIV was not significantly more frequently detected in persons infected with Chlamydia trachomatis (28 of 67 participants, 42%) than in those without C trachomatis infection (375 of 1149 participants, 33%; P = 0.13). Median HIV load reported in only one study was greater in men with urethritis (12.4 x 10(4) versus 1.51 x 10(4) copies/ml; P = 0.04). In the only cohort study in which this could be fully assessed, treatment of women with any STD reduced the proportion of those with detectable HIV from 39% to 29% (P = 0.05), whereas this proportion remained stable among controls (15-17%), A second cohort study reported fully on HIV load; among men with urethritis, viral load fell from 12.4 to 4.12 x 10(4) copies/ml 2 weeks posttreatment, whereas viral load remained stable in those without urethritis. Conclusion: Few high-quality studies were found. HIV is detected moderately more frequently in genital secretions of men and women with a STD, and HIV load is substantially increased among men with urethritis, Successful STD treatment reduces both of these parameters, but not to control levels. More high-quality studies are needed to explore this important relationship further.

Early Control of PTH and FGF23 in Normophosphatemic CKD Patients: A New Target in CKD-MBD Therapy?

Background and objectives: Levels of parathyroid hormone (PTH) and the phosphaturic hormone FGF23, a fibroblast growth factor (FGF) family member, increase early in chronic kidney disease (CKD) before the occurrence of hyperphosphatemia. This short-term 6-wk dose titration study evaluated the effect of two phosphate binders on PTH and FGF23 levels in patients with CKD stages 3 to 4. Design, setting, participants, and measurements: Patients were randomized to receive over a 6-wk period either calcium acetate (n = 19) or sevelamer hydrochloride (n = 21). Results: At baseline, patients presented with elevated fractional excretion of phosphate, serum PTH, and FGF23. During treatment with both phosphate binders there was a progressive decline in serum PTH and urinary phosphate, but no change in serum calcium or serum phosphate. Significant changes were observed for FGF23 only in sevelamer-treated patients. Conclusions: This study confirms the positive effects of early prescription of phosphate binders on PTH control. Prospective and long-term studies are necessary to confirm the effects of sevelamer on serum FGF23 and the benefits of this decrease on outcomes. Clin J Am Soc Nephrol 5: 286-291, 2010. doi: 10.2215/CJN.05420709

Protein crystallography and examples of its applications in medicinal chemistry

The field of protein crystallography inspires and enthrals, whether it be for the beauty and symmetry of a perfectly formed protein crystal, the unlocked secrets of a novel protein fold, or the precise atomic-level detail yielded from a protein-ligand complex. Since 1958, when the first protein structure was solved, there have been tremendous advances in all aspects of protein crystallography, from protein preparation and crystallisation through to diffraction data measurement and structure refinement. These advances have significantly reduced the time required to solve protein crystal structures, while at the same time substantially improving the quality and resolution of the resulting structures. Moreover, the technological developments have induced researchers to tackle ever more complex systems, including ribosomes and intact membrane-bound proteins, with a reasonable expectation of success. In this review, the steps involved in determining a protein crystal structure are described and the impact of recent methodological advances identified. Protein crystal structures have proved to be extraordinarily useful in medicinal chemistry research, particularly with respect to inhibitor design. The precise interaction between a drug and its receptor can be visualised at the molecular level using protein crystal structures, and this information then used to improve the complementarity and thus increase the potency and selectivity of an inhibitor. The use of protein crystal structures in receptor-based drug design is highlighted by (i) HIV protease, (ii) influenza virus neuraminidase and (iii) prostaglandin H-2-synthetase. These represent, respectively, examples of protein crystal structures that (i) influenced the design of drugs currently approved for use in the treatment of HIV infection, (ii) led to the design of compounds currently in clinical trials for the treatment of influenza infection and (iii) could enable the design of highly specific non-steroidal anti-inflammatory drugs that lack the common side-effects of this drug class.