20,531 research outputs found

    Analysis of reliable deployment of TDOA local positioning architectures

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    .Local Positioning Systems (LPS) are supposing an attractive research topic over the last few years. LPS are ad-hoc deployments of wireless sensor networks for particularly adapt to the environment characteristics in harsh environments. Among LPS, those based on temporal measurements stand out for their trade-off among accuracy, robustness and costs. But, regardless the LPS architecture considered, an optimization of the sensor distribution is required for achieving competitive results. Recent studies have shown that under optimized node distributions, time-based LPS cumulate the bigger error bounds due to synchronization errors. Consequently, asynchronous architectures such as Asynchronous Time Difference of Arrival (A-TDOA) have been recently proposed. However, the A-TDOA architecture supposes the concentration of the time measurement in a single clock of a coordinator sensor making this architecture less versatile. In this paper, we present an optimization methodology for overcoming the drawbacks of the A-TDOA architecture in nominal and failure conditions with regards to the synchronous TDOA. Results show that this optimization strategy allows the reduction of the uncertainties in the target location by 79% and 89.5% and the enhancement of the convergence properties by 86% and 33% of the A-TDOA architecture with regards to the TDOA synchronous architecture in two different application scenarios. In addition, maximum convergence points are more easily found in the A-TDOA in both configurations concluding the benefits of this architecture in LPS high-demanded applicationS

    RELATIONSHIP BETWEEN BODY-SEAT INTERFACE PRESSURE AND DISCOMFORT DURING ROWING

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    Discomfort and pressure-related tissue injury to the buttocks are common complaints among rowers. The soft tissues of the buttocks are non-uniformly loaded during rowing. The current state of literature on seating discomfort is inconclusive as to a desirable body-seat interface pressure pattern. The purpose of this study was to determine whether localising pressure under bony protuberances or diffusing pressure over soft tissues would result in the least amount of discomfort. Force sensing arrays were used to measure body-seat interface pressures in 11 elite female rowers during rowing. Peak pressure measures were identified and pressure gradients were calculated. Discomfort was quantified using a questionnaire, and pressure data were then correlated with discomfort scores.Discomfort was weakly correlated with each of maximal pressure gradient (r=0.45) and peak pressure (r=0.43). The findings indicate pressure should be redistributed in order to avoid concentrating pressure under the bony protuberances o f the buttocks

    Exploring the effects of spinal cord stimulation for freezing of gait in parkinsonian patients

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    Dopaminergic replacement therapies (e.g. levodopa) provide limited to no response for axial motor symptoms including gait dysfunction and freezing of gait (FOG) in Parkinson’s disease (PD) and Richardson’s syndrome progressive supranuclear palsy (PSP-RS) patients. Dopaminergic-resistant FOG may be a sensorimotor processing issue that does not involve basal ganglia (nigrostriatal) impairment. Recent studies suggest that spinal cord stimulation (SCS) has positive yet variable effects for dopaminergic-resistant gait and FOG in parkinsonian patients. Further studies investigating the mechanism of SCS, optimal stimulation parameters, and longevity of effects for alleviating FOG are warranted. The hypothesis of the research described in this thesis is that mid-thoracic, dorsal SCS effectively reduces FOG by modulating the sensory processing system in gait and may have a dopaminergic effect in individuals with FOG. The primary objective was to understand the relationship between FOG reduction, improvements in upper limb visual-motor performance, modulation of cortical activity and striatal dopaminergic innervation in 7 PD participants. FOG reduction was associated with changes in upper limb reaction time, speed and accuracy measured using robotic target reaching choice tasks. Modulation of resting-state, sensorimotor cortical activity, recorded using electroencephalography, was significantly associated with FOG reduction while participants were OFF-levodopa. Thus, SCS may alleviate FOG by modulating cortical activity associated with motor planning and sensory perception. Changes to striatal dopaminergic innervation, measured using a dopamine transporter marker, were associated with visual-motor performance improvements. Axial and appendicular motor features may be mediated by non-dopaminergic and dopaminergic pathways, respectively. The secondary objective was to demonstrate the short- and long-term effects of SCS for alleviating dopaminergic-resistant FOG and gait dysfunction in 5 PD and 3 PSP-RS participants without back/leg pain. SCS programming was individualized based on which setting best improved gait and/or FOG responses per participant using objective gait analysis. Significant improvements in stride velocity, step length and reduced FOG frequency were observed in all PD participants with up to 3-years of SCS. Similar gait and FOG improvements were observed in all PSP-RS participants up to 6-months. SCS is a promising therapeutic option for parkinsonian patients with FOG by possibly influencing cortical and subcortical structures involved in locomotion physiology

    The applied psychology of addictive orientations : studies in a 12-step treatment context.

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    The clinical data for the studies was collected at The PROMIS Recovery Centre, a Minnesota Model treatmentc entre for addictions,w hich encouragesth e membership and use of the 12 step Anonymous Fellowships, and is abstinence based. The area of addiction is contextualised in a review chapter which focuses on research relating to the phenomenon of cross addiction. A study examining the concept of "addictive orientations" in male and female addicts is described, which develops a study conductedb y StephensonM, aggi, Lefever, & Morojele (1995). This presents study found a four factor solution which appeared to be subdivisions of the previously found Hedonism and Nurturance factors. Self orientated nurturance (both food dimensions, shopping and caffeine), Other orientated nurturance (both compulsive helping dimensions and work), Sensation seeking hedonism (Drugs, prescription drugs, nicotine and marginally alcohol), and Power related hedonism (Both relationship dimensions, sex and gambling. This concept of "addictive orientations" is further explored in a non-clinical population, where again a four factor solution was found, very similar to that in the clinical population. This was thought to indicate that in terms of addictive orientation a pattern already exists in this non-clinical population and that consideration should be given to why this is the case. These orientations are examined in terms of gender differences. It is suggested that the differences between genders reflect power-related role relationships between the sexes. In order to further elaborate the significance and meaning behind these orientations, the next two chapters look at the contribution of personality variables and how addictive orientations relate to psychiatric symptomatology. Personality variables were differentially, and to a considerable extent predictably involved with the four factors for both males and females.Conscientiousness as positively associated with "Other orientated Nurturance" and negatively associated with "Sensation seeking hedonism" (particularly for men). Neuroticism had a particularly strong association with the "Self orientated Nurturance" factor in the female population. More than twice the symptomatology variance was explained by the factor scores for females than it was for males. The most important factorial predictors for psychiatric symptomatology were the "Power related hedonism" factor for males, and "Self oriented nurturance" for females. The results are discussed from theoretical and treatment perspectives

    Reforming the United Nations

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    The thesis deals with the financial crisis that the United Nations faced starting in 1985 when the US Congress decided to withhold a significant part of the US contribution to the UN regular budget in order to force a greater say for the major contributors on budgetary issues, budgetary restraint and greater efficiency. The UN responded by the adoption of resolution 41/213 of 19 December 1986 that was based on the recommendations of a Group of High-level Intergovernmental Experts ("G-18") set up a year earlier. A new system was introduced regarding the formulation of the regular budget of the United Nations Organisation and a broader process of reform was initiated including a restructuring of the Secretariat and of the intergovernmental machinery in the economic and social fields. After an introductory chapter (Chapter I), the thesis examines the UN problems at the budgetary/financial and administrative/structural levels, the solutions proposed from within and without the United Nations established framework and the actual attempts at reform (Chapters II and ifi). The realisation that the implementation of reforms is rather disjointed and often unsuccessful (e.g. the failure to restructure the intergovernmental machi.neiy) prompts a search for the deeper causes of the UN problems at the political level and the attitudes of the main actors, namely the USA, the USSR, some up-and-coming states, notably Japan, the Third World states and, finally, of the UN Secretary-General and the Secretariat (Chapter 1V). Although the financial crisis may have subsided since 1988 and the USA seem committed to paying up their dues, the deeper UN crisis of identity has not been resolved and is expected to resurface if no bold steps are taken. In that direction, some possible alternative courses for the UN in the future are discussed drawing upon theory and practice (Chapte

    Patterns of subspecies diversity in the giraffe, Giraffa camelopardalis (L. 1758): comparison of systematic methods and their implications for conservation policy

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    This thesis examines the subspecific taxonomic status of the giraffe and considers the role of formal taxonomy in the formulation of conservation policy. Where species show consistent. geographically structured phenotypic variation such geographic patterns may indicate selective forces (or other population-level effects) acting. upon local populations. These consistent geographic patterns may be recognised formally as subspecies and may be of interest in single or multi-species biodiversity or biogeography studies for delimiting areas of conservation priority. Subspecies may also be used in the formulation of management policies and legislation. Subspecies are, by definition, allopatric. This thesis explicitly uses methodology of systematic biology and phylogenetic reconstruction to investigate patterns of variation between geographic groups. The taxonomic status of the giraffe is apposite for review. The species provides three independent data sets that may be analysed quantitatively for geographic structure; pelage patterns, morphology and genetics. Museum specimens. grouped according to geographic origin, were favoured for study as more than one type of data was often available for an individual. Population aggregation analysis of forty pelage pattern characters maintained six separate subspecies, while agglomerating some neighbouring populations into a subspecies. A 'traditional' morphometric approach, using multivariate statistical analysis of adult skull measurements, was complemented by a geometric morphometric approach; landmarkrestricted eigenshape analysis. Four morphologically distinct groups were recognised by both morphological analyses. Phylogenetic analysis of mitochondrial DNA control region sequences indicates five major cIades. Nested cIade analysis identifies population fragmentation, range expansion and genetic isolation by distance as contributing to the genetic structure of the giraffe. The results of the analyses show remarkable congruence. These results are discussed in terms of the formulation of conservation policy and the differing requirements of'blological and legal classification systems. The value of a formal taxonomic framework to the recognition, and subsequent conservation, of biodiversity is emphasised

    Why people tolerate transgressive leaders: Social identity advancement, group prototypicality, and charisma

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    Transgressive leaders have the potential to cause widespread disruption and damage to organisations. Not only can leaders' misconduct have economic, legal, and social ramifications for organisational functioning, but national leaders who violate established rules may also threaten the social fabric of entire societies. Despite these implications, transgressive leadership is a rampant problem within groups and organisations, and such leaders are often treated sympathetically by in-group members. This thesis aimed to identify some of the social psychological constructs and mechanisms that encourage followers to tolerate the transgressive behaviours of their leaders. Across eight studies using a variety of methods, populations, and contexts, I demonstrate the role of group prototypicality, identity advancement, and charisma in upholding the lenient treatment of transgressive leaders. Overall, findings from this thesis suggest that leaders who are perceived as having the group's best interests at heart are treated more sympathetically following their transgression. In part, this is because advancing group interests contributes towards perceptions of group prototypicality and charisma, which subsequently also encourage followers to treat their leader lightly. Additionally, perceptions of identity advancement encourage followers to rationalise the transgressive behaviour of their leader by downplaying how unethical their misconduct is, which paves the way for continued support of transgressive leaders. The research in this thesis has theoretical implications for the social identity theory of leadership, subjective group dynamics theory, and the deviance credit model. This research also provides practical insights into the difficulties faced in managing or mitigating transgressive leadership, and point to potential mechanisms that may be targeted by future interventions in resolving such a key societal problem

    3D printed Microneedles for Transdermal Drug Delivery

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    3D printing is a revolutionary manufacturing and prototyping technology that has altered the outlooks of numerous industrial and scientific fields since its introduction. Recently, it has attracted attention for its potential as a manufacturing tool for transdermal microneedles for drug delivery. In the present thesis, the 3D printability of solid and hollow microneedles via photopolymerisation-based 3D printing was investigated, aiming at establishing robust manufacturing strategies for reproducible, mechanically strong and versatile microneedles. The developed microneedles were employed as drug delivery systems for the treatment of diabetes via insulin administration. Solid microneedles featuring different geometries were designed and 3D printed. It was demonstrated that the printing and post-printing parameters affected the printed quality, a finding that was employed to optimise the manufacturing strategy. Microneedle geometry was also found to have an impact on the piercing and fracture behaviour; however all microneedle designs were found to be mechanically safe upon application. The solid microneedles were subsequently coated with insulin-polymer films, using a 2D inkjet printing technology. The coating process achieved spatial control of the drug deposition, with quantitative accuracy. The microneedle geometry was shown to influence the morphology of the coating film, an effect that was pronounced during in the in vitro delivery studies of insulin to porcine skin. Furthermore, hollow microneedles were designed and 3D printed, featuring different heights. Two photopolymerisation-based technologies were studied, and their performance was compared. The key influential parameters of the printing outcome and microneedle quality were identified to be the printing angle and the size of the microneedle opening. The hollow microneedles were found to be effective in piercing porcine skin without structural damaging. The hollow microneedles were incorporated into complex patches with internal microfluidic structures for the provision and distribution of drug-containing solutions. The developed complex hollow microneedle patches were coupled with a microelectromechanical system to create a novel platform device for controlled, personalised transdermal drug delivery. Advanced imaging techniques revealed that the device achieved distribution of the liquid within porcine skin tissue without the creation of depots that would delay absorption. The device was evaluated for its efficacy to transdermally deliver a model dye and insulin in vitro. In vivo trials were also conducted using diabetic rodents, with the device achieving faster onset of insulin action and sustained glycemic control, in comparison to subcutaneous injections. Overall, the findings of the present research are anticipated to elucidate key problematic areas associated with the application of 3D printing for microneedle manufacturing and propose feasible solutions. The outermost goal of this work is to contribute to the advancement of knowledge in the field of 3D printed transdermal drug delivery systems, in order to bring them one step closer to their adoption in the clinical setting

    Estudio del mecanismo de reacción e inhibición de cisteína proteasas mediante métodos multiescala

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    En esta tesis doctoral se realizaron estudios computacionales para las enzimas caspasa-1 y la 3CLpro del SARS-CoV-2. Estas enzimas pertenecen a la familia de las cisteína proteasas, las cuales hidrolizan sus respectivos sustratos rompiendo un enlace peptídico en particular. En esta reacción interviene una diada catalítica conformada por un par Cis-His. La caspasa-1 fue seleccionada debido a su importancia farmacológica en la enfermedad de Alzheimer, y la enzima 3CLpro del SARS-CoV-2 por estar involucrada en el proceso de replicación del virus responsable de la enfermedad del COVID-19. Para ambas se realizaron estudios que ayudaron a racionalizar el mecanismo de reacción con su sustrato natural utilizando m todos QM/MM. También se realizaron estudios de una serie de inhibidores enzimáticos covalentes identificando las interacciones clave enzima-sustrato que ayudar n a mejorar el desempeño de los inhibidores frente a sus respectivas enzimas. El mecanismo de reacción encontrado para la enzima caspasa-1 ocurre por una ruta alternativa al mecanismo estándar de este tipo de enzimas. En el mecanismo encontrado en nuestras simulaciones la cisteína catalítica se activa directamente por el grupo amino de su sustrato natural, lo que facilita el posterior ataque nucleofílico del azufre al carbonilo y la ruptura del enlace peptídico. En este estudio se determinó que el estado de protonación de la dada catalítica que mejor correlaciona con los resultados experimentales es aquel en el que ambos residuos están neutros, encontrándose el protón de la histidina sobre el nitrógeno delta. También se determina que los inhibidores más potentes para la caspasa-1 son aquellos que, presentan mejores interacciones con los residuos His342, Pro343 and Arg383, adicionalmente a las interacciones ya bien caracterizadas para la estabilización del oxianión formado durante la reacción. En el caso de la 3CLpro del SARSCoV-2, los resultados apuntan a que la dada catalítica en el complejo de Michaelis se encuentra en estado neutro, siendo necesaria la activación de la cisteína por parte de la histidina catalítica para que la reacción proceda. Posteriormente el grupo amino del sustrato abstrae el protón de la histidina mientras se da el ataque nucleofílico del azufre de la cisteína sobre el carbono del carbonilo del enlace peptídico. Para la etapa de de-acilación se describió un mecanismo de reacción alternativo, en donde el grupo amino del grupo saliente desprotona la molécula de agua que posteriormente va a hidrolizar el complejo acil-enzima. En cuanto a la inhibición enzimática, se encontró un mecanismo de intercambio de protones mediado por una molécula de agua, o un grupo hidroxilo. Los hallazgos de esta tesis doctoral abren la puerta para el desarrollo de potentes inhibidores para las dos enzimas involucradas en este estudio, esperando así contribuir al desarrollo de medicamentos que ayuden a tratar las enfermedades en las que se encuentran involucradas.In this doctoral thesis, computational studies were carried out for the enzymes caspase-1 and 3CLpro of SARS-CoV-2. These enzymes belong to the cysteine ​​protease family, which hydrolyze their respective substrates by breaking a particular peptide bond. This reaction involves a catalytic dyad made up of a Cis-His pair. The enzymes Caspase-1 and the SARS-CoV-2 enzyme 3CLpro were selected due to its pharmacological importance in Alzheimer's disease and in the COVID-19 disease respectively. For both, studies were carried out that helped to rationalize the reaction mechanism with its natural substrate using QM/MM methods. Also, studies on a series of covalent inhibitors were conducted in order to identify the key enzyme-substrate interactions that will help improve the performance of the inhibitors against their respective enzymes. The reaction mechanism found for the caspase-1 enzyme occurs through an alternative route to the standard mechanism of this type of enzyme. In the mechanism found in our simulations, the catalytic cysteine ​​is activated directly by the amino group of its natural substrate, which facilitates the subsequent nucleophilic attack of sulfur on the carbonyl and the breaking of the peptide bond. In this study it was determined that the protonation state of the catalytic dyad that best correlates with the experimental results is the one in which both residues are neutral, with the histidine protonated on the delta nitrogen. It was also determined that the most potent inhibitors for caspase-1 are those that present better interactions with residues His342, Pro343 and Arg383, in addition to the interactions already well characterized for the stabilization of the oxyanion formed during the reaction. In the case of the 3CLpro of SARSCoV-2, the results indicate that the catalytic dyad in the Michaelis complex exist in a neutral state, requiring the cysteine be activated ​​by the catalytic histidine for the reaction to proceed. Subsequently, the amino group of the substrate abstracts the proton from the histidine while the nucleophilic attack of the cysteine ​​sulfur on the carbonyl carbon of the peptide bond takes place. An alternative reaction mechanism was described for the deacylation step, where the amino group of the leaving group deprotonates the water molecule that subsequently hydrolyzes the acyl-enzyme complex. Regarding enzyme inhibition, a proton exchange mechanism mediated by a water molecule or a hydroxyl group was found. The findings of this doctoral thesis open the door for the development of powerful inhibitors for the two enzymes involved in this study, thus hoping to contribute to the development of drugs that help treat the diseases in which they are involved
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