HIV-1 protease (PR) inhibitors (PIs) are important anti-HIV drugs for the treatment of AIDS and have shown great success in reducing mortality and prolonging the life of HIV-infected individuals. However, the rapid development of drug resistance is one of the major factors causing the reduced effectiveness of PIs. Consequently, various drug resistant mutants of HIV-1 PR have been extensively studied to gain insight into the mechanisms of drug resistance. In this study, the crystal structures, dimer stabilities, and kinetics data have been analyzed for wild type PR and over 10 resistant mutants including PRL24I, PRI32V, PRM46L, PRG48V, PRI50V, PRF53L, PRI54V, PRI54M, PRG73S and PRL90M. These mutations lie in varied structural regions of PR: adjacent to the active site, in the inhibitor binding site, the flap or at protein surface. The enzymatic activity and inhibition were altered in mutant PR to various degrees. Crystal structures of the mutants complexed with a substrate analog inhibitor or drugs indinavir, saquinavir and darunavir were determined at resolutions of 0.84 – 1.50 Å. Each mutant revealed distinct structural changes, which are usually located at the mutated residue, the flap and inhibitor binding sites. Moreover, darunavir was shown to bind to PR at a new site on the flap surface in PRI32V and PRM46L. The existence of this additional inhibitor binding site may explain the high effectiveness of darunavir on drug resistant mutants. Moreover, the unliganded structure PRF53L had a wider separation at the tips of the flaps than in unliganded wild type PR. The absence of flap interactions in PRF53L suggests a novel mechanism for drug resistance. Therefore, this study enhanced our understanding of the role of individual residues in the development of drug resistance and the structural basis of drug resistance mechanisms. Atomic resolution crystal structures are valuable for the design of more potent protease inhibitors to overcome the drug resistance problem.

Over the last few decades the design of high lift devices has become a very important part of the total aircraft design process. Reviews of the design process are performed on a regular basis, with the intent to improve and optimize the design process. This thesis describes a new and innovative methodology for the design and evaluation of mechanisms for Trailing Edge High-Lift devices. The initial research reviewed existing High-Lift device design methodologies and current flap systems used on existing commercial transport aircraft. This revealed the need for a design methodology that could improve the design process of High-Lift devices, moving away from the conventional "trial and error" design approach, and cover a wider range of design attributes. This new methodology includes the use of the innovative design tool called SYNAMEC. This is a state-of-the-art engineering design tool for the synthesis and optimizations of aeronautical mechanisms. The new multidisciplinary design methodology also looks into issues not usually associated with the initial stages of the design process, such as Maintainability, Reliability, Weight and Cost. The availability of the SYNAMEC design tool and its ability to perform Synthesis and Optimization of mechanisms led to it being used as an important module in the development of the new design methodology. The SYNAMEC tool allows designers to assess more mechanisms in a given time than the traditional design methodologies. A validation of the new methodology was performed and showed that creditable results were achieved. A case study was performed on the ATRA - Advance Transport Regional Aircraft, a Cranfield University design project, to apply the design methodology and select from within a group of viable solutions the most suitable type of mechanism for the Variable Camber Wing concept initially defined for the aircraft. The results show that the most appropriate mechanism type for the ATRA Variable Camber Wing is the Link /Track Mechanism. It also demonstrated how a wide range of design attributes can now be considered at a much earlier stage of the design.

This thesis describes the analysis, fabrication and testing of a rotor with extremely flexible blades, focusing on application to a micro-helicopter. The flexibility of the rotor blades is such that they can be rolled into a compact volume and stowed inside the rotor hub. Stiffening and stabilization of the rotor is enabled by centrifugal forces acting on a tip mass. Centrifugal effects such as bifilar and propeller moments are investigated and the torsional equation of motion for a blade with low torsional stiffness is derived. Criteria for the design of the tip mass are also derived and it is chosen that the center of gravity of each blade section must be located ahead of the aerodynamic center. This thesis presents the design of 18-inch diameter two-bladed rotors having untwisted circular arc airfoil profile with constant chord. A systematic experimental investigation of the effect of various blade parameters on the stability of the rotor is conducted in hover and forward flight. These parameters include blade flexibility in bending and torsion, blade planform and mass distribution. Accordingly, several sets of blades varying these parameters are constructed and tested. It is observed that rotational speed and collective pitch angles have a significant effect on rotor stability. In addition, forward flight velocity is found to increase the blade stability. Next, the performance of flexible rotors is measured. In particular, they are compared to the performance of a rotor with rigid blades having an identical planform and airfoil section. It is found that the flexible blades are highly twisted during operation, resulting in a decreased efficiency compared to the rigid rotor blades. This induced twist is attributed to an unfavorable combination of tip body design and the propeller moment acting on it. Consequently, the blade design is modified and three different approaches to passively tailor the spanwise twist distribution for improved efficiency are investigated. In a first approach, extension-torsion composite material coupling is analyzed and it is shown that the centrifugal force acting on the tip mass is not large enough to balance the nose-down twist due to the propeller moment. The second concept makes use of the propeller moment acting on the tip mass located at an index angle to produce an untwisted blade in hover. It is constructed and tested. The result is an untwisted 18-inch diameter rotor whose maximum Figure of Merit is equal to 0.51 at a blade loading of 0.14. Moreover, this rotor is found to be stable for any collective pitch angle greater than 11 degrees. Finally, in a third approach, addition of a trailing-edge flap at the tip of the flexible rotor blade is investigated. This design is found to have a lower maximum Figure of Merit than that of an identical flexible rotor without a flap. However, addition of this control surface resulted in a stable rotor for any value of collective pitch angle. Future plans for increasing the efficiency of the flexible rotor blades and for developing an analytical model are described. / text

No description available.

Diss. (sammanfattning) Umeå : Univ., 2008. / Härtill 4 uppsatser.

Over the last few decades the design of high lift devices has become a very important part of the total aircraft design process. Reviews of the design process are performed on a regular basis, with the intent to improve and optimize the design process. This thesis describes a new and innovative methodology for the design and evaluation of mechanisms for Trailing Edge High-Lift devices. The initial research reviewed existing High-Lift device design methodologies and current flap systems used on existing commercial transport aircraft. This revealed the need for a design methodology that could improve the design process of High-Lift devices, moving away from the conventional "trial and error" design approach, and cover a wider range of design attributes. This new methodology includes the use of the innovative design tool called SYNAMEC. This is a state-of-the-art engineering design tool for the synthesis and optimizations of aeronautical mechanisms. The new multidisciplinary design methodology also looks into issues not usually associated with the initial stages of the design process, such as Maintainability, Reliability, Weight and Cost. The availability of the SYNAMEC design tool and its ability to perform Synthesis and Optimization of mechanisms led to it being used as an important module in the development of the new design methodology. The SYNAMEC tool allows designers to assess more mechanisms in a given time than the traditional design methodologies. A validation of the new methodology was performed and showed that creditable results were achieved. A case study was performed on the ATRA - Advance Transport Regional Aircraft, a Cranfield University design project, to apply the design methodology and select from within a group of viable solutions the most suitable type of mechanism for the Variable Camber Wing concept initially defined for the aircraft. The results show that the most appropriate mechanism type for the ATRA Variable Camber Wing is the Link /Track Mechanism. It also demonstrated how a wide range of design attributes can now be considered at a much earlier stage of the design.

Objetivos: Investigar o efeito da cirurgia de retalho faríngeo (CRF) sobre as dimensões internas nasais de pacientes com insuficiência velofaríngea (IVF), a curto e longo prazo, e, correlacionar esses achados com o aparecimento de queixas respiratórias após a cirurgia. Modelo/Pacientes: Estudo prospectivo em 58 pacientes com fissura palatina operada e IVF, avaliados 2 dias antes (PRE) e, 5 (POS1) e 14 meses (POS2) após a cirurgia, em média, divididos em 2 grupos: um queixas respiratórias (CQ) em POS2 e outro, sem queixas (SQ). Diferenças entre grupos e etapas foram consideradas significantes ao nível de 5%. Local: Laboratório de Fisiologia, Hospital de Reabilitação de Anomalias Craniofaciais, USP, Bauru. Intervenções: CRF de pedículo superior. Variáveis: Queixas (respiração oral, ronco e dificuldade respiratória durante o sono) e área de secção transversa mínima nasal (AN) e nasofaríngea (ANF) avaliada por rinomanometria. Resultados: Queixas respiratórias foram observadas em 55% dos pacientes em POS1 e 36% em POS2. Observou-se na rinomanometria posterior: 1) redução significativa da AN média em POS1 e POS2, relativamente ao PRE, em ambos os grupos. Não foram observadas variações significativas na rinomanometria anterior; 2) AN média do grupo CQ significantemente menor que a do grupo SQ em POS2; 3) redução da AN mais pronunciada no grupo CQ. Medidas da ANF confirmaram esses achados. Conclusões: A curto prazo, a CRF levou à redução significativa da dimensão nasofaríngea em proporção expressiva de pacientes, parte dos quais passaram a apresentar queixas respiratórias; a longo prazo, esse efeito atenuou-se sem, contudo, desaparecer por completo. / Objectives: To investigate the short- and long-term effect of pharyngeal flap surgery (PFS) on the internal nasal dimensions of patients with velopharyngeal insufficiency (VPI) and to correlate the findings with the onset of respiratory complaints (RC) after surgery. Model/Patients: Prospective study in 58 patients with repaired cleft palate and VPI, evaluated, on average, 2 days before (PRE), 5 (POST1) and 14 months (POST2) after surgery, divided into 2 groups: one consisting of patients with RC (WRC) at POST2 and the other without RC (WtRC). Differences between groups and stages were considered to be significant at the 5% level. Site: Laboratory of Physiology, Hospital for Rehabilitation of Craniofacial Anomalies, Brazil. Interventions: Superiorly based PFS. Variables: RC (oral respiration, snoring and respiratory difficulty during sleep), and minimal nasal (NA) and nasopharyngeal (NPA) cross-sectional area assessed by rhinomanometry. Results: RC were observed in 55% of patients at POST1 and 36% at POST2. Posterior rhinomanometry showed: 1) a significant reduction of mean NA at POST1 and POST2 compared to PRE, in both groups. No significant changes were observed by anterior rhinomanometry; 2) significantly lower mean NA in the WC group compared to the WtC group at POST2; 3) more pronounced reduction in NA values in the WC group. NPA measurements confirmed these findings. Conclusions: In the short term, PFS led to a significant reduction in the nasopharyngeal dimensions in a significant proportion of patients, part of whom started to present RC; in the long term, this effect was attenuated but did not fully disappear.

INTRODUÇÃO: As ressecções oncológicas da cavidade oral, orofaringe, hipofaringe e laringe, que têm como objetivo a extirpação completa do tumor com margens de segurança, podem determinar grandes defeitos anatômicos tridimensionais e que afetam funções nobres, entre elas a deglutição, a fala e a respiração. Entre as alternativas de reconstrução o retalho miocutâneo de platisma (RMP) pode ser empregado, dada sua versatilidade e facilidade de execução técnica, com a vantagem de ser menos espesso que os outros retalhos miocutâneos e adaptar-se melhor a uma série de condições clínicas. O objetivo deste trabalho foi estudar os resultados do RMP empregado nas reconstruções após ressecções oncológicas de tumores da cavidade oral, orofaringe, hipofaringe e laringe do ponto de vista funcional e complicações. CASUÍSTICA E MÉTODO: Estudo retrospectivo, aprovado pelo CEP-FMUSP.O banco de dados utilizado é constituído de pacientes matriculados no ambulatório do Hospital Santa Marcelina (Serviço de Cirurgia de Cabeça e Pescoço), com o diagnóstico de neoplasias malignas de boca, orofaringe, hipofaringe e laringe, sendo critério de inclusão todos aqueles que foram operados e reconstruídos com o RMP de pedículo superior e de exclusão aqueles submetidos a outro tipo de reconstrução ou tratamento oncológico, o diagnóstico foi sempre confirmado com biópsia prévia e o estadiamento clínico, TNM, Classificação de Tumores Malignos, seguiu a padronização da União Internacional Contra o Câncer. Foram operados 250 casos de tumores malignos de cabeça e pescoço no período de janeiro de 1990 a dezembro de 2015, todos reconstruídos com o RMP. Destes 184 casos eram elegíveis para o presente estudo. A técnica utilizada para a reconstrução foi o RMP com pedículo superior. A avaliação funcional da reconstrução pelo retalho foi realizada para a respiração, deglutição, aspiração e comunicação. RESULTADOS: Dos 184 casos, 90,2% eram do estádio III e IVA. A dieta ficou normal em 153 (83,1%) dos pacientes, 29(15,8%) ficaram com dieta pastosa e líquida e 2(1,1%) somente com dieta liquida, 146(79,3%) dos casos ficaram com voz laríngea e 38(20,7) com outro tipo de voz. A aspiração da dieta ocorreu em 60,5% dos pacientes e 39,5% não tiveram. Os tumores da base de língua tiveram aspiração em 40,4% dos casos, nos primeiros 7 a 15 dias comparado com outras regiões (p < 0,001). Os pacientes com tumores da hipofaringe tiveram aspiração moderada e os da cavidade oral tiveram a taxa mais baixa. Necroses parciais ocorreram em 10 (4,5%) e foram mais frequentes na cavidade oral 6(3,3%) dos casos. As fístulas ocorreram em 15(8,1%) dos pacientes, a mais alta incidência ocorreu na hipofaringe com 8(4,3%) dos casos. CONCLUSÕES: A reabilitação funcional quanto à deglutição, aspiração, respiração e comunicação foi efetiva, a maioria dos pacientes ficaram com dieta normal por via oral. O RMP mostrou-se um procedimento cirúrgico seguro com índices de complicações baixos, mesmo em pacientes de estádios oncológicos avançados / INTRODUCTION: Oncological resections of the oral cavity, oropharynx, hypopharynx and larynx, which aim at the complete removal of the tumor with safety margins, can determine large anatomical defects in three dimensions and affect noble functions, such as swallowing, speech and breathing. Among the alternatives of reconstruction, the platysma myocutaneous flap (PMF) have been employed given its versatility and ease of technical execution with the advantage of being less thick than the other myocutaneous flaps, making it better for adaptation in a series of clinical conditions. To study the results of PMF used in reconstructions after resections of tumors of oral cavity, oropharynx and hypopharynx from a functional point of view as well as its possible complications. PATIENTS AND METHOD: Retrospective study of patients enrolled in the outpatient clinic of Santa Marcelina Hospital (Department of Head and Neck Surgery), with the diagnosis of malignant neoplasms of the oral cavity, oropharynx, hypopharynx an larynx, being inclusion criteria all those that were operated and reconstructed with RMP. The diagnosis was always confirmed by previous biopsy and clinical staging TNM, followed the standardization of the UICC, There were 250 cases of malignant head and neck tumors from January 1990 to December 2015. Of these, 184 cases were eligible for the present study. The reconstructive technique used was PMF with superior pedicle and the functional evaluation was performed for breathing, swallowing, aspiration and communication Project approved by the Research Ethics Committee of the Faculty of Medicine of the University of São Paulo. RESULTS: From 184 cases operated, 90.2% of the cases were stage III and IVa. The diet was normal in 153 (83.1%) of the patients, 29 (15.8%) had a pasty and liquid diet and 2 (1.1%) had a liquid diet. As for the type of speech: 146 (79.3%), another type of speech 38 (20.7%) had laryngeal voice. The postoperative diet aspiration occurred in 60.5% and did not have aspiration 39.5 % of cases. Tumors of the tongue base when compared to other regions had aspiration in 40.3% in the first 7 to 15 days. Those of the hypopharynx had intermediate aspiration and those of the mouth had the lowest aspiration. Partial necrosis occurred in 10 (4.5%) and total 6 (3.3%) were more frequent in the oral cavity. We had a total of 15 (8.1%) fistulas, the highest incidence occurred in the hypopharynx in 8 (4.3%). CONCLUSIONS: Functional rehabilitation was effective regarding swallowing, breathing and communication, most of the patients were on a normal oral diet. PMF has shown to be a safe technique with low complications rates, even in patients with advanced oncologic stages

A transferência de retalhos livres e o reimplante de tecidos têm em comum a exposição dos tecidos à isquemia e tempos de reperfusão variáveis, que são importantes na determinação dos danos celulares estruturais e ultraestruturais, às vezes irreversíveis. O tempo de isquemia dificilmente pode ser controlado no período pré ou transoperatório, mas pode-se tentar prevenir ou diminuir as alterações celulares com soluções preservadoras, como, por exemplo, a da Universidade de Wisconsin, amplamente utilizada na prática clínica dos transplantes de tecidos. Porém a disponibilidade e o custo alto destas soluções dificultam seu uso rotineiro nos centros cirúrgicos. O presente trabalho propõe a utilização de solução de preservação (Solução Plástica-USP) que pode ser facilmente preparada com medicamentos accessíveis e baixo custo; a eficiência desta solução foi comparada com a da solução de Wisconsin. Os resultados demonstraram que não existe diferencia significativa entre a solução Plástica-USP, comparável à solução de Wisconsin; conferindo, ambas, um maior nível de proteção celular sobre os controles; beneficiando significativamente os resultados, e diminuindo assim os riscos de perdas do transplante a baixo custo / The free flaps transfer and reimplantation of tissue has in common the exposure of the tissue to ischemia and different time of reperfusion which are important for the determination of the extent of the cellular injury, being sometimes irreversible. In the pre and trans-surgical procedure the control of the ischemic period is difficult. Although efforts are made to prevent and decrease cellular changes using preservative solution, such as University of Wisconsin (UW) used in routine transplant of organs. The availability and high cost of this solution some time is one problem. The present study was made in a rat model that we have been reported in others works, we proposed the utilization of a preservation solution that we called Plastic Surgery-USP solution (PS-USP); witch can be easily prepared with accessible and low cost drugs. The efficiency of this PS-USP solution was compared to UW; our result showed that there is not significative difference in the protective effects of the PS-USP and UW solutions; both solutions were efficient considering cellular protection to ischemia/reperfusion injury, decreasing the risks of flap lost, with low cost and easy disposition

A circular cylinder is a geometrically simple bluff body that occurs in various practical applications. As with any bluff body, it exhibits large drag forces and a strong fluctuating lift force, both related to the strong shedding of vortices from the body, which is commonly referred to as the Karman Street. Rigid splitter plates in the wake of the cylinder are known to suppress shedding from the body, and thereby result in reduced drag and fluctuating lift forces, the latter being important to reduce flow-induced vibrations of the body. In the present work, the flow past a cylinder with a downstream flexible splitter plate/flap is studied, the length (L) and flexural rigidity (EI) of the flap being the main parameters besides the flow speed (U). Two flaps length to cylinder diameter ratios (L/D), namely, a short (L/D = 2) and a long (L/D = 5) flaps have been studied, the shorter one being smaller than the recirculation zone, while the larger is longer than the recirculation zone. In both these cases, the flexural rigidity (EI) and the flow speed are systematically varied. In all cases, the flaps motion are directly visualized, the lift and drag forces are measured with a force balance, and the wake velocity field is measured using PIV. In both the long and short flaps cases, the flexural rigidity (EI) of the flexible flap has been varied over a large range of values, and it has been found that the results for flaps tip motion and forces collapse well when plotted with a non-dimensional bending stiffness (K∗), which is defined as K∗ = EI/(1/2ρU2L3). This collapse occurs across flexible flaps with different values of EI, as long as Re > 5000. The collapse is not found to be good for Re < 5000. This difference appears to be related to the large reduction in fluctuating lift for a bare cylinder in the Re range between approximately 1600 and 5000 discussed by Norberg[41]. In the long flap case, the existence of two types of periodic modes is found within the range of K∗ values from 5 × 10−6 to 1 × 10−1 studied. The first one corresponds to a local peak in amplitude at K∗ ≈ 1.5 × 10−3 that is referred to as mode I, and the second that occurs at low values of K∗ (K∗ < 3 × 10−5) that is referred to as mode II. The fluctuating lift is found to be minimum for the mode I oscillation. The mean drag is also found to reach a broad minimum that starts at K∗ corresponding to mode I and continues to be at the same low level of approximately 65% of the bare cylinder drag for all higher K∗ values, representing an approximately 35% decrease in mean drag of the cylinder. The wake measurements also show significant changes with K∗. The formation length (lf /D) obtained from the closure point of the mean separation bubble is found to continuously increase with K∗, reaching values of approximately 2.6 at mode I and thereafter only small increases are seen as K∗ is increased to large values corresponding to the rigid splitter plate case, consistent with the observed variations in the mean drag. The stream wise and cross-stream turbulent intensities and the Reynolds shear stress are all found to be strikingly lower in the mode I case compared to the bare cylinder case, and more importantly, these values are even lower than the rigid splitter plate case. This is consistent with the shedding of weaker vortices and with the minimum in fluctuating lift found in the mode I case. The results for this flap length show that the mode I flap oscillation, corresponding to K∗ ≈ 1.5 × 10−3, may be useful to reduce lift, drag, velocity fluctuations in the wake and the strength of the shed vortices. In particular, the wake fluctuations corresponding to this mode are found to be significantly lower than the rigid splitter plate case. In the short flap case (L/D = 2), it is found that there exists a richer set of flapping modes compared to the long flap, with these modes being dependent on K∗. At low K∗ values, the flap exhibits large amplitude symmetric flap motion that is referred to as mode A, while clearly asymmetric flaps motion are seen at higher K∗ values corresponding to modes B and C. Mode B corresponds to asymmetric large amplitude flapping motion, while mode C is also asymmetric with the flap clearly deflected off to one side, but having small oscillation amplitudes. At even higher K∗ values, corresponding to mode D, symmetric flaps motion are again seen with the amplitudes being smaller than in mode A. Apart from the flap tip amplitude, the non-dimensional frequency of flap tip motion also changes as the flap changes modes. In this case, there is a minimum in the fluctuating lift corresponding to mode B and C oscillation. The mean drag is found to reach a minimum again corresponding to mode C, which corresponds to an approximately 35% decrease in mean drag of the cylinder. In this case, there is a large increase in fluctuating lift (approximately 150% of the bare cylinder case) at higher values of K∗ that appears to correspond to a “resonant” condition between the structural natural frequency of the flexible splitter plate/flap and the wake shedding frequency of the bare cylinder. The wake measurements show that the formation length (lf /D) is the largest for mode C (deflected flap state), which is consistent with the observed minimum in mean drag observed for this mode. The stream wise and cross-stream turbulent intensities and the Reynolds shear stress are all found to be strikingly lower in the mode C case compared to the bare cylinder case, with the values for the Reynolds shear stress being lower than the rigid splitter plate case. This is again consistent with the minimum in fluctuating lift found in the mode C case. The results for this flap length show that the mode C flap oscillation, corresponding to K∗ ≈ 5 × 10−2 that correspond to a deflected flap state with very small oscillation may be useful to reduce lift, drag, velocity fluctuations in the wake and the strength of the shed vortices. The results from the present study show that the flexible flap/splitter plate down-stream of the cylinder exhibits a variety of mode shapes depending on the effective bending rigidity of the flap K∗ for both the long and short flaps cases. The forces and the wake are also found to be strongly dependent on this parameter K∗ with the wake fluctuations, lift fluctuations and the drag being very effectively suppressed at an intermediate value of K∗ that is found to be dependent on the plate/flap length.