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No / The pyrrolobenzodiazepine monomer DRH-417 is a member of the anthramycin group of anti-tumor antibiotics that bind covalently to the N2 of guanine within the minor groove of DNA. DRH-417 emerged from the EORTC-Drug Discovery Committee and NCI 60 cell line in vitro screening programs as a potent antiproliferative agent with differential sensitivity towards certain cancer types such as melanoma, breast and renal cell carcinoma (mean IC(50) = 3 nM). DRH-417 was therefore tested for in vivo activity. The maximum tolerated dose (MTD) was established as 0.5 mg/kg given i.p. Marked anti-tumor activity was seen in two human renal cell cancers, one breast cancer and a murine colon tumor model (p<0.01). A selective HPLC (LC/MS) analytical method was developed and plasma pharmacokinetics determined. At a dose of 0.5 mg kg(-1), the plasma AUC was 540 nM h (197.1 ng h ml(-1)) and the peak plasma concentration (171 nM [62.4 ng ml(-1)]) occurred at 30 min., reaching doses levels well above those needed for in vitro antiproliferative activity. Genomic profiling of in vivo sensitive tumors revealed that the latter have an activated insulin-like growth factor signaling pathway.

The interaction of a liquid drop with a solid surface is being actively studied to understand practically encountered scenarios such as the impact of fuel spray droplets onto the walls of engine combustion chamber, the formation of thermal barrier coating on the surfaces of turbine blades, the process of ink-jet printing, etc. The surface topography of solid surface is one of the major parameters influencing the dynamics of drop-surface interaction process. Understanding the precise role of surface topography features such as micro asperities and grooves on the spreading and receding processes of impacting liquid drops is crucial for the improvement in abovementioned applications. Recent developments in the fabrication of micro- and nano-structures on solid surfaces provide fabulous opportunities to investigate the role of single/multiple micro asperities and grooves on the dynamics of impacting drops. The thesis deals with an experimental work on the impact of water drops on stainless steel surfaces comprising unidirectional parallel grooves. A group of six target grooved surfaces covering a wide range of surface wettability were considered. The target surfaces were prepared using the techniques of photolithography, electro discharge machining, and laser machining. Scanning electron microscope and optical surface profilometer were used to characterize the groove texture geometrical parameters of the target grooved surfaces. The experiments of drop impact were carried out in an experimental apparatus consisting of a liquid drop generator, a substrate table, and a digital video imaging system. Free-falling distilled water drops released from a certain height were allowed to impact normally on the target surfaces. The image sequences of drop impact dynamics were constructed from the images captured using the digital video imaging system. Majority of the drop impact experiments were captured using a high speed video camera operating with frame speed ranging from 3000 to 10000 fps. For the target grooved surfaces, the impact dynamics was analyzed for the impacting drop liquid oriented both in the direction perpendicular to the grooves ( ) and in the direction parallel to the grooves (||) via independent test runs. The captured digital frames were used to deduce the temporal variation of impacting drop parameters such as drop contact diameter, drop contact angle, and drop height at the center of impacting drop with the aid of image processing software. The impacting drops were characterized in terms of Weber number, We expressed in terms of drop impact velocity and drop diameter measured just before the start of impact process. The study covered We ranging from 1.8 to 170. In general, the groove texture on the solid surface influences the drop impact process for all We examined in the study. The effect is more pronounced for the receding of impacting drops. For high We drops, the groove texture enhances the perturbations seen at the periphery of spreading lamella. The study showed quantitatively that the drop impact process on a target grooved surface comprising unidirectional parallel grooves develops a non-axisymmetric drop flow on the grooved surface exhibiting different spreading and receding processes of impacting drop liquid in the directions perpendicular ( ) and parallel (||) to the grooves. The maximum spreading diameter reached immediately after the completion of early inertia-dominated spreading in is less than that obtained in || due to the loss of drop kinetic energy caused by the pinned motion of drop liquid in . The non- axisymmetric drop flow on the target grooved surface develops a difference between the frequencies of contact angle oscillation of impacting drop liquid in  and ||. The frequency difference in contact angle oscillation causes the beating phenomenon in the temporal variation of the contact angle anisotropy, Δθ and drop height at the center of impacting drop, Z. For a given target grooved surface, the experimental measurements suggested that the beat frequency is almost independent of We. The temporal variation of Δθ and Z do not show the traces of beating phenomenon for the impact of high We drops. Owing to the non-axisymmetric drop flow, the final equilibrium drop shape is eccentric for the impact of low We drops and approaches a circular shape for the impact of high We drops. The role of groove texture geometrical parameters is seen in the drop impact process via the surface wettability especially for the impact of low We drops. Larger surface roughness factor makes the target grooved surface to exhibit hydrophobic characteristics.

Solid surfaces featuring a spatial variation of surface wettability along particular directions on their surface, referred to as wettability gradient surfaces, are becoming increasingly important in practical applications such as enhancement of boiling and condensation heat transfer and separation of immiscible liquids in smart micro-fluidic devices. With the aid of an external energy input, such as mechanical vibration or impact kinetic energy, a liquid drop on such surfaces gets propelled towards more wettable region on the surface. A fundamental study of impact dynamics of liquid drops on such solid surfaces is relevant in understanding their effectiveness. The present thesis reports a combined experimental and theoretical study on the impact dynamics of liquid drops on solid surfaces comprising a smooth portion and a groove-textured portion separated by a junction line (dual-textured surfaces). Three different dual-textured surfaces – two made of intrinsically hydrophilic stainless steel and one of intrinsically hydrophobic poly-di-methyl-siloxane (PDMS) – are considered. Liquid drops, with Weber number (We) in the range 1–100, are impacted on the junction of the dual-textured surfaces and the entire impact dynamics across the junction is captured using a high speed video camera. Experiments of drop impact on the homogeneous surface portions of dual-textured surfaces (far away from the junction) are also conducted. The temporal variation of drop contact radius measured from the junction line on smooth and groove-textured portions of the dual-textured surfaces exhibits four distinct stages – primary spreading, primary receding, secondary spreading on more wettable surface portion, and final equilibrium – with the final outcome being the bulk movement and deposition of liquid drop away from the junction towards the more hydrophilic surface portion. Secondary parameters characterizing each of these different stages are extracted from these measurements and a one-to-one comparison between dual-textured and homogenous surfaces is presented. A significant effect of dual-texture nature is seen on the receding process of impacting drops. On the dual-textured surfaces, the receding velocity of impacting drop on the groove-textured portion is always greater than that on the smooth portion. The asymmetry in drop receding results in a drop drift velocity towards the more wettable surface portion leading to an enhanced secondary drop spreading on the more wettable smooth portion. The drop drift velocity shows a decrease with We at low We and remains almost constant at higher We after a particular value of We. Correspondingly, the ratio of the maximum drop spread factor achieved during the secondary spreading (βm2) to that during the primary spreading (βm) is seen to decrease with We at low We and remains constant at higher We. Owing to the differences in the static equilibrium wetting difference, βm2/βm is more on the stainless steel dual-textured surfaces than on the PDMS dual-textured surface. The presence of dual-texture results in a higher final spread on more wettable smooth portion and smaller final spread on less wettable textured portion of the dual-textured surfaces and this difference decreases with We. The difference in final spread factors between the smooth and textured portions is more on the stainless steel dual-textured surfaces than the PDMS dual-textured surface. The bulk drop movement (ξ), characterized in terms of distance measured from the junction to the final drop center, decreases with We at low We and remains constant at higher We on the stainless steel dual-textured surfaces whereas it remains constant at low We and decreases at higher We on the PDMS dual-textured surface. ξ on the PDMS dual-textured surface is always less than that on the stainless dual-textured surface due to the lower wetting difference across the junction of the former. Comparison of the trends of secondary parameters with the predictions from theoretical models reported in literature showed a lack of agreement. This is due to various physical processes encountered by impacting drop on the groove-textured surface, identified through experiments of drop impact on homogeneous groove-textured surfaces, such as (i) convex shape of liquid-vapor interface near contact line at maximum spreading, (ii) impregnation of drop liquid into the grooves during impact, and (iii) contact line pinning of spreading drop at the asperity edges of surface texture, as well as the wetting difference in dual-textured surfaces. The inclusion of these physical processes under conventional energy conservation approach is seen to predict the experimentally observed trends of maximum drop spread factor on the groove-textured portions. A force balance model, applied to the liquid drop configuration at the beginning of drop receding on the dual-textured surfaces, predicts the qualitative trend of ξ with We on all surfaces. Drop liquid impregnation into the grooves of textured portion at We > Wecr (critical We corresponding to transition from Cassie to impaled state) is proposed as a possible physical mechanism to account for the explanation of the specific trends of ξ with We. A theoretical model formulated using force balance at the three phase contact line beneath impacting drop on groove-textured surface is presented for the prediction of Wecr.

La musique et le mouvement sont inséparables. Les mouvements produits spontanément lors de l'écoute musicale seraient le reflet d'un lien étroit entre le système perceptif et moteur. Ce lien est l'objet d'étude de cette thèse. Une première approche concernait l'impact des mouvements induits par la musique sur la cognition musicale. Dans deux études, nous montrons que bouger en rythme sur la musique n'améliore ni la rétention de nouveaux morceaux de musique (Etude 1) ni la rétention d'informations contextuelles relatives à leur encodage (Etude 2). Les résultats des ces deux études suggèrent la superficialité du traitement inhérent à l'expression des affordances musicales nécessaire à la production de mouvements induits par la musique dans la tâche motrice ainsi qu'un traitement moteur automatique de la musique indépendamment de la tâche. L'importance du groove musical a également été mise en évidence. Une deuxième approche concernait l'influence de la perception de rythmes musicaux sur la production de mouvements rythmiques. Notre troisième étude testait l'hypothèse selon laquelle les membres du corps seraient influencés de manière différente en fonction du tempo musical. Les résultats montrent que la tâche de tapping était la plus influencée par la perception de rythmes musicaux. Ceci serait dû à la nature similaire de la pulsation musicale et des mécanismes de timing impliqués dans le tapping ainsi qu'à des phénomènes de résonance motrice. Nous avons également observé la mise en place de certaines stratégies face à la tâche. L'ensemble de ces résultats est discuté à la lumière du lien entre perception et action, de la cognition musicale incarnée et des affordances musicales. / Music and movement are inseparable. The movements that are spontaneously procuded when listening to music are thought to be related to the close relationship between the perceptual and motor system in listeners. This particular link is the main topic of this thesis. A first approach was focused on the impact of music-induced movements on music cognition. In two studies, we show that moving along to music neither enhances the retention of new musical pieces (Study 1) nor the retention of the contextual information related to their encoding (Study 2). These results suggest a shallow processing inherent to the expression of musical affordances required for the production of music-induced movements in the motor task. Moreover, they suggest that music is automatically processed in a motoric fashion independantly of the task. Our results also brought forward the importance of the musical groove. A second approach focused on the influence of the perception of musical rhythms on the production of rythmic movements. Our third study tested the hypothesis that different limbs would be differentially influenced depending on the musical tempo. Results show that the tapping taks was the most influenced by the perception of musical rhythms. We argued that this would come from the similar nature of the musical pulse and the timing mecanisms involved in the tapping task and motor resonance phenomena. We also observed different strategies put in place to cope with the task. All these results are discussed in light of the link between perception and action, embodied musical cognition and musical affordances.

Exterior vehicle noise has a very big impact when it comes to environmental noise pollution. Due to the decrease of the other noise sources of a passenger car, like power-train and air turbulence noise in the last decade, the tyre/road noise has become a more important part in the overall noise generation of a vehicle nowadays. It is considered as the main noise source in nearly all driving conditions, especially with increasing vehicle speed. The easiest idea to tackle this pollution is to introduce rules like speed-limits to control the noise at a certain area or time. More interesting, however, is to approach the problem of unwanted noise directly at the source. This Thesis, carried out at Loughborough University, aims to give a better understanding about the basic noise generation mechanisms at the tyre/road interface. Especially, the air related mechanisms of closed cavities are analysed. With the usage of a solid rubber tyre, unique measurements have been carried out and the results are compared to the theories already existing in the literature. These measurements reveal some of the strengths and weaknesses of the current understanding of air related noise generation.

Na reabilitação protética, a oclusão e os movimentos mandibulares estão intrinsecamente ligados. A harmonia entre estes dois fatores torna-se indispensável para o sucesso do tratamento. Um dos conceitos sempre abordados na busca deste ideal é a relação entre os sulcos e as cúspides dos dentes com os movimentos mandibulares, onde as segundas devem passar livremente sobre os primeiros durante a movimentação mandibular. Assim, foi proposto avaliar o grau de coincidência da angulação do sulco de trabalho do primeiro molar inferior artificial, quando posicionado no arco, em relação à trajetória descrita pela cúspide mésiopalatina do primeiro molar superior em relação ao eixo de rotação vertical de lateralidade da mandíbula no articulador semi-ajustável. O autor utilizou uma metodologia que permitiu identificar esta trajetória com o auxílio de um programa de editoração gráfica. Foi possível avaliar as imagens digitais de montagens em cera de dentes artificiais em prótese totais inferiores e de seus respectivos planos de orientação posicionados em articulador. Através das imagens, localizou-se o sulco de trabalho do primeiro molar inferior, a trajetória da cúspide mésio-palatina do primeiro molar superior adotando-se o eixo de rotação vertical no centro das esferas condilares, e a perpendicular à tangente ao plano de orientação. Assim, mediu-se o ângulo formado entre a perpendicular à tangente e o sulco de trabalho e o ângulo entre a trajetória do eixo de rotação vertical e o sulco de trabalho. Os resultados mostraram que houve casos onde o sulco de trabalho coincidiu com a perpendicular à tangente do plano de orientação, nos demais casos a angulação apresentou, em média, valores baixos demonstrando que as montagens dos dentes artificiais seguiram os parâmetros adotados no plano de orientação segundo a técnica proposta. Estatisticamente, a distância intercondilar não interferiu nas médias dos ângulos entre o sulco de trabalho e a trajetória do eixo vertical de rotação. Não foi observada a coincidência entre o sulco de trabalho e a trajetória do eixo de rotação vertical, indicando que, durante a reprodução do movimento de lateralidade no articulador, ocorre interferência na excursão da cúspide mésio-palatina do primeiro molar superior. / In prosthetic rehabilitation, occlusion and mandibular movements are closely linked. Harmony between these factors is essential for treatment success. One of the main concepts approached when aiming for this goal is the relationship between teeth grooves and cuspids and mandibular movements, where cuspids must not touch grooves during these movements. Therefore, the present study proposes to evaluate the degree of coincidence of the working groove angulation from the artificial mandibular first molar, when positioned on the arch, with the trajectory traced by the mesio-palatal cuspid from the maxillary first molar during mandibular lateral translation determined by the vertical axis rotation in a semi-adjustable articulator. To identify this trajectory, the author utilized a graphical editing program. It was possible to evaluate digital images from artificial teeth mounted on wax for mandibular complete dentures, and their respective orientation planes positioned on the articulator. Through these images, the author located the working groove from the mandibular first molar, the trajectory described by the mesio-palatal cuspid from the maxillary first molar considering the vertical axis rotation at the center of the condilar spheres, and the perpendicular to the tangent of orientation plane. Thus, the angle between the perpendicular to the tangent and working groove and the angle between the trajectory of the vertical axis rotation and the working groove were measured. The results showed some cases where the working groove coincided with the perpendicular to the tangent of the orientation plane. In the remaining cases, the angulation displayed low mean values, illustrating that the mounting of artificial teeth followed the parameters adopted for the orientation plane according to the proposed technique. The distance between condoles did not significantly interfere in the mean values for the angles between the working groove and the trajectory of the vertical axis rotation. The coincidence between the working groove and the trajectory of the vertical axis rotation was not observed, indicating that, during the lateral translation movement in the articulator, there is interference in the trajectory of the maxillary first molar mesio-palatal cuspid.

Computer-aided drug discovery involves the application of computer science and programming to solve chemical and biological problems. Specifically, the QSAR (Quantitative Structure Activity Relationships) methodology is used in drug development to provide a rational basis of drug synthesis, rather than a trial and error approach. Molecular dynamics (MD) studies focus on investigating the details of drug-target interactions to elucidate various biophysical characteristics of interest. Infectious diseases like Trypanosoma brucei rhodesiense (TBR) and P. falciparum (malaria) are responsible for millions of deaths annually around the globe. This necessitates an immediate need to design and develop new drugs that efficiently battle these diseases. As a part of the initiatives to improve drug efficacy QSAR studies accomplished the formulation of chemical hypothesis to assist development of drugs against TBR. Results show that CoMSIA 3D QSAR models, with a Pearson’s correlation coefficient of 0.95, predict a compound with meta nitrogens on the phenyl groups, in the combinatorial space based on a biphenyl-furan diamidine design template, to have higher activity against TBR relative to the existing compound set within the same space. Molecular dynamics study, conducted on a linear benzimidazole-biphenyl diamidine that has non-classical structural similarity to earlier known paradigms of minor groove binders, gave insights into the unique water mediated interactions between the DNA minor groove and this ligand. Earlier experiments suggested the interfacial water molecules near the terminal ends of the ligand to be responsible for the exceptianlly high binding constant of the ligand. Results from MD studies show two other modes of binding. The first conformation has a single water molecule with a residency time of 6ns (average) that is closer to the central part of the ligand, which stabilizes the structure in addition to the terminal water. The second conformation that was detected had the ligand completely away from the floor of the minor groove, and hydrogen bonded to the sugar oxygens.

Cell surface saccharides are involved in a variety of essential biological events. Fluorescent sensors for saccharides can be used for detection, diagnosis, analysis and monitoring of pathological processes. The boronic acid functional group is known to bind strongly and reversibly to compounds with diol groups, which are commonly found on saccharides. Sensors that have been developed for the purpose of saccharide recognition have shown great potential. However, they are very hydrophobic and this lack of essential water-solubility makes them useful in biological applications. The first section of this dissertation details the process of developing water-soluble saccharide sensors that change fluorescent properties upon binding to saccharides. The second section of the dissertation focuses on the development of DNA-minor groove binders as antiparasitical agents. Parasitical diseases comprise some of the world’s largest health problems and yet current medication and treatments for these parasitical diseases are often difficult to administer, costly to the patients, and have disruptive side effects. Worse yet, these parasites are developing drug resistance, thus creating an urgent need for new treatments. Dicationic molecules constitute a class of antimicrobial drug candidates that possess high activity against various parasites. The second section details the development of a series of di-cationic agents that were then screened in in vitro activities against parasitical species.

The development of small-molecules which target nucleic acids, more specifically the minor groove of DNA, in a sequence specific manner and control gene expression are currently being investigated as potential therapeutic compounds for the treatment of various diseases, including cancer, as well as viral and bacterial infections. The naturally occurring compounds netropsin and distamycin have been shown to demonstrate antitumor and antibacterial properties. Currently, there are synthetic efforts to create pyrrole and imidazole-containing polyamide derivatives of netropsin and distamycin that show potential as medicinal agents. Synthetic pyrrole and imidazole-containing polyamides are potentially useful for targeting and modulating the expression of genes, including those associated with cancer cell growth. The key challenges that must be overcome to realize this goal of using synthetic polyamides in the treatment of disease are the development of polyamides with low molar mass so the molecules can readily diffuse into cells and concentrate in the nucleus. In addition, the molecules must have appreciable water solubility, bind DNA sequence specifically, and with high affinity. As part of a systematic study within the authors’ laboratory, our goal is to develop polyamides which can be synthesized readily yet possess excellent sequence specificity, stronger binding affinity, high solubility in biological media and enhanced cell penetration and nuclear localization properties. There is a need to develop a library of modified polyamides which target DNA and exhibit improved biological properties. The present study is a systematic examination of the binding properties of various modified synthetic polyamide compounds. The synthetic polyamide derivatives presented have more potential as therapeutic candidates over other synthetic polyamides because of their increased water solubility, smaller molecular weights, and molecular design, thus, allowing them to penetrate into cells and localize in the nucleus.