Primary cilia are evolutionarily conserved organelles required in a number of signalling pathways influencing the development and behaviour of a diverse range of organisms. More recently, studies into a new class of human diseases known as ciliopathies have helped to shed light on the critical role of this once-ignored signalling centre. Bardet-Biedl syndrome (BBS) proteins localize to the primary cilium and participate in cilium biogenesis and function. BBS is a pleiotropic human disorder with variable severity that is suitable as a disease model for investigating the pathogenesis of a number of common ciliopathy features such as photoreceptor degeneration, renal cysts, and obesity. The C. elegans genome encodes a number of BBS proteins which undergo intraflagellar transport (IFT) at the primary cilium. Given the conservation between C. elegans and human BBS proteins, I hypothesize the existence of unidentified conserved genetic pathways related to the functions of these proteins. Using C. elegans, I characterize novel features of bbs mutants while identifying sources of genomic variation that may elucidate the variability of human BBS features. I show that C. elegans bbs mutants exhibit smaller body size, delayed development, and decreased exploration behaviour. Moreover, I identify a role for the soluble guanylate cyclases GCY-35/GCY-36 in modifying these bbs phenotypes. I conclude that BBS proteins non-cell autonomously influence a set of body cavity neurons in which GCY-35/GCY-36 function genetically upstream of a cGMP-dependent protein kinase (PKG), EGL-4, to control body size. Furthermore, the role of GCY-35/GCY-36 is unique amongst a large number of guanylate cyclases and BBS proteins may influence body size via an IFT-independent function. I explore the biological functions of EGL-4 and conclude that it may regulate body size through multiple cellular mechanisms. I also examine potential candidate genes related to cGMP production and turnover, confirming that additional cGMP-related factors can influence body size although not necessarily in body cavity neurons. In conclusion, I propose a model where BBS-expressing sensory neurons influence body size and development through cGMP-PKG signalling in body cavity neurons while functioning in parallel with additional sensory neurons (possibly BBS-independent) that use similar cGMP-PKG signalling dynamics.

The SUMO protein was named Small Ubiquitin-like MOdifier because its 3-D structure was similar to Ubiquitin. In human, three SUMO proteins were discovered, namely, SUMO-1/2/3. The recombinant ¡µ1-8, 94-95 SUMO-2 protein with 10 histidine residues at its N-terminus was expressed using E. coli. BL-21(DE3), purified at 4 oC and crystallized at room temperature. The surface properties of human SUMO-1/2/3 proteins and 3-D structure of ¡µ1-8, 94-95 SUMO-2 protein were analyzed using computer modeling and X-ray diffraction technology respectively. The two-step purification by immobilized metal ion affinity chromatography(IMAC) was developed to yield ¡µ1-8, 94-95 SUMO-2 protein that reached 60 mg/ml for crystallization. On protein expression, 120 mg protein was obtained from 6 L bacterial growth broth. Crystals of ¡µ1-8, 94-95 SUMO-2 were obtained by the hanging-drop vapor diffusion method and many different crystal forms were observed. One of single crystal with triangular plate polyhedron form diffracted to 1.6 Å resolution, the other one with rectangular polyhedron form diffracted to 1.2 Å. Analysis of the diffraction pattern suggests the crystals belong to R3 space group, the former one owned unit cell parameters a= b=75.3 Å, c=29.2 Å, £\=90¢X, £]=90¢X,£^=120¢X, and the later one owned unit cell parameters a= b=74.9 Å, c=33.2 Å and the same angles respectively. The R factor and Rfree of refinement are 0.133 and 0.190 with highly precise phase on 3-D structure of SUMO-2 protein. Comparison of crystal structure between human SUMO-2 and yeast SMT3 showed that the r.m.s. deviation of C£\ coordinate is 1.054 Å. In addition, comparison of SUMO-1 NMR structure and SMT3 crystal structure showed that the r.m.s. deviation of C£\ coordinates is 2.736 Å. Hence, the structures of SUMO-2 and SMT3 are more similar each other than those of SUMO-1and SMT3.

We consider the problem of Adaptive Control of finite-dimensional, stable, Linear Time Invariant (LTI) plants. Amongst such plants, the subclass regarding which an upper bound on the order is not known or which are known to be nonminimum phase (zeros in the unstable region) pose formidable problems in their own right. On one hand, if an upper bound on the order of the plant is not known, adaptive control usually involves some form of order estimation. On the other hand, when the plant is allowed to be either minimum phase or nonminimum phase, the adaptive control problem, as is well-known, becomes considerably-less tractable. In this study, the class of unknown plants considered is such that no information is available on the upper bound of the plant order and, further, the plant may be either minimum phase or nonminimum phase. Albeit known to be stable, such plants throw myriads of challenges in the context of adaptive control. Adaptive control involving such plants has been addressed [79] in a Model Reference Adaptive Control (MRAC) framework. There, the inputs and outputs of the unknown plant are the only quantities available by measurement in terms of which any form of modeling of the unknown plant may be made. Inputs to the reference model have been taken from certain restricted classes of bounded signals. In particular, the three classes of inputs considered are piecewise continuous bounded functions which asymptotically approach • a nonzero constant, • a sinusoid, and • a sinusoid with a nonzero shift. Moreover, the control law is such that adaptation is carried out at specific instants separated by progressively larger intervals of time. The schemes there have been proved to be e-optimal in the sense of a suitably formulated optimality criterion. If, however, the reference model inputs be extended to the class of piecewise continuous bounded functions, that would compound the complexity of the adaptive control problem. Only one attempt [78] in adaptive control in such a setting has come to our notice. The problem there has been tackled by an application of the theory of Pade Approximations to time moments of an LTI system. Based on a time moments estimation procedure, a simple adaptive scheme for Single-Input Single-Output (SISO) systems with only a cascade compensator has been reported. The first chapter is essentially meant to ensure that the problem we seek to address in the field of adaptive control indeed has scope for research. Having defined Adaptive Control, we selectively scan through the literature on LTI systems, with focus on MRAC. We look out in particular for studies involving plants of which not much is known regarding their order and systems which are possibly nonminimum phase. We found no evidence to assert that the problem of adaptive control of stable LTI systems, not necessarily minimum phase and of unknown upper bound on the order, was explored enough, save two attempts involving SISO systems. Taking absence of evidence (of in-depth study) for evidence of absence, we make a case for the problem and formally state it. We preview the thesis. We set two targets before us in Chapter 2. The first is to review one of the existing procedures attacking the problem we intend to address. Since the approach is based on the notion of time moments of an LTI system, and as we are to employ Pade Approximations as a tool, we uncover these concepts to the limited extent of our requirement. The adaptive procedure, Plant Command Modifier Scheme (PCMS) [78], for SISO plants is reported in some detail. It stands supported on an algorithm specially designed to estimate the time moments of an LTI system given no more than its input and output. Model following there has been sought to be achieved by matching the first few time moments of the reference model by the corresponding ones of the overall compensated plant. The plant time moment estimates have been taken to represent the unknown plant. The second of the goals is to analyze PCMS critically so that it may serve as a forerunner to our work. We conclude the chapter after accomplishing these goals. In Chapter 3, we devise a time moment estimator for SISO systems from a perspective which is conceptually equivalent to, yet functionally different from, that appropriated in [78]. It is a recipe to obtain estimates of time moments of a system by computing time moment estimates of system input and output signals measured up to current time. Pade approximations come by handy for this purpose. The lacunae exposed by a critical examination of PCMS in Chapter 2 guide us to progressively refine the estimator. Infirmities in the control part of PCMS too have come to light on our probing into it. A few of these will be fixed by way of fabricating two exclusively cascade compensators. We encounter some more issues, traceable to the estimator, which need redressal. Instead of directly fine-tuning the estimator itself, as is the norm, we propose the idea of 'estimating' the lopsidedness of the estimator by using it on the fully known reference model. This will enable us to effect corrections and obtain admissible estimates. Next, we explore the possibility of incorporating feedback compensation in addition to the existing cascade compensation. With output error minimization in mind, we come up with three schemes in this category. In the process, we anticipate the risk of instability due to feedback and handle it by means of an instability preventer with an inbuilt instability detector. Extensive simulations with minimum and rionminimum phase unknown plants employing the various schemes proposed are presented. A systematic study of simulation results reveals a dyad of hierarchies of progressively enhanced overall performance. One is in the sequence of the proposed schemes and the other in going for matching more and more moments. Based on our experiments we pick one of the feedback schemes as the best. Chapter 4 is conceived of as a bridge between SISO and multivariable systems. A transition from SISO to Multi-Input Multi-Output (MIMO) adaptive control is not a proposition confined to the mathematics of dimension-enhancement. A descent from the MIMO to the SISO case is expected to be relatively simple, though. So to transit as smoothly and gracefully as possible, some issues have to be placed in perspective before exploring multivariable systems. We succinctly debate on the efforts in pursuit of the exact vis-a-vis the accurate, and their implications. We then set some notations and formulate certain results which serve to unify and simplify the development in the subsequent three chapters. We list a few standard results from matrix theory which are to be of frequent use in handling multivariable systems. We derive control laws for Single-Input Multi-Output (SIMO) systems in Chapter 5. Expectedly, SIMO systems display traits of observability and uncontrollability. Results of illustrative simulations are furnished. In Chapter 6, we formulate control laws for Multi-Input Single-Output (MISO) systems. Characteristics of unobservability and controllability stand out there. We present case studies. Before actually setting foot onto MIMO systems, we venture to conjecture on what to expect there. We work out all the cascade and feedback adaptive schemes for square and nonsquare MIMO systems in Chapter 7. We show that MIMO laws when projected to MISO, SIMO and SISO cases agree with the corresponding laws in the respective cases. Thus the generality of our treatment of MIMO systems over other multivariable and scalar systems is established. We report simulations of instances depicting satisfactory performance and highlight the limitations of the schemes in tackling the family of plants of unknown upper bound on the order and possibly nonminimum phase. This forms the culmination of our exercise which took off from the reported work involving SISO systems [78]. Up to the end of the 7th chapter, we are in pursuit of solutions for the problem as general as in §1.4. For SISO systems, with input restrictions, the problem has been addressed in [79]. The laws proposed there carry out adaptation only at certain discrete instants; with respect to a suitably chosen cost, the final laws are proved to be e>optimal. In Chapter 8, aided by initial suboptimal control laws, we finally devise two algorithms with continuous-time adaptation and prove their optimality. Simulations with minimum and nonminimum phase plants reveal the effectiveness of the various laws, besides throwing light on the bootstrapping and auto-rectifying features of the algorithms. In the tail-piece, we summarize the work and wind up matters reserved for later deliberation. As we critically review the present work, we decant the take-home message. A short note on applications followed by some loud thinking as a spin-off of this report will take us to finis.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

No description available.

Antimony trioxide (Sb203) and halogenated additives are used together in flameretarded formulations due to their synergistic retardant properties. A study has been made to determine the effects of adding different grades of Sb203 (dSD particle sizes 0.11 um, 0.52um and 1.31 um) into ABS polymer either alone or with commercial brominated materials (BTBPE, TBBA, DBDPO) and an experimental bromine grade (sDBDPO). The Sb20 3 was added at 4wt% loadings and the bromines at 20wt% loadings. The results consider the influence of the additives on processing, mechanical, morphological and flame retardant properties. All compounds were produced using a twin-screw co-rotating extruder and then an injection moulder was used to mould notched impact (falling weight testing), flexural, LOI and UL-94 flame test bars. Samples of all the compounded formulations were titrated to determine Sb20 3 and Br contents. Fracture surface, morphology, size and dispersion analysis was carried out using both SEM and TEM equipment. Osmium tetroxide (OS04) staining was used to determine relative locations of filler particles and polybutadiene phase. Additions of the different antimony trioxide grades showed that the 0.52um and 1.31 um grades lowered impact energy absorption (-25 to -30%) when added at 4wt% loading. The use of a sub-micron size grade (0.1 um) did not significantly lower impact properties (-3%) and had similarly small effects on the flexural modulus and flexural strength. Additions of the brominated materials had much greater effects causing large reductions in impact properties (-20 to :70%). The presence of the bromines generally increased flexural modulus and lowered flexural strength with the exception of TB BA, which increased both modulus and strength. Compounds containing both 1.31 um Sb203 and bromines suffered a further reduction in impact energies, with the bromine properties dominating. Using the 0.1 um Sb20 3 grade again improved impact and flexural properties compared to the 1.31 um grade. The 0.1 um grade resulted in improvements in fire resistance as measured by the UL-94 properties when used with all bromine grades.

This thesis aims to design a test equipment for positive change the adhesion contact between the wheel and the rail head. This can be achieved by changing the size of the coefficient of friction, which are eliminated negative effects accompanying the operation of the rail transport (acoustic emissions and excessive wear). Reducing friction must not be compromised traction or braking. Equipment ranks among to Top of Rail systems where as medium is used the friction modifier. The study includes an overview of available types of friction modifiers and applicators Top of rail system. The design of the applicator is built based on the off-board system that is placed in front of the arc track with a small radius of curvature.

Made available in DSpace on 2014-06-11T19:33:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-10-09Bitstream added on 2014-06-13T19:04:35Z : No. of bitstreams: 1 watanabe_ph_dr_jabo.pdf: 1270273 bytes, checksum: f355eac74c8081b78de6f867b0504d27 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Objetivou-se avaliar os efeitos de concentrações crescentes de ractopamina em dietas para fêmeas suínas, abatidas com 110 kg de peso, quanto ao desempenho, características de carcaça, rendimento de cortes comerciais, composição e cortes cárneos do pernil, qualidades física, química, sensorial e perfil de ácidos graxos da carne, potencial para impacto ambiental e avaliação econômica. Foram utilizadas 468 fêmeas suínas, distribuídas entre quatro dietas: DC – dieta controle, composta principalmente por milho e farelo de soja; DC5 – dieta controle contendo 5 mg de ractopamina/kg; DC10 – dieta controle contendo 10 mg de ractopamina/kg e DC15 – dieta controle contendo 15 mg de ractopamina/kg. O peso inicial foi de 84,77±7,20 kg e final de 110,59±7,70 kg. O período experimental foi de 28 dias, quando então os animais foram destinados ao abate. Utilizou-se o delineamento em blocos ao acaso, para controlar diferenças de peso entre os animais. Encontrou-se reduções lineares para o consumo diário de ração e conversão alimentar, e aumentos lineares para área de olho de lombo, pesos de cortes inteiros do pernil e paleta, assim como para os pesos do coxão mole (Semitendinosus) e da alcatra (Gluteus medius), havendo efeito inverso para a quantidade de gordura no pernil, conforme o aumento das concentrações de ractopamina nas dietas. Não foi observado efeito sobre a qualidade e o perfil de ácidos graxos da carne. Houve diminuição da produção de fezes+urina por animal nas duas primeiras semanas de fornecimento, e alteração na composição das fezes. Notou-se aumentos nos custos da alimentação, e redução linear na receita líquida parcial sem bonificação. Para a receita líquida parcial com bonificação, observou-se efeito quadrático, sendo a concentração estimada de 4,05 mg de ractopamina/kg de dieta, a que determinou a melhor receita... / The aim of this study was to evaluate the effects of increasing ractopamine concentration in diets for gilts, slaughtered at 110 kg of body weight, on performance, carcass characteristics, whosale cuts, composition and retail cuts of ham, physical, chemical and sensorial quality and fat acids profile of meat, potential environmental impact and economical evaluation of using this additive. It was used 468 gilts, allotted into four diets: DC – control diet, based on corn and soybean meal; DC5 – control diet containing 5 mg of ractopamine/kg; DC10 – control diet containing 10 mg of ractopamine/kg; DC15 – control diet containing 15 mg of ractopamine/kg. The initial weight of animals was 84.77±7.20 kg and the final 110.59±7.70 kg. The assay was carried out by 28 days and the animals were conducted to slaughter. It was used a randomized block design, to control the differences of body weight. Linear reductions were observed for daily feed intake and feed:gain ratio, and linear increases in loin eye area, wholesale cuts of ham and shoulder and retail cuts of Semimembranosus and Gluteus medius and an inverse effect for fat of ham, by increasing the ractopamine concentration in diets. There was no effect on meat quality and fat acids profile of meat. A reduction on feces+urine production by animal was observed in the two weeks of ractopamine administration and a change on feces composition was noted. An increasing trend on feeding cost and a linear reduction in the net income without bonification was noted. For net income with bonification, there was a quadratic trend and better results were obtained with the estimated concentration of 4.05 mg of ractopamine/kg of diet. These results indicate that ractopamine inclusion in diets for gilts slaughtered at 110 kg of body weight is justified with bonification for lean carcass, and in this scenario, it was recomended to use 4 mg of ractopamine/kg of diet

Les séquences non-codantes régulatrices de l’expression des gènes sont tout aussi importantes pour le phénotype d’un individu que les séquences codantes. De nombreux travaux se sont attachés à identifier les forces influençant l’évolution de ces séquences non-codantes. Ici, nous théorisons une nouvelle force sélective influençant potentiellement l’évolution de certaines séquences régulatrices. En utilisant des modèles multi-locus, nous montrons que les promoteurs génétiques les plus forts (activateurs de la transcription) gagnent un avantage à voir la copie du gène qui leur est associée (située sur le même chromosome) davantage exprimée que la copie homologue, contrôlée par un promoteur homologue moins fort. La surexpression des copies associées aboutit à une meilleure purge des mutations délétères chez ces copies, et ainsi à une association génétique entre promoteurs forts et contexte génétique favorable. Si la recombinaison entre le gène et le promoteur est suffisamment faible pour que cette association persiste, la force des promoteurs est sélectionnée pour augmenter. L’escalade des forces des promoteurs ne conduit pas forcément à une surproduction de protéines : d’autres régulateurs peuvent co-évoluer pour maintenir un niveau d’expression optimal, à condition que la sélection stabilisante tolère des niveaux d’expression transitoirement sub-optimaux. En variant les modes de reproduction, nous avons montré que ce nouveau processus sélectif ne menait pas nécessairement à une escalade de la force des promoteurs. Lorsque les chromosomes sont suffisamment isolés génétiquement (peu de recombinaison, peu de fécondation croisée), la sélection pour des associations génétiques favorables mène à une divergence des chromosomes : un chromosome accumule des promoteurs forts et possède des copies viables du gène, tandis que le chromosome homologue accumule des promoteurs faibles et des mutations délétères sur le gène. Dans le cas de lignées clonales peu ou pas recombinantes, on s’attend ainsi à observer une haploïdisation de l’expression des gènes : une copie de chaque gène concerné est éteinte et dégénère. Cette divergence s’applique aussi à des chromosomes sexuels ayant cessé de recombiner : on a pu montrer que la divergence des chromosomes menait à une extinction et une dégénérescence des gènes situés sur les chromosomes Y, et à une surexpression des gènes situés sur le chromosome X. En utilisant notre modèle, on propose ainsi une nouvelle théorie pour expliquer l’évolution des chromosomes sexuels non-recombinants. Enfin, on a utilisé des données de divergence entre Mus musculus et Rattus norvegicus pour isoler un signal ne pouvant être expliqué que par une sélection positive pour des promoteurs proximaux plus forts. Ce signal est faible, mais détectable, nous permettant d’apporter une première confirmation empirique du processus d’escalade des forces des promoteurs. / Non-coding sequences, that regulate gene expression, are as important as coding sequences to determine phenotypes. Many studies have identified the main forces affecting regulatory sequence evolution. Here, we theoretically identify a new selective force that may also play a role in this matter. Using multi-locus models, we show that stronger (activating more transcription) enhancers gain some benefit in having its associated gene copy more expressed than the homolog gene copy, controlled by a weaker homolog enhancer. Overexpressed gene copies are better purged from deleterious mutations, such that stronger enhancers get associated with a better genetic background. If recombination between the gene and the enhancer is low enough for this association to persist, enhancer strength selectively increases. Enhancer strength escalation does not necessarily lead to protein overproduction. Other regulators may indeed co-evolve to maintain optimal expression levels, provided that stabilizing selection allows for transitory sub-optimal expression levels. Implementing in the models different reproductive systems, we show that this new selective process does not necessarily lead to an enhancer strength escalation. When chromosomes are genetically isolated enough (little recombination, little outcrossing, selection for favorable genetic associations leads to chromosome divergence: one accumulates stronger enhancers and viable gene alleles, while the other accumulates weaker enhancers and deleterious gene mutations. For non-recombining clonal lineages, we expect gene expression to become haploid: for each gene, one copy is shut down and degenerates. Such divergence also applies to non-recombining sex chromosomes. We show that in such case, chromosome divergence leads to a shut down and degeneration of Y chromosome genes, and to an overexpression of genes located on X chromosomes. With our model, we propose a new theory to explain sex chromosome evolution after they stop recombining. Finally, we used divergence data between Mus musculus and Rattus norvegicus to find a signal that can only be explained by positive selection for stronger proximal enhancers. This signal is weak, but significant: this is the first empirical confirmation of enhancer strength escalation process we studied here.

Ce travail porte sur l’immobilisation du plomb dans les verres et les vitrocéramiques. Le premier volet de cette étude porte sur l’effet de l’incorporation du plomb sur la structure et les propriétés des verres silicatés. Il a été réalisé à partir de compositions de verre simples dans le binaire PbO-SiO2 et les deux ternaires PbO-CaO-SiO2 et PbO-Al2O3-SiO2. Le choix de ces compositions a permis de clarifier le rôle (Modificateur/formateur) du plomb dans ces verres. Des mesures de viscosité, de densité et de la température de transition vitreuse ont été effectuées sur les trois systèmes. Les résultats de ces analyses ont été complétés par des études spectroscopiques (spectroscopies Raman & d’absorption des rayons X) afin de lier les propriétés macroscopiques aux informations structurales dans un ordre à courte- et moyenne-distance. Le deuxième volet de cette étude porte sur la mise en œuvre et la caractérisation de vitrocéramiques obtenues par dévitrification. Les tests de dévitrification ont été effectués principalement sur quelques compositions issues des deux systèmes ternaires PbO-Al2O3-SiO2 et PbO-CaO-SiO2 / This thesis deals with the immobilization of lead in glasses and glass-ceramics. The first part of this study deals with the effect of the incorporation of lead on the structure and properties of silicate glass. It was conducted on simple glass compositions, in the binary PbO-SiO2 and the two ternaries PbO-CaO-SiO2 and PbO-Al2O3-SiO2. The choice of these compositions made it possible to clarify the role of lead (modifier / former) in these glasses. Measurements of viscosity, density and glass transition temperature were carried out on the three systems. The results of these analysis have been supplemented by spectroscopic studies (Raman and X-ray absorption spectroscopy) in order to link macroscopic properties to structural information in a short- and medium-range order. The second part of this study concerns the implementation and characterization of glass-ceramics obtained by devitrification. The devitrification tests were carried out mainly on some compositions resulting from the two ternary systems PbO-Al2O3-SiO2 and PbO-CaO-SiO2