No description available.

No description available.

No description available.

No description available.

Universiẗat, Diss.--Jena, 2007.

In the first half of this work, titin's role in cardiac function was studied using intact cardiac myocytes. The development of a carbon fiber based cell-attachment system allowed diastolic and systolic function of the isolated intact myocyte to be investigated. Addition of actomyosin inhibitor to the intact myocyte revealed that the majority of the cell's diastolic stiffness is due to titin but that actomyosin interaction exists as well and contributes ~ 30% of total diastolic stiffness. The details of this study are provided in chapter 1. Heart failure with preserved ejection fraction (HFpEF) accounts for up to 50% of total heart failure cases and is characterized by increased diastolic stiffness. An effective treatment for HFpEF does not exist. Reducing titin stiffness as a therapeutic strategy for lowering left ventricular (LV) chamber stiffness in HFpEF is currently under consideration. To understand the functional consequence of reduced titin stiffness on global cardiac function a Rbm20 Δᴿᴿᴹ mouse model was created. The Rbm20 Δᴿᴿᴹ model has deficiency in titin splicing that results in expression of very large and compliant titin isoforms in the sarcomeres. Study of Rbm20 Δᴿᴿᴹ cells revealed that cellular diastolic stiffness was inversely related to the size of titin and was reduced in a graded manner in Rbm20 Δᴿᴿᴹ heterozygous (+/-) and homozygous (-/-) cells. Importantly, reduced titin-based stiffness manifested in vivo as reduced LV chamber stiffness, which could be observed by echocardiography and pressure volume (PV) analysis. The systolic function of Rbm20 Δᴿᴿᴹ was studied by measuring the Frank-Starling mechanism (FSM), first at the intact myocyte level. The FSM was reduced in Rbm20 Δᴿᴿᴹ +/- and -/- with the largest reduction in -/- cells. PV analysis demonstrated a reduced FSM at the LV chamber level, consistent with the result at the cellular level. Surprisingly, exercise testing showed an enhanced exercise performance in cardiac specific Rbm20 Δᴿᴿᴹ +/- mice (relative to wild-type mice). Thus, this work indicates that increasing titin compliance improves diastolic function but negatively impacts systolic function. Importantly, findings suggest that the beneficial effect of improving diastolic function is a dominant effect. This work is described in Chapter 2.

L'accumulation du soluté à la surface d'une membrane entraîne le phénomène de polarisation de concentration. Ceci est un problème qui affecte tous les systèmes de filtration membranaire car il a pour effet une augmentation de la pression osmotique et par conséquence une réduction substantielle du flux de perméat. Afin de comprendre ce phénomène, nous avons d'abord mené une étude analytique de la filtration tangentielle en solvant pur prenant en compte de l'influence de la pression motrice locale sur le taux de perméation. Lors de cette étude, des solutions analytiques qui augmentent en précision avec l'ordre développé ont ete dérivées. Ensuite nous avons développé une approche analytique qui couple l'hydrodynamique aux transferts de matière pour le cas d'un système de filtration qui opère sous haute pression avec un taux de récupération faible. Dans le but d'intégrer à la fois la dépendance de la pression transmembranaire locale sur le flux de perméat et l'influence de la polarisation de concentration à travers leurs effets osmotiques sur la pression effective, nous avons développé un modèle numérique qui résout l'équation de conservation du soluté couplée aux équations de Navier-Stokes en régime stationnaire dans l'approximation de Prandtl. Nous avons validé cette approche grâce aux solutions analytiques précédemment dérivées. Ensuite, nous avons testé l'influence des principaux paramètres de fonctionnement sur la performance du système et comparé nos résultats avec ceux d'autres modèles numériques. Finalement, la pertinence du modèle a été quantitativement vérifiée grâce à des données tirées des expériences bien documentées en osmose inverse. / Concentration polarization of solute at the membrane surface, because of osmotic pressure effects, is an important phenomenon that can cause substantial reductions in permeation. To understand these phenomena: we first analyze the filtration process for a pure solvent, imposing the influence of the driving pressure on permeation at the membrane. We obtain accurate analytical solutions for the flow fields. We then derive an analytical solution that coupled hydrodynamics to mass transfer for filtration systems working in a situation of High Pressure and Low Recovery. Second, we develop a numerical model that incorporates both physical aspects: the dependency of pressure on permeation and the influence of concentration polarization and their related osmotic effects in the effective pressure at the membrane. For that, the numerical approach solves the solute conservation equation coupled with the Navier-Stokes equations under the steady Prandtl approximation. The solution of the system is performed using a finite difference method of order 2. The validity of this approach is successfully demonstrated with the previous analytical solutions for hydrodynamics, as well as for the coupling with mass transfer. We then test the influence of the main operating parameters (inlet concentration, axial flow rate, operating pressure and membrane permeability) on the performance of the filtration system and compare the results with other numerical models that takes into account concentration polarization phenomenon. Finally, the validity of this model is quantitatively well-proved when using the reported data resulting from reverse osmosis experiments.

Selection operates when the variability among individuals in heritable traits translates to differences in the number of offspring that survive to breed, which is a close estimate of fitness. Consequently, the outcome of sexual-selection should be higher reproductive success for individuals with a greater expression of the selected traits. In this thesis, the relationship between some male spotless starling (Sturnus unicolor) traits and reproductive success was assessed. A particular focus was given to the role of throat feathers (TF) as sexually selected trait. The study was conducted in a wild population using a correlative approach in 2004, while in 2005 and 2006 the TF of males were experimentally shortened. The genetic parentage of the offspring was required for determining the reproductive success of males. Nine highly polymorphic microsatellites (with 11.7± 3.2 alleles per locus) were developed and optimised for this species. Parentage analyses were conducted in NEWPAT XL and CERVUS 3.0.3 and confirmed using observational data. Eighty-five percent of the offspring had at least one parent assigned. The levels of intra-specific brood parasitism, extra-pair paternity and quasi-parasitism were 7%, 7% and 1% of the offspring, respectively. Polygamy levels decreased with year, as the study population matured. The correlative study showed that males with longer TF and with better condition had a higher probability of reproducing and sired more offspring, but their offspring were not of higher quality as measured by their weight and immune response to phytohaemagglutinin. Polygynous males were also in better condition. In the experimental study, males in better condition had a higher chance of reproducing and sired more fledglings. Conversely, males with reduced TF sired significantly fewer eggs and lighter fledglings than control males. Body condition and TF length are shown to be good predictors of reproductive success and TF length is shown to be under sexual selection.

Titin is a giant protein spanning from the Z-disk to the M-band of the cardiac sarcomere. In the I-band titin acts as a molecular spring, contributing to passive mechanical characteristics of the myocardium throughout a heartbeat. RNA Binding Motif Protein 20 (RBM20) is required for normal titin splicing, and its absence or altered function leads to greater expression of a very large, more compliant N2BA titin isoform in Rbm20 homozygous mice (Rbm20(Delta RRm)) compared to wild-type mice (WT) that almost exclusively express the stiffer N2B titin isoform. Prior studies using Rbm20(Delta RRm) animals have shown that increased titin compliance compromises muscle ultrastructure and attenuates the Frank-Starling relationship. Although previous computational simulations of muscle contraction suggested that increasing compliance of the sarcomere slows the rate of tension development and prolongs cross-bridge attachment, none of the reported effects of Rbm20(Delta RRm) on myocardial function have been attributed to changes in cross-bridge cycling kinetics. To test the relationship between increased sarcomere compliance and cross-bridge kinetics, we used stochastic length-perturbation analysis in Ca2+-activated, skinned papillary muscle strips from Rbrn20<^>R'Rm and WT mice. We found increasing titin compliance depressed maximal tension, decreased Ca2+-sensitivity of the tension-pCa relationship, and slowed myosin detachment rate in myocardium from Rbm20(Delta RRm) vs. WT mice. As sarcomere length increased from 1.9 to 2.2 mu m, length-dependent activation of contraction was eliminated in the Rbrn20<^>R'Rm myocardium, even though myosin MgADP release rate decreased similar to 20% to prolong strong cross-bridge binding at longer sarcomere length. These data suggest that increasing N2BA expression may alter cardiac performance in a length-dependent manner, showing greater deficits in tension production and slower cross-bridge kinetics at longer sarcomere length. This study also supports the idea that passive mechanical characteristics of the myocardium influence ensemble cross-bridge behavior and maintenance of tension generation throughout the sarcomere.

A quarter of the world's population experience wheezing. These sounds have been used for diagnosis since the time of the Ebers Papyrus (ca. 1500 BC), but the underlying physical mechanism responsible for the sounds is still poorly understood. The main purpose of this thesis is to change this, developing a theory for the onset of wheezing using both experimental and analytical approaches, with implications for both scientific understanding and clinical diagnosis. Wheezing is caused by a fluid structure interaction between the airways and the air flowing through them. We have developed the first systematic set of experiments of direct relevance to this physical phenomena. We have also developed new tools in shell theory using geometric algebra to improve our physical understanding of the self-excited oscillations observed when air flows through flexible tubes. In shell theory, the use of rotors from geometric algebra has enabled us to develop improved physical understanding of how changes of curvature, which are of direct importance to constitutive laws, come about. This has enabled a scaling analysis to be applied to the self-excited oscillations of flexible tubes, showing for the first time that bending energy is dominated by strain energy. We made novel use of multiple camera reconstruction to validate this scaling analysis by directly measuring the bending and strain energies during oscillations. The dominance of strain energy allows a simplification of the governing shell equations. We have developed the first theory for the onset of self-excited oscillations of flexible tubes based on a flutter instability. This has been validated with our experimental work, and provides a predictive tool that can be used to understand wheezing in the airways of the lung. Our theory for the onset of wheezing relates the frequency of oscillation to the airway geometry and material properties. This will allow diagnoses based on wheezing sounds to become more specific, which will allow the stethoscope, which has changed little in the last 200 years, to be brought into the 21st century.