For the last two decades heart disease has been the highest single cause of death for the human population. With an alarming number of patients requiring heart transplant, and donations not able to satisfy the demand, treatment looks to mechanical alternatives. Rotary Ventricular Assist Devices, VADs, are miniature pumps which can be implanted alongside the heart to assist its pumping function. These constant flow devices are smaller, more efficient and promise a longer operational life than more traditional pulsatile VADs. The development of rotary VADs has focused on single pumps assisting the left ventricle only to supply blood for the body. In many patients however, failure of both ventricles demands that an additional pulsatile device be used to support the failing right ventricle. This condition renders them hospital bound while they wait for an unlikely heart donation. Reported attempts to use two rotary pumps to support both ventricles concurrently have warned of inherent haemodynamic instability. Poor balancing of the pumps’ flow rates quickly leads to vascular congestion increasing the risk of oedema and ventricular ‘suckdown’ occluding the inlet to the pump. This thesis introduces a novel Bi-Ventricular Assist Device (BiVAD) configuration where the pump outputs are passively balanced by vascular pressure. The BiVAD consists of two rotary pumps straddling the mechanical passive controller. Fluctuations in vascular pressure induce small deflections within both pumps adjusting their outputs allowing them to maintain arterial pressure. To optimise the passive controller’s interaction with the circulation, the controller’s dynamic response is optimised with a spring, mass, damper arrangement. This two part study presents a comprehensive assessment of the prototype’s ‘viability’ as a support device. Its ‘viability’ was considered based on its sensitivity to pathogenic haemodynamics and the ability of the passive response to maintain healthy circulation. The first part of the study is an experimental investigation where a prototype device was designed and built, and then tested in a pulsatile mock circulation loop. The BiVAD was subjected to a range of haemodynamic imbalances as well as a dynamic analysis to assess the functionality of the mechanical damper. The second part introduces the development of a numerical program to simulate human circulation supported by the passively controlled BiVAD. Both investigations showed that the prototype was able to mimic the native baroreceptor response. Simulating hypertension, poor flow balancing and subsequent ventricular failure during BiVAD support allowed the passive controller’s response to be assessed. Triggered by the resulting pressure imbalance, the controller responded by passively adjusting the VAD outputs in order to maintain healthy arterial pressures. This baroreceptor-like response demonstrated the inherent stability of the auto regulating BiVAD prototype. Simulating pulmonary hypertension in the more observable numerical model, however, revealed a serious issue with the passive response. The subsequent decrease in venous return into the left heart went unnoticed by the passive controller. Meanwhile the coupled nature of the passive response not only decreased RVAD output to reduce pulmonary arterial pressure, but it also increased LVAD output. Consequently, the LVAD increased fluid evacuation from the left ventricle, LV, and so actually accelerated the onset of LV collapse. It was concluded that despite the inherently stable baroreceptor-like response of the passive controller, its lack of sensitivity to venous return made it unviable in its present configuration. The study revealed a number of other important findings. Perhaps the most significant was that the reduced pulse experienced during constant flow support unbalanced the ratio of effective resistances of both vascular circuits. Even during steady rotary support therefore, the resulting ventricle volume imbalance increased the likelihood of suckdown. Additionally, mechanical damping of the passive controller’s response successfully filtered out pressure fluctuations from residual ventricular function. Finally, the importance of recognising inertial contributions to blood flow in the atria and ventricles in a numerical simulation were highlighted. This thesis documents the first attempt to create a fully auto regulated rotary cardiac assist device. Initial results encourage development of an inlet configuration sensitive to low flow such as collapsible inlet cannulae. Combining this with the existing baroreceptor-like response of the passive controller will render a highly stable passively controlled BiVAD configuration. The prototype controller’s passive interaction with the vasculature is a significant step towards a highly stable new generation of artificial heart.

[Truncated abstract] Neuregulins (NRG’s) are pleiotropic growth factors that participate in a wide range of biological processes. The family of membrane-bound growth factors bind to and activate ErbB receptors on adjacent target cells, mediating multiple biological processes. NRG-1, NRG-2 and NRG-3 are all highly expressed in the nervous system, where it has been shown that NRG-1 is important for neuronal development, migration, synapse formation and glial cell proliferation. Little is known, however, on the specific roles of NRG-2 and NRG-3, although it is apparent that despite similar expression patterns and overlapping receptor specificity, NRG-2 and NRG-3 do not compensate for the loss of NRG-1 and mediate their own distinct activities. … Subcellular localisation experiments showed that this domain is important for trafficking of the fulllength protein to various intracellular compartments in an activity dependent manner. In addition, the ICD is required to elicit a cell death response in cultured cells and provoke an elevated α-amino-3-hydroxyl-5-methylisoxazole-4-propionate (AMPA) response in organotypic neuronal cultures following transient expression of NRG-3. A yeast two-hybrid screen identified 14-3-3ζ and PICK1 as two proteins that interacte with the human NRG-3 ICD. These interactions were confirmed both in vitro and in vivo, and were further characterised at a molecular level. This study demonstrates the ability of NRG-3 to mediate signal transduction through a biologically active ICD; a conclusion supported by identifying cytoplasmic proteins that interact with the ICD. These observations point to an additional layer of complexity where bi-directional signalling contributes to the full repertoire of NRG-3 functions.

Thesis (M.CM)--Hong Kong Baptist University, 2006. / Dissertation submitted to the School of Chinese Medicine. Includes bibliographical references (leaves 1-12 (3rd group)).

Inaug.-Diss.--Geschichte--Mainz, 1968. / Bibliogr. p. 181-193. Index.

Thesis (S.T.M.)--Concordia Seminary, 1999. / Includes bibliographical references (leaves 138-144). Includes additional title p. and some bibliographical references in Chinese.

How do microbes adapt to challenges from the environment? In this thesis, two distinct cases were examined through structural and biochemical methods. In the first, we followed a real-time protein evolution of HisA to a novel function. The second case was fusidic acid (FA) resistance mediated by the protein FusB in Staphylococcus aureus. In the first study, the aim was to understand how mutants of HisA from the histidine biosynthetic pathway could evolve a novel TrpF activity and further evolve to generalist or specialist enzymes. We solved the crystal structure of wild type Salmonella enterica HisA in its apo-state and the structures of the mutants D7N and D7N/D176A in complex with the substrate ProFAR. These two distinct complex structures showed us the coupled conformational changes of HisA and ProFAR before catalysis. We also solved crystal structures of ten mutants, some in complex with substrate or product. The structures indicate that bi-functional mutants adopt distinct loop conformations linked to the two functions and that mutations in specialist enzymes favor one of the conformations. We also observed biphasic relationships in which small changes in the activities of low-performance enzymes had large effects on fitness, until a threshold, above which large changes in enzyme performance had little effect on fitness. Fusidic acid blocks protein translation by locking elongation factor G (EF-G) to the ribosome after GTP hydrolysis in elongation and recycling of bacterial protein synthesis. To understand the rescue mechanism, we solved the crystal structure of FusB at 1.6Å resolution. The structure showed that FusB is a two-domain protein and C-terminal domain contains a treble clef zinc finger. Using hybrid constructs between S. aureus EF-G that binds to FusB, and E. coli EF-G that does not, the binding determinants were located to domain IV of EF-G. This was further supported by small-angle X-ray scattering studies of the FusB·EF-G complex. Using single-molecule methods, we observed FusB frequently binding to the ribosome and rescue of FA-inhibited elongation by effects on the non-rotated state ribosome. Ribosome binding of FusB was confirmed by isothermal titration calorimetry.

Unregelmäßig erscheinende Berichte über wissenschaftliche Ergebnisse aus den einzelnen Forschungsbereichen der zum HZDR gehörenden Institute.

Unregelmäßig erscheinende Berichte über wissenschaftliche Ergebnisse aus den einzelnen Forschungsbereichen der zum FZD gehörenden Institute.

Unregelmäßig erscheinende Berichte über wissenschaftliche Ergebnisse aus den einzelnen Forschungsbereichen der zum FZR gehörenden Institute.

Business Intelligence (BI) möjliggör bättre och effektivare beslutsfattande genom att förse beslutsfattare med relevant information vid rätt tillfälle, plats och format och har därmed möjligheten att stärka verksamheter. Idag är det svårt att hitta en framgångsrik verksamhet som inte tillämpar BI. Implementeringen och underhållningen av BI är dock kopplad till några förebyggande faktorer. Cloud Computing (CC) är en ny typ av lösning som har potentialen att åtgärda de förebyggande faktorerna som brukar hindra verksamheter från att utnyttja fördelarna hos BI. Kombinationen av BI och CC brukar kallas för Cloud BI, vilket är området som denna undersökningen berör. Styrkor och svagheter hos CC blir ärvda till Cloud BI i samband med kombinationen. Precis som BI har sina förebyggande faktorer har även Cloud BI förebyggande faktorer i form av svagheter. Verksamheter måste överväga styrkor mot svagheter innan de väljer att tillämpa Cloud BI. Under denna undersökningen genomförde författaren en litteraturgranskning och upptäckte både inkonsekvens och motsägelser angående styrkor och svagheter hos Cloud BI samt en brist på empiriska och kvalitativa studier. Författaren valde därmed att undersöka styrkor och svagheter hos Cloud BI i praktiken, genom att ta reda på hur praktiska användare i Sverige upplever Cloud BI. Användarnas upplevelser samlades in genom semi-strukturerade intervjuer och analyserades genom tematisk analys. Totalt deltog sex respondenter från fyra olika verksamheter. Resultatet visar att styrkorna som användarna upplever är (1) skalbarhet, (2) tidsbesparingar, (3) mobilitet, (4) potentiella kostnadsbesparingar, (5) inbyggd säkerhetskopiering, (6) effektivitet samt (7) tillgång till de senaste versionerna medan svagheterna som användarna upplever är (1) svårt att estimera kostnader, (2) lagstiftningsproblem, (3) leverantörsberoende, (4) kompatibilitetsproblem, (5) mognad samt (6) valmöjligheter.