Cancer became recently the leading cause of death in industrialized countries. Even though standard treatments achieve significant effects in growth inhibition and tumor elimination, they cause severe side effects as most of the applied drugs exhibit only minor selectivity for the malignant tissue. Hence, specific addressing of tumor cells without affecting healthy tissue is currently a major desire in cancer therapy. Cell surface receptors, which bind peptides are frequently overexpressed on cancer cells and can therefore be considered as promising targets for selective tumor therapy. In this review, the benefits of peptides as tumor homing agents are presented and an overview of the most commonly addressed peptide receptors is given. A special focus was set on the bombesin receptor family and the neuropeptide Y receptor family. In the second part, the specific requirements of peptide-drug conjugates (PDC) and intelligent linker structures as an essential component of PDC are outlined. Furthermore, different drug cargos are presented including classical and recent toxic agents as well as radionuclides for diagnostic and therapeutic approaches. In the last part, boron neutron capture therapy as advanced targeted cancer therapy is introduced and past and recent developments are reviewed.

Heat flux and heat conductance at the metal mold interface plays a key role in controlling the final metal casting strength. It is difficult to obtain these parameters through direct measurement because of the required placement of sensors, however they can be obtained through inverse heat conduction calculations. Existing inverse heat conduction methods are analyzed and classified into three categories, i.e., direct inverse methods, observer-based methods and optimization methods. The solution of the direct inverse methods is based on the linear relationship between heat flux and temperature (either in the time domain or in the frequency domain) and is calculated in batch mode. The observer-based method consists on the application of observer theory to the inverse heat conduction problem. The prominent characteristic in this category is online estimation, but the methods in this category show weak robustness. Transforming estimation problems into optimization problems forms the methods in the third category. The methods in third category show very good robustness property and can be easily extended to multidimensional and nonlinear problems. The unknown parameters in some inverse heat conduction methods can be obtained by a proposed calibration procedure. A two-index property evaluation (accuracy and robustness) is also proposed to evaluate inverse heat conduction methods and thus determine which method is suitable for a given situation. The thermocouple dynamics effect on inverse calculation is also analyzed. If the thermocouple dynamics is omitted in the inverse calculation, the time constant of thermocouple should be as small as possible. Finally, a simple model is provided simulating the temperature measurement using a thermocouple. FEA (Finite Element Analysis) is employed to simulate temperature measurement.

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This dissertation presents a detailed account of the study undertaken on the subject of heat and mass transfer phenomena in porous media. The current work specifically targets the general reaction-diffusion systems arising in separation processes using porous sorbent particles. These particles are comprised of pore channels spanning length scales over almost three orders of magnitude while involving a variety of physical processes such as mass diffusion, heat transfer and surface adsorption-desorption. A novel methodology is proposed in this work that combines models that account for the multi-scale and multi-physics phenomena involved. Pore-resolving DNS calculations using an immersed boundary method (IBM) framework are used to simulate the macro-scale physics while the phenomena at smaller scales are modeled using a sub-pore modeling technique. The IBM scheme developed as part of this work is applicable to complex geometries on curvilinear grids, while also being very efficient, consuming less than 1% of the total simulation time per time-step. A new method of implementing the conjugate heat transfer (CHT) boundary condition is proposed which is a direct extension of the method used for other boundary conditions and does not involve any complex interpolations like previous CHT implementations using IBM. Detailed code verification and validation studies are carried out to demonstrate the accuracy of the developed method. The developed IBM scheme is used in conjunction with a stochastic reconstruction procedure based on simulated annealing. The developed framework is tested in a two-dimensional channel with two types of porous sections - one created using a random assembly of square blocks and another using the stochastic reconstruction procedure. Numerous simulations are performed to demonstrate the capability of the developed framework. The computed pressure drops across the porous section are compared with predictions from the Darcy-Forchheimer equation for media composed of different structure sizes. The developed methodology is also applied to CO2 diffusion studies in porous spherical particles of varying porosities. For the pore channels that are unresolved by the IBM framework, a sub-pore modeling methodology developed as part of this work which solves a one-dimensional unsteady diffusion equation in a hierarchy of scales represented by a fractal-type geometry. The model includes surface adsorption-desorption, and heat generation and absorption. It is established that the current framework is useful and necessary for reaction-diffusion problems in which the adsorption time scales are very small (diffusion-limited) or comparable to the diffusion time scales. Lastly, parametric studies are conducted for a set of diffusion-limited problems to showcase the powerful capability of the developed methodology. / Ph. D.

In the post-genomic era, recognition of the importance of sugars is increasing in biological research. For the precise analysis of their functions, homogeneous materials are required. Chemical synthesis is a powerful tool for preparation of homogeneous oligosaccharides and glycoconjugates. Glycosidases are potent catalysts for this purpose because they realize high stereo- and regio- selectivities under conditions benign to biomolecules without repetitive protection/deprotection procedures. A glycosynthase is an aritificial enzyme which is derived from a glycosidase and is devised for glycosylation reaction. To suppress the mechanistically inherent oligomerization side reaction of this class of biocatalysts, a glycosidase with plastic substrate recognition was engineered to afford the first α-mannosynthase. This novel biocatalyst showed low occurrence of oligomerized products as designed and was applied to prepare a wide range of oligosaccharides. Glycosidases are also valuable tools for glycan engineering of glycoconjugates, which is a pivotal issue in the development of pharmaceutical agents, including immunoglobulin G (IgG)-based drugs. EndoS, an endo-β-N-acetylglucosaminidase from Streptococcus pyogenes, natively cleaves N-glycans on IgG specifically. When the latent glycosylation activity of this enzyme was applied, the N-glycan remodelling of full-length IgG was successfully achieved for the first time and a highly pure glycoform was obtained using the chemically synthesized oxazoline tetrasaccharide as glycosyl donor. This biocatalytic reaction allows development of a novel type of antibody-drug conjugates (ADCs) in which drug molecules are linked to N-glycans site-specifically. For this purpose, glycans with bioorthogonal reaction handles were synthesized and conjugated to IgG. A model reaction using a dye compound as reaction partner worked successfully and the synthetic method for this newly designed ADC was validated. Glycan trimming of glycoproteins expressed from Pichia pastoris was performed using exoglycosidases to derive homogeneous glycoform. Jack Bean α-mannosidase (JBM) trimmed native N-glycans down to the core trisaccharide structure but some of the glycoforms were discovered to be resistant to the JBM activity. Enzymatic analyses using exoglycosidases suggested that the JBM-resistant factor was likely to be β-mannoside. In summary, this work advanced application of modified glycosidases for preparation of oligosaccharides and also demonstrated biocatalytic utility of glycosidases to produce biologically relevant glycoconjugates with homogeneous glycoforms.

Low-frequency vibrations typically occur in many practical structures and systems when in use, for example, in aerospaces and industrial machines. Piezoelectric materials feature compactness, lightweight, high integration potential, and permit to transduce mechanical energy from vibrations into electrical energy. Because of their properties, piezoelectric materials have been receiving growing interest during the last decades as potential vibration- harvested energy generators for the proliferating number of embeddable wireless sensor systems in applications such as structural health monitoring (SHM). The basic idea behind piezoelectric energy harvesting (PEH) powered architectures, or energy harvesting (EH) more in general, is to develop truly “fit and forget” solutions that allow reducing physical installations and burdens to maintenance over battery-powered systems. However, due to the low mechanical energy available under low-frequency conditions and the relatively high power consumption of wireless sensor nodes, PEH from low-frequency vibrations is a challenge that needs to be addressed for the majority of the practical cases. Simply saying, the energy harvested from low-frequency vibrations is not high enough to power wireless sensor nodes or the power consumption of the wireless sensor nodes is higher than the harvested energy. This represents a main barrier to the widespread use of PEH technology at the current state of the development, despite the advantages it may offer. The main contribution of this research work concerns the proposal of a novel EH circuitry, which is based on a whole-system approach, in order to develop enhanced PEH powered wireless sensor nodes, hence to compensate the existing mismatch between harvested and demanded energy. By whole-system approach, it is meant that this work develops an integrated system-of-systems rather than a single EH unit, thus getting closer to the industrial need of a ready- to-use energy-autonomous solution for wireless sensor applications such as SHM. To achieve so, this work introduces: Novel passive interfaces in connection with the piezoelectric harvester that permit to extract more energy from it (i.e., a complex conjugate impedance matching (CCIM) interface, which uses a PC permalloy toroidal coil to achieve a large inductive reactance with a centimetre- scaled size at low frequency; and interfaces for resonant PEH applications, which exploit the harvester‟s displacement to achieve a mechanical amplification of the input force, a magnetic and a mechanical activation of a synchronised switching harvesting on inductor (SSHI) mechanism). A novel power management approach, which permits to minimise the power consumption for conditioning the transduced signal and optimises the flow of the harvested energy towards a custom-developed wireless sensor communication node (WSCN) through a dedicated energy-aware interface (EAI); where the EAI is based on a voltage sensing device across a capacitive energy storage. Theoretical and experimental analyses of the developed systems are carried in connection with resistive loads and the WSCN under excitations of low frequency and strain/acceleration levels typical of two potential energy- autonomous applications, that are: 1) wireless condition monitoring of commercial aircraft wings through non-resonant PEH based on Macro-Fibre Composite (MFC) material bonded to aluminium and composite substrates; and wireless condition monitoring of large industrial machinery through resonant PEH based on a cantilever structure. shown that under similar testing conditions the developed systems feature a performance in comparison with other architectures reported in the literature or currently available on the market. Power levels up to 12.16 mW and 116.6 µW were respectively measured across an optimal resistive load of 66 277 kΩ for an implemented non-resonant MFC energy harvester on aluminium substrate and a resonant cantilever-based structure when no interfaces were added into the circuits. When the WSCN was connected to the harvesters in place of the resistive loads, data transmissions as fast as 0.4 and s were also respectively measured. By use of the implemented passive interfaces, a maximum power enhancement of around 95% and 452% was achieved in the two tested cases and faster data transmissions obtained with a maximum percentage improvement around 36% and 73%, respectively. By the use of the EAI in connection with the WSCN, results have also shown that the overall system‟s power consumption is as low as a few microwatts during non- active modes of operation (i.e., before the WSCN starts data acquisition and transmission to a base station). Through the introduction of the developed interfaces, this research work takes a whole-system approach and brings about the capability to continuously power wireless sensor nodes entirely from vibration-harvested energy in time intervals of a few seconds or fractions of a second once they have been firstly activated. Therefore, such an approach has potential to be used for real-world energy- autonomous applications of SHM.

This study performed detailed measurements on and around scaled up conducting and adiabatic airfoils with and without film cooling. The conducting vane was a matched Bi airfoil, which accurately scaled the convective heat transfer and conduction through the solid, in order to produce non-dimensional surface temperatures and thermal boundary layers that were representative of an actual engine. Measurements made on all vane models included surface temperature measurements and thermal profiles above the walls. Separate measurements on non-film cooled and film cooled conducting models allowed for the individual contributions of the internal convective cooling and external film cooling to the overall cooling scheme to be quantified. Surface temperature and thermal field measurements above the wall were also performed on a film cooled adiabatic model. For the conducting model with internal cooling only, strong streamwise temperature variations were seen. The surface temperature variations were highly dependent on the local external and internal heat transfer coefficients. Spanwise temperature variations also existed, but were modest in comparison to streamwise variations. Comparing the thermal fields above the film cooled adiabatic and conducting walls allowed for the assumption that the conducting wall would not significantly affect the thermal field in the film cooling jet to be tested. Near the edge of the film cooling jet the developing thermal boundary layer had a clear effect on the overlying gas temperature, suggesting that the common assumption that the adiabatic wall temperature is the appropriate driving temperature for heat transfer to a film cooled wall was invalid. On the jet centerline thermal boundary layer effects were less influential, due to the development of a new, thin boundary layer. This suggested that the adiabatic wall temperature as driving temperature for heat transfer was a reasonable assumption on the jet centerline for most cases tested. As film cooling momentum flux ratio increase, thermal boundary layer effects became more influential on the jet centerline. Additionally, the high resolution surface temperature measurements and thermal field measurements above the wall presented in the current study represent a significant improvement in the data available for validation of computational simulations of conducting turbine airfoils. / text

This thesis is concerned with the application of the conjugate addition of functionalised lithium amides in the asymmetric syntheses of (−)-morphine and all members of the homalium alkaloids. Chapter 1 introduces the conjugate addition reaction as an important bond forming reaction, and explores its utility in the asymmetric synthesis of a variety of natural products. The conjugate addition of secondary lithium amides derived from α-methylbenzylamine is discussed, along with its application to the asymmetric synthesis of alkaloids. Chapter 2 describes two distinct attempts towards the asymmetric synthesis of (−)-morphine, both reliant upon the lithium amide conjugate addition and an intramolecular Diels-Alder reaction to set the five required stereogenic centres. The use of the novel and highly functionalised reagent lithium (R)-N-[2′-(7-methoxybenzofuran-3-yl)ethyl]-N-(α-methylbenzyl)amide and its derivatives is reported. Chapter 3 focuses on the use of the novel reagent lithium (R)-N-(3-chloroprop-1-yl)-N-(α-methylbenzyl)amide and its derivatives in the asymmetric synthesis of two of the homalium alkaloids, (−)-(S,S)-homaline and (−)-(R,R)-hopromine, culminating in the most efficient syntheses of these alkaloids to date. Further, a sample of the (4′R,4′′S)-diastereoisomer of hopromine was synthesised, serving to confirm the proposed absolute configuration within natural (−)-(R,R)-hopromine. Chapter 4 extends the methodology developed in chapter 3 to the asymmetric synthesis of all possible diastereoisomers of the remaining homalium alkaloids, (−)-hopromalinol and (−)-hoprominol. These syntheses were used to propose the absolute configurations within these alkaloids, and therefore represented the first asymmetric syntheses of natural (−)-(4′S,4″R,2‴R)-hopromalinol and (−)-(R,R,R)-hoprominol. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.

This thesis is concerned with the development of methodology for the asymmetric synthesis of a range of amino polyol containing compounds. Chapter 1 highlights the abundance of the amino polyol motif in nature, the wide range of biological activities displayed by amino polyol containing compounds, and their occurrence in drug molecules. A variety of different methods for the synthesis of stereodefined amino polyols is then discussed. Chapter 2 details a full investigation into the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to enantiopurealpha,beta-unsaturated esters which contain a dioxolane unit. The “matched” conjugate addition reactions were further coupled with a highly diastereoselective in situ enolate oxidation using camphorsulfonyloxaziridine for the synthesis of keyalpha-hydroxy-beta-amino ester intermediates. Subsequent cyclisation and further elaboration allowed access to a range of amino polyol containing compounds including imino sugars, amino sugars, and amino acids. Chapter 3 extends the investigation into the doubly diastereoselective lithium amide conjugate addition reaction to enantiopure alpha,beta-unsaturated esters which contain two dioxolane units. A full assessment into the conjugate addition of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a series of D-pentose derived alpha,beta-unsaturated esters is reported. Subsequent elaboration of thebeta-amino ester products of these conjugate addition reactions resulted in the synthesis of (2'S,3'S,4'R)-dihydroxyhomoproline and (2'S,3'R,4'S)-dihydroxyhomoproline. Chapter 4 describes the asymmetric syntheses of protected forms of APTO and AETD, the 2,4,5-trihydroxy substitutedbeta-amino acid residues found within the hexapeptide marine natural products microsclerodermins C, D and E. The optimised synthetic routes to APTO and AETD involved three key steps: a diastereoselective aminohydroxylation [via conjugate addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide to an achiralalpha,beta-unsaturated ester followed by in situ enolate oxidation with camphorsulfonyloxaziridine], a diastereoselective dihydroxylation, and an olefination. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.

The analogue models and the kinematic models based on the seismic data results were used to simulate the fault pattern which develops above a basement horst. The two major normal faults intersect with each other along the strike in the sedimentary covers. The fault pattern developed in the sedimentary cover is controlled by the dip of the basement fault and the width of the basement horst. The single horst structure was only developed in the sedimentary covers above the wider end of the basement horst. The hourglass structure was developed in the sedimentary covers above the narrower end of the basement horst. The precursor faults developed ahead of the major second-order normal faults when the dip angle of the basement fault is larger than 60°. The antithetic faults developed ahead of the major second-order normal faults when the dip angle of the basement fault is less than 50°. The analogue models were designed in a way that the two hanging wall blocks glide down along the basement horst simultaneously to simulate the activity of the basement faults. The kinematic models were designed based on the alternative sequential slip method to study the kinematic behaviors of the conjugate normal faults. The Lufeng Sag was characterized by the basement horst in the center and the deep half-grabens developed beside the horst. The width of the basement horst decreases along its strike. The models indicates that the second-order normal faults developed above the basement horst, observed in the Lufeng Sag seismic profiles, were reproducible and much more detailed structures were revealed / Detta projekt har analog modellering och kinematiska modeller baserade på seismiska data använts för att simulera förkastningsmönster ovanför en berggrundshorst. Två stora normal förkastningar möts i strykningsriktningen hos de ovanliggande sedimentlagren. Förkastningsmönstret som utvecklats i ovanliggande sedimentlager styrs av stupningen hos underliggande urberg samt bredden hos den underliggande horsten. Den enda horststrukturen som utvecklades i sedimentlagren skedde i fallet med en bredare underliggande horststruktur. En timglasstruktur bildades i den sedimentära successionen vid den smalare ändan av berggrundshorsten. De initiala förkastningarna bildades tidigt för att sedan övergå i andra ordningens normalförkastningar i de fall då stupningen hos underliggande berggrund överstiger 60°. Mindre antitetiska förkastningar bildades före andra ordningens förkastningar där berggrunds-stupningen understiger 50°. Den analoga modell som nyttjades experimentellt var konstruerad så att de två hängväggskomponenterna kunde röra sig fritt samtidigt längs med berggrundshorsten för att simulera aktivering av befintliga förkastningar i berggrunden. De kinematiska modeller som nyttjades var konstruerade enligt metoden för sekventiella rörelser (eng - sequential slip method) för att studera kinematiska beteenden hos konjugerande förkastningspar. Lufeng-sänkans utseende har kontrollerats av berggrundshorsten i mitten samt av de djupa halv-grabens på båda sidorna av horsten. Bredden på berggrundshorsten minskar längs dess stupning. Modellerna påvisar att andra ordningens normal-förkastningar bildades ovanför berggrundshorsten, likt i de seismiska profilerna över området, samt att strukturerna var reproducerbara och väldigt detaljrika.