Design and in vitro characterization of highly sst2-selective somatostatin antagonists suitable for radiotargeting

Radiolabeled sst 2 and sst 3 antagonists are better candidates for tumor targeting than agonists with comparable binding characteristics (Ginj, M.; Zhang, H.; Waser, B.; Cescato, R.; Wild, D.; Erchegyi, J.; Rivier, J.; Mäcke, H. R.; Reubi, J. C. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 16436-16441.). Because most of the neuroendocrine tumors express sst 2, we used the known antagonists acetyl- pNO 2Phe (2)- c[ dCys (3)-Tyr (7)- dTrp (8)-Lys (9)-Thr (10)-Cys (14)]- dTyr (15)-NH 2 ( 1) (Bass, R. T.; Buckwalter, B. L.; Patel, B. P.; Pausch, M. H.; Price, L. A.; Strnad, J.; Hadcock, J. R. Mol. Pharmacol. 1996, 50, 709-715. Bass, R. T.; Buckwalter, B. L.; Patel, B. P.; Pausch, M. H.; Price, L. A.; Strnad, J.; Hadcock, J. R. Mol. Pharmacol. 1997, 51, 170; Erratum.) and H-Cpa (2)- c[ dCys (3)-Tyr (7)- dTrp (8)-Lys (9)-Thr (10)-Cys (14)]-2Nal (15)-NH 2 ( 7) (Hocart, S. J.; Jain, R.; Murphy, W. A.; Taylor, J. E.; Coy, D. H. J. Med. Chem. 1999, 42, 1863-1871.) as leads for analogues with increased sst 2 binding affinity and selectivity. Among the 32 analogues reported here, DOTA- pNO 2Phe (2)- c[ dCys (3)-Tyr (7)- dAph (8)(Cbm)-Lys (9)-Thr (10)-Cys (14)- dTyr (15)-NH 2 ( 3) and DOTA-Cpa (2)- c[ dCys (3)-Aph (7)(Hor)- dAph (8)(Cbm)-Lys (9)-Thr (10)-Cys (14)]- dTyr (15)-NH 2 ( 31) had the highest sst 2 binding affinity and selectivity. All of the analogues tested kept their sst 2 antagonistic properties (i.e., did not affect calcium release in vitro and competitively antagonized the agonistic effect of [Tyr (3)]octreotide). Moreover, in an immunofluorescence-based internalization assay, the new analogues prevented sst 2 internalization induced by the sst 2 agonist [Tyr (3)]octreotide without being active by themselves. In conclusion, several analogues (in particular 3, 31, and 32) have outstanding sst 2 binding and functional antagonistic properties and, because of their DOTA moiety, are excellent candidates for in vivo targeting of sst 2-expressing cancers.

DESIGN AND FABRICATION OF RESONANT GAS SENSOR FOR HIGH SENSITIVITY IN THE PRESENCE OF AIR DAMPING

Gas sensors have been used widely in different important area including industrial control, environmental monitoring, counter-terrorism and chemical production. Micro-fabrication offers a promising way to achieve sensitive and inexpensive gas sensors. Over the years, various MEMS gas sensors have been investigated and fabricated. One significant type of MEMS gas sensors is based on mass change detection and the integration with specific polymer. This dissertation aims to make contributions to the design and fabrication of MEMS resonant mass sensors with capacitance actuation and sensing that lead to improved sensitivity. To accomplish this goal, the research has several objectives: (1) Define an effective measure for evaluating the sensitivity of resonant mass devices; (2) Model the effects of air damping on microcantilevers and validate models using laser measurement system (3) Develop design guidelines for improving sensitivity in the presence of air damping; (4) Characterize the degree of uncertainty in performance arising from fabrication variation for one or more process sequences, and establish design guidelines for improved robustness. Work has been completed toward these objectives. An evaluation measure has been developed and compared to an RMS based measure. Analytic models of air damping for parallel plate that include holes are compared with a COMSOL model. The models have been used to identify cantilever design parameters that maximize sensitivity. Additional designs have been modeled with COMSOL and the development of an analytical model for Fixed-free cantilever geometries with holes has been developed. Two process flows have been implemented and compared. A number of cantilever designs have been fabricated and the uncertainty in process has been investigated. Variability from processing have been evaluated and characterized.

Animal Guts as Ideal Chemical Reactors: Maximizing Absorption Rates

I solved equations that describe coupled hydrolysis in and absorption from a continuously stirred tank reactor (CSTR), a plug flow reactor (PFR), and a batch reactor (BR) for the rate of ingestion and/or the throughput time that maximizes the rate of absorption (=gross rate of gain from digestion). Predictions are that foods requiring a single hydrolytic step (e.g., disaccharides) yield ingestion rates that vary inversely with the concentration of food substrate ingested, whereas foods that require multiple hydrolytic and absorptive reactions proceeding in parallel (e.g., proteins) yield maximal ingestion rates at intermediate substrate concentrations. Counterintuitively, then, animals acting to maximize their absorption rates should show compensatory ingestion (more rapid feeding on food of lower concentration), except for the lower range of diet quality fur complex diets and except for animals that show purely linear (passive) uptake. At their respective maxima in absorption rates, the PFR and BR yield only modestly higher rates of gain than the CSTR but do so at substantially lower rates of ingestion. All three ideal reactors show milder than linear reduction in rate of absorption when throughput or holding time in the gut is increased (e.g., by scarcity or predation hazard); higher efficiency of hydrolysis and extraction offset lower intake. Hence adding feeding costs and hazards of predation is likely to slow ingestion rates and raise absorption efficiencies substantially over the cost-free optima found here.

Fluorescence-encoded gold nanoparticles: library design and modulation of cellular uptake into dendritic cells.

In order to harness the unique properties of nanoparticles for novel clinical applications and to modulate their uptake into specific immune cells we designed a new library of homo- and hetero-functional fluorescence-encoded gold nanoparticles (Au-NPs) using different poly(vinyl alcohol) and poly(ethylene glycol)-based polymers for particle coating and stabilization. The encoded particles were fully characterized by UV-Vis and fluorescence spectroscopy, zeta potential and dynamic light scattering. The uptake by human monocyte derived dendritic cells in vitro was studied by confocal laser scanning microscopy and quantified by fluorescence-activated cell sorting and inductively coupled plasma atomic emission spectroscopy. We show how the chemical modification of particle surfaces, for instance by attaching fluorescent dyes, can conceal fundamental particle properties and modulate cellular uptake. In order to mask the influence of fluorescent dyes on cellular uptake while still exploiting its fluorescence for detection, we have created hetero-functionalized Au-NPs, which again show typical particle dependent cellular interactions. Our study clearly prove that the thorough characterization of nanoparticles at each modification step in the engineering process is absolutely essential and that it can be necessary to make substantial adjustments of the particles in order to obtain reliable cellular uptake data, which truly reflects particle properties.

Conceptual design and simulation of a water Cherenkov muon veto for the XENON1T experiment

XENON is a dark matter direct detection project, consisting of a time projection chamber (TPC) filled with liquid xenon as detection medium. The construction of the next generation detector, XENON1T, is presently taking place at the Laboratori Nazionali del Gran Sasso (LNGS) in Italy. It aims at a sensitivity to spin-independent cross sections of 2 10-47 c 2 for WIMP masses around 50 GeV2, which requires a background reduction by two orders of magnitude compared to XENON100, the current generation detector. An active system that is able to tag muons and muon-induced backgrounds is critical for this goal. A water Cherenkov detector of ~ 10 m height and diameter has been therefore developed, equipped with 8 inch photomultipliers and cladded by a reflective foil. We present the design and optimization study for this detector, which has been carried out with a series of Monte Carlo simulations. The muon veto will reach very high detection efficiencies for muons (>99.5%) and showers of secondary particles from muon interactions in the rock (>70%). Similar efficiencies will be obtained for XENONnT, the upgrade of XENON1T, which will later improve the WIMP sensitivity by another order of magnitude. With the Cherenkov water shield studied here, the background from muon-induced neutrons in XENON1T is negligible.

Multifunctional Coordination Compounds: Design and Properties

Cleverly designed molecular building blocks provide chemists with the tools of a powerful molecular-scale construction set. They enable them to engineer materials having a predictable order and useful solid-state properties. Hence, it is in the realm of supramolecular chemistry to follow a strategy for synthesizing materials which combine a selected set of properties, for instance from the areas of magnetism, photophysics and electronics. As a successful approach, host/guest solids which are based on extended anionic, homo- and bimetallic oxalato-bridged transition-metal compounds with two-and three-dimensional connectivities have been investigated. In this report, a brief review is given on the structural aspects of this class of compounds followed by a presentation of a thermal and magnetic study for two distinct, heterometallic oxalato-bridged layer compounds.

Efficient design and optimization of bio-photonic sensing cells (BICELLs) for label free biosensing

In previous works we demonstrated the benefits of using micro–nano patterning materials to be used as bio-photonic sensing cells (BICELLs), referred as micro–nano photonic structures having immobilized bioreceptors on its surface with the capability of recognizing the molecular binding by optical transduction. Gestrinone/anti-gestrinone and BSA/anti-BSA pairs were proven under different optical configurations to experimentally validate the biosensing capability of these bio-sensitive photonic architectures. Moreover, Three-Dimensional Finite Difference Time Domain (FDTD) models were employed for simulating the optical response of these structures. For this article, we have developed an effective analytical simulation methodology capable of simulating complex biophotonic sensing architectures. This simulation method has been tested and compared with previous experimental results and FDTD models. Moreover, this effective simulation methodology can be used for efficiently design and optimize any structure as BICELL. In particular for this article, six different BICELL's types have been optimized. To carry out this optimization we have considered three figures of merit: optical sensitivity, Q-factor and signal amplitude. The final objective of this paper is not only validating a suitable and efficient optical simulation methodology but also demonstrating the capability of this method for analyzing the performance of a given number of BICELLs for label-free biosensing.

Ventilation system design and large scale fire tests

The design, construction and operation of the tunnels of M-30, the major ring road in the city of Madrid (Spain), represent a very interesting project in wich a wide variety of situations -geometrical, topographical, etc.- had to be covered, in variable conditions of traffic. For that reasons, the M-30 project is a remarkable technical challenge, which, after its completion, turned into an international reference. From the "design for safety" perspective, a holistic approach has been used to deal with new technologies, integration of systems and development of the procedures to reach the maximum level. However, one of the primary goals has been to achieve reasonable homogeneity characteristics which can permit operate a netword of tunels as one only infraestructure. In the case of the ventilation system the mentioned goals have implied innovative solutions and coordination efforts of great interest. Consequently, this paper describes the principal ideas underlying the conceptual solution developed focusing on the principal peculiarities of the project.

Design and analysis of helium Brayton power cycles for HiPER reactor

Helium Brayton cycles have been studied as power cycles for both fission and fusion reactors obtaining high thermal efficiency. This paper studies several technological schemes of helium Brayton cycles applied for the HiPER reactor proposal. Since HiPER integrates technologies available at short term, its working conditions results in a very low maximum temperature of the energy sources, something that limits the thermal performance of the cycle. The aim of this work is to analyze the potential of the helium Brayton cycles as power cycles for HiPER. Several helium Brayton cycle configurations have been investigated with the purpose of raising the cycle thermal efficiency under the working conditions of HiPER. The effects of inter-cooling and reheating have specifically been studied. Sensitivity analyses of the key cycle parameters and component performances on the maximum thermal efficiency have also been carried out. The addition of several inter-cooling stages in a helium Brayton cycle has allowed obtaining a maximum thermal efficiency of over 36%, and the inclusion of a reheating process may also yield an added increase of nearly 1 percentage point to reach 37%. These results confirm that helium Brayton cycles are to be considered among the power cycle candidates for HiPER.

Advancements in the design and validation of an air pollution integrated assessment model for Spain

This paper describes the design and application of the Atmospheric Evaluation and Research Integrated model for Spain (AERIS). Currently, AERIS can provide concentration profiles of NO2, O3, SO2, NH3, PM, as a response to emission variations of relevant sectors in Spain. Results are calculated using transfer matrices based on an air quality modelling system (AQMS) composed by the WRF (meteorology), SMOKE (emissions) and CMAQ (atmospheric-chemical processes) models. The AERIS outputs were statistically tested against the conventional AQMS and observations, revealing a good agreement in both cases. At the moment, integrated assessment in AERIS focuses only on the link between emissions and concentrations. The quantification of deposition, impacts (health, ecosystems) and costs will be introduced in the future. In conclusion, the main asset of AERIS is its accuracy in predicting air quality outcomes for different scenarios through a simple yet robust modelling framework, avoiding complex programming and long computing times.

Greenfield shopping center development. The integration between environmental features, building design and investment analysis at the decision making stage

The Shopping centre is a long term investment in which Greenfield development decisions are often taken based on risks analysis regarding construction costs, location, competition, market and an expected DCF. Furthermore, integration between the building design, project planning, operational costs and investment analysis is not entirely considered by the investor at the decision making stage. The absence of such information tends to produce certain negative impacts on the future running costs and annual maintenance of the building, especially on energy demand and other occupancy expenses paid by the tenants to the landlord. From the investor´s point of view, this blind spot in strategy development will possibly decrease their profit margin as changes in the occupancy expenses[ ] have a direct outcome on the profit margin. In order to try to reduce some higher operating cost components such as energy use and other utility savings as well as their CO2 emissions, quite a few income properties worldwide have some type of environmental label such as BREEAM and LEED. The drawback identified in this labelling is that usually the investments required to get an ecolabel are high and the investor finds no direct evidence that it increases market value. However there is research on certified commercial properties (especially offices) that shows better performance in terms of occupancy rate and rental cost (Warren-Myers, 2012). Additionally, Sayce (2013) says that the certification only provides a quick reference point i.e. the lack of a certificate does not indicate that a building is not sustainable or efficient. Based on the issues described above, this research compares important components of the development stages such as investments costs, concept/ strategy development as well as the current investor income and property value. The subjects for this analysis are a shopping centre designed with passive cooling/bioclimatic strategies evaluated at the decision making stage, a certified regional shopping centre and a non-certified standard regional shopping centre. Moreover, the proposal intends to provide decision makers with some tools for linking green design features to the investment analysis in order to optimize the decision making process when looking into cost savings and design quality.

Library of libraries: approach to synthetic combinatorial library design and screening of "pharmacophore" motifs.

Construction of synthetic combinatorial libraries is described that allows for the generation of a library of motifs rather than a library of compounds. Peptide libraries based on this strategy were synthesized and screened with model targets streptavidin and anti-beta-endorphin antibody. The screens resulted in observation of expected motifs providing evidence of the effectiveness of the suggested approach.

Evaluation of safety, design, and operation of shared-use paths : final report /

"HRDS-06/07-07(500)E"--Back cover.

Single-fluid two-region aqueous homogeneous reactor power plant : conceptual design and feasibility study : final report /

"Other issues of this report may bear the number BAW-7."

Stem design and shotcrete, grout, and concrete support /

Project pre-SCHOONER.