Developing of Germyldesulonylation and Thiodesulfonylation Reactions for the Synthesis of Novel Nucleoside Analogues. Efficient Synthesis of Novel (α-Fluoro)vinyl Sulfides

S-adenosyl-L-homocysteine (AdoHcy) hydrolase effects hydrolytic cleavage of AdoHcy to produce both adenosine and L-homocysteine and is a feedback inhibitor of S-adenosyl- L-methionine (SAM). Nucleoside analogues bearing an alkenyl or fluoroalkenyl chain between sulfur and C5' utilizing Negishi coupling reactions were synthesized. Palladium-catalyzed cross-coupling between the 5'-deoxy-5'-(iodomethylene) nucleosides and alkylzinc bromides gives analogues with the alkenyl unit. Palladium-catalyzed selective monoalkylation of 5'-(bromofluoromethylene)-5'-deoxy-adenosine with alkylzinc bromide afford adenosylhomocysteine analogues with a 6'-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases. Stannydesulfonylation reaction is a critical step in the synthesis of E-fluorovinyl cytidine (Tezacitabine) a ribonucleoside reductase inhibitor with a potent anticancer activity. The synthesis involves the removal of the sulfonyl group by a radical-mediated stannyldesulfonylation reaction using tributyltin hydride. In order to eliminate the toxicity of tin, I developed a radical-mediated germyldesulonylation utilizing less toxic germane hydrides. Treatment of the protected (E)-5'-deoxy-5'-[(p-toluenesulfonyl)-methylene]uridine and adenosine derivatives with tributyl- or triphenylgermane hydride effected radical-mediated germyldesulfonylations to give 5'-(tributyl- or triphenylgermyl)methylene-5'-deoxynucleoside derivatives as single (E)-isomers. Analogous treatment of 2'-deoxy-2'-[(phenylsulfonyl)methylene]uridine with Ph3GeH afforded the corresponding vinyl triphenylgermane product. Stereoselective halodegermylation of the (E)-5'-(tributylgermyl)-methylene-5'-deoxy nucleosides with NIS or NBS provided the Wittig-type (E)-5'-deoxy-5'-(halomethylene) nucleosides quantitatively. Radical-mediated thiodesulfonylation of the readily available vinyl and (α-fluoro) vinyl sulfones with aryl thiols in organic or aqueous medium to provide a bench and environmentally friendly protocol to access (α-fluoro)vinyl sulfides were developed. Methylation of the vinyl or (α-fluoro)vinyl phenyl sulfide gave access to the corresponding vinyl or (α-fluoro)vinyl sulfonium salts. These sulfonium ions were tested as possible methyl group donors during reactions with thiols, phenols or amino groups which are commonly present in natural amino acids.

Parameter design considerations in precision engineering

Parameter design is an experimental design and analysis methodology for developing robust processes and products. Robustness implies insensitivity to noise disturbances. Subtle experimental realities, such as the joint effect of process knowledge and analysis methodology, may affect the effectiveness of parameter design in precision engineering; where the objective is to detect minute variation in product and process performance. In this thesis, approaches to statistical forced-noise design and analysis methodologies were investigated with respect to detecting performance variations. Given a low degree of process knowledge, Taguchi's methodology of signal-to-noise ratio analysis was found to be more suitable in detecting minute performance variations than the classical approach based on polynomial decomposition. Comparison of inner-array noise (IAN) and outer-array noise (OAN) structuring approaches showed that OAN is a more efficient design for precision engineering. ^

Temporal analysis of land use and transportation investments with geographic information system

Land use and transportation interaction has been a research topic for several decades. There have been efforts to identify impacts of transportation on land use from several different perspectives. One focus has been the role of transportation improvements in encouraging new land developments or relocation of activities due to improved accessibility. The impacts studied have included property values and increased development. Another focus has been on the changes in travel behavior due to better mobility and accessibility. Most studies to date have been conducted in metropolitan level, thus unable to account for interactions spatially and temporally at smaller geographic scales. ^ In this study, a framework for studying the temporal interactions between transportation and land use was proposed and applied to three selected corridor areas in Miami-Dade County, Florida. The framework consists of two parts: one is developing of temporal data and the other is applying time series analysis to this temporal data to identify their dynamic interactions. Temporal GIS databases were constructed and used to compile building permit data and transportation improvement projects. Two types of time series analysis approaches were utilized: univariate models and multivariate models. Time series analysis is designed to describe the dynamic consequences of time series by developing models and forecasting the future of the system based on historical trends. Model estimation results from the selected corridors were then compared. ^ It was found that the time series models predicted residential development better than commercial development. It was also found that results from three study corridors varied in terms of the magnitude of impacts, length of lags, significance of the variables, and the model structure. Long-run effect or cumulated impact of transportation improvement on land developments was also measured with time series techniques. The study offered evidence that congestion negatively impacted development and transportation investments encouraged land development. ^

Lattice Boltzmann modeling of fluid flow and solute transport in karst aquifers

A novel modeling approach is applied to karst hydrology. Long-standing problems in karst hydrology and solute transport are addressed using Lattice Boltzmann methods (LBMs). These methods contrast with other modeling approaches that have been applied to karst hydrology. The motivation of this dissertation is to develop new computational models for solving ground water hydraulics and transport problems in karst aquifers, which are widespread around the globe. This research tests the viability of the LBM as a robust alternative numerical technique for solving large-scale hydrological problems. The LB models applied in this research are briefly reviewed and there is a discussion of implementation issues. The dissertation focuses on testing the LB models. The LBM is tested for two different types of inlet boundary conditions for solute transport in finite and effectively semi-infinite domains. The LBM solutions are verified against analytical solutions. Zero-diffusion transport and Taylor dispersion in slits are also simulated and compared against analytical solutions. These results demonstrate the LBM’s flexibility as a solute transport solver. The LBM is applied to simulate solute transport and fluid flow in porous media traversed by larger conduits. A LBM-based macroscopic flow solver (Darcy’s law-based) is linked with an anisotropic dispersion solver. Spatial breakthrough curves in one and two dimensions are fitted against the available analytical solutions. This provides a steady flow model with capabilities routinely found in ground water flow and transport models (e.g., the combination of MODFLOW and MT3D). However the new LBM-based model retains the ability to solve inertial flows that are characteristic of karst aquifer conduits. Transient flows in a confined aquifer are solved using two different LBM approaches. The analogy between Fick’s second law (diffusion equation) and the transient ground water flow equation is used to solve the transient head distribution. An altered-velocity flow solver with source/sink term is applied to simulate a drawdown curve. Hydraulic parameters like transmissivity and storage coefficient are linked with LB parameters. These capabilities complete the LBM’s effective treatment of the types of processes that are simulated by standard ground water models. The LB model is verified against field data for drawdown in a confined aquifer.

Lattice Boltzmann Modeling of Fluid Flow and Solute Transport in Karst Aquifers

A novel modeling approach is applied to karst hydrology. Long-standing problems in karst hydrology and solute transport are addressed using Lattice Boltzmann methods (LBMs). These methods contrast with other modeling approaches that have been applied to karst hydrology. The motivation of this dissertation is to develop new computational models for solving ground water hydraulics and transport problems in karst aquifers, which are widespread around the globe. This research tests the viability of the LBM as a robust alternative numerical technique for solving large-scale hydrological problems. The LB models applied in this research are briefly reviewed and there is a discussion of implementation issues. The dissertation focuses on testing the LB models. The LBM is tested for two different types of inlet boundary conditions for solute transport in finite and effectively semi-infinite domains. The LBM solutions are verified against analytical solutions. Zero-diffusion transport and Taylor dispersion in slits are also simulated and compared against analytical solutions. These results demonstrate the LBM’s flexibility as a solute transport solver. The LBM is applied to simulate solute transport and fluid flow in porous media traversed by larger conduits. A LBM-based macroscopic flow solver (Darcy’s law-based) is linked with an anisotropic dispersion solver. Spatial breakthrough curves in one and two dimensions are fitted against the available analytical solutions. This provides a steady flow model with capabilities routinely found in ground water flow and transport models (e.g., the combination of MODFLOW and MT3D). However the new LBM-based model retains the ability to solve inertial flows that are characteristic of karst aquifer conduits. Transient flows in a confined aquifer are solved using two different LBM approaches. The analogy between Fick’s second law (diffusion equation) and the transient ground water flow equation is used to solve the transient head distribution. An altered-velocity flow solver with source/sink term is applied to simulate a drawdown curve. Hydraulic parameters like transmissivity and storage coefficient are linked with LB parameters. These capabilities complete the LBM’s effective treatment of the types of processes that are simulated by standard ground water models. The LB model is verified against field data for drawdown in a confined aquifer.

Improving caches in consolidated environments

Memory (cache, DRAM, and disk) is in charge of providing data and instructions to a computer's processor. In order to maximize performance, the speeds of the memory and the processor should be equal. However, using memory that always match the speed of the processor is prohibitively expensive. Computer hardware designers have managed to drastically lower the cost of the system with the use of memory caches by sacrificing some performance. A cache is a small piece of fast memory that stores popular data so it can be accessed faster. Modern computers have evolved into a hierarchy of caches, where a memory level is the cache for a larger and slower memory level immediately below it. Thus, by using caches, manufacturers are able to store terabytes of data at the cost of cheapest memory while achieving speeds close to the speed of the fastest one.^ The most important decision about managing a cache is what data to store in it. Failing to make good decisions can lead to performance overheads and over-provisioning. Surprisingly, caches choose data to store based on policies that have not changed in principle for decades. However, computing paradigms have changed radically leading to two noticeably different trends. First, caches are now consolidated across hundreds to even thousands of processes. And second, caching is being employed at new levels of the storage hierarchy due to the availability of high-performance flash-based persistent media. This brings four problems. First, as the workloads sharing a cache increase, it is more likely that they contain duplicated data. Second, consolidation creates contention for caches, and if not managed carefully, it translates to wasted space and sub-optimal performance. Third, as contented caches are shared by more workloads, administrators need to carefully estimate specific per-workload requirements across the entire memory hierarchy in order to meet per-workload performance goals. And finally, current cache write policies are unable to simultaneously provide performance and consistency guarantees for the new levels of the storage hierarchy.^ We addressed these problems by modeling their impact and by proposing solutions for each of them. First, we measured and modeled the amount of duplication at the buffer cache level and contention in real production systems. Second, we created a unified model of workload cache usage under contention to be used by administrators for provisioning, or by process schedulers to decide what processes to run together. Third, we proposed methods for removing cache duplication and to eliminate wasted space because of contention for space. And finally, we proposed a technique to improve the consistency guarantees of write-back caches while preserving their performance benefits.^

Sistematización in Urban Disaster Risk Reduction

Purpose – The purpose of this paper is to provide an analysis of sistematización’s use as a research tool in the operationalization of a “neighborhood approach” to the implementation of disaster risk reduction (DRR) in informal urban settlements. Design/methodology/approach – The first section highlights sistematización’s historical origins in Latin America in the fields of popular adult education, social work, and rural development. The second explains why sistematización was made a required component of project implementation. The third section addresses the approach to sistematización used. The final discusses how this experience both contributes to sistematización’s theoretical development and practical application as a methodology. Findings – The introduction of “sistematización” as a research tool facilitated real-time assessment of project implementation, providing timely information that positively influenced decision-making processes. This on-going feedback, collective learning, and open-exchange of know-how between NGOs and partner institutions allowed for the evaluation of existing practices and development of new ways of collaborating to address disaster risk in complex and dynamic urban environments. Practical implications – Sistematización transcends the narrow focus of traditional monitoring and evaluation on final results, emphasizing a comprehensive understanding of processes and contexts. Originality/value – Its use in the implementation of DRR initiatives in informal urban environments is particularly novel, highlighting the capacity of the methodology to be tailored to a variety of needs, in this case, bridging the gap between NGOs, local governments, and vulnerable communities, as well as between urban, development, and disaster risk management planning.