Design, synthesis and biological evaluation of 5$\sp\prime$-mononucleotide prodrugs: Strategies to introduce nucleotides into cells

The neutral bis ((pivaloyloxy)methyl) (PIV$\sb2\rbrack$ derivatives of FdUMP, ddUMP, and AZTMP were synthesized as potential membrane-permeable prodrugs of FdUMP, ddUMP, and AZTMP. These compounds were designed to enter cells by passive diffusion and revert to the parent nucleotides after removal of the PIV groups by hydrolytic enzymes. These prodrugs were prepared by condensation of FUdR, ddU, and AZT with PIV$\sb2$ phosphate in the presence of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobo reagent). PIV$\sb2$-FdUMP, PIV$\sb2$-ddUMP, and PIV$\sb2$-AZTMP were stable in the pH range 1.0-4.0 (t$\sb{1/2} = {>}$100 h). They were also fairly stable at pH 7.4 (t$\sb{1/2} = {>}$40 h). In 0.05 M NaOH solution, however, they were rapidly degraded (t$\sb{1/2} < 2$ min). In the presence hog liver carboxylate esterase, they were converted quantitatively to the corresponding phosphodiesters, PIV$\sb1$-FdUMP, PIV$\sb1$-ddUMP, and PIV$\sb1$-AZTMP; after 24 h incubation, only trace amounts of FdUMP, ddUMP, and AZTMP (1-5%) were observed indicating that the PIV$\sb1$ compounds were poor substrates for the enzyme. In human plasma, the PIV$\sb2$ compounds were rapidly degraded with half-lives of less than 5 min. The rate of degradation of the PIV$\sb2$ compounds in the presence of phosphodiesterase I was the same as that in buffer controls, indicating that they were not substrates for this enzyme. In the presence of phosphodiesterase I, PIV$\sb1$-FdUMP, PIV$\sb1$-ddUMP, and PIV$\sb1$-AZTMP were converted quantitatively to FdUMP, ddUMP, and AZTMP.^ PIV$\sb2$-ddUMP and PIV$\sb2$-AZTMP were effective at controlling HIV type 1 infection in MT-4 and CEM tk$\sp-$ cells in culture. Mechanistic studies demonstrated that PIV$\sb2$-ddUMP and PIV$\sb2$-AZTMP were taken up by the cells and converted to ddUTP and AZTTP, both potent inhibitors of HIV reverse transcriptase. However, a potential shortcoming of PIV$\sb2$-ddUMP and PIV$\sb2$-AZTMP as clinical therapeutic agents is that they are rapidly degraded (t$\sb{1/2}$ = approx. 4 minutes) in human plasma by carboxylate esterases. To circumvent this limitation, chemically-labile nucleotide prodrugs and liposome-encapsulated nucleotide prodrugs were investigated. In the former approach, the protective groups bis(N, N-(dimethyl)carbamoyloxymethyl) (DM$\sb2$) and bis (N-(piperidino)carbamoyloxymethyl) (DP$\sb2$) were used to synthesize DM$\sb2$-ddUMP and DP$\sb2$-ddUMP, respectively. In aqueous buffers (pH range 1.0-9.0) these compounds were degraded with half-lives of 3 to 4 h. They had similar half-lives in human plasma demonstrating that they were resistant to esterase-mediated cleavage. However, neither compound gave rise to significant concentrations of ddUMP in CEM or CEM tk$\sp-$ cells. In the liposome-encapsulated nucleotide prodrug approach, three different liposomal formulations of PIV$\sb2$-ddUMP (L-PIV$\sb2$-ddUMP) were investigated. The half-lifes of these L-PIV$\sb2$-ddUMP preparations in human plasma were 2 h compared with 4 min for the free drug. The preparations were more effective at controlling HIV-1 infection than free PIV$\sb2$-ddUMP in human T cells in culture. Collectively, these data indicate that PIV$\sb2$-FdUMP, PIV$\sb2$-ddUMP, and PIV$\sb2$-AZTMP are effective membrane-permeable prodrugs of FdUMP, ddUMP, and AZTMP. ^

Design and evaluation of acceleration strategies for speeding up the development of dialog applications

In this paper, we describe a complete development platform that features different innovative acceleration strategies, not included in any other current platform, that simplify and speed up the definition of the different elements required to design a spoken dialog service. The proposed accelerations are mainly based on using the information from the backend database schema and contents, as well as cumulative information produced throughout the different steps in the design. Thanks to these accelerations, the interaction between the designer and the platform is improved, and in most cases the design is reduced to simple confirmations of the “proposals” that the platform dynamically provides at each step. In addition, the platform provides several other accelerations such as configurable templates that can be used to define the different tasks in the service or the dialogs to obtain or show information to the user, automatic proposals for the best way to request slot contents from the user (i.e. using mixed-initiative forms or directed forms), an assistant that offers the set of more probable actions required to complete the definition of the different tasks in the application, or another assistant for solving specific modality details such as confirmations of user answers or how to present them the lists of retrieved results after querying the backend database. Additionally, the platform also allows the creation of speech grammars and prompts, database access functions, and the possibility of using mixed initiative and over-answering dialogs. In the paper we also describe in detail each assistant in the platform, emphasizing the different kind of methodologies followed to facilitate the design process at each one. Finally, we describe the results obtained in both a subjective and an objective evaluation with different designers that confirm the viability, usefulness, and functionality of the proposed accelerations. Thanks to the accelerations, the design time is reduced in more than 56% and the number of keystrokes by 84%.

Operation of polymer electrolyte membrane fuel cells with dry feeds: Design and operating strategies

The operation of polymer electrolyte membrane fuel cells (PEMFCs) with dry feeds has been examined with different fuel cell flow channel designs as functions of pressure, temperature and flow rate. Auto-humidified (or self-humidifying) PEMFC operation is improved at higher pressures and low gas velocities where axial dispersion enhances back-mixing of the product water with the dry feed. We demonstrate auto-humidified operation of the channel-less, self-draining fuel cell, based on a stirred tank reactor; data is presented showing auto-humidified operation from 25 to 115 degrees C at 1 and 3 atm. Design and operating requirements are derived for the auto-humidified operation of the channel-less, self-draining fuel cell. The auto-humidified self-draining fuel cell outperforms a fully humidified serpentine flow channel fuel cell at high current densities. The new design offers substantial benefits for simplicity of operation and control including: the ability to self-drain reducing flooding, the ability to uniformly disperse water removing current gradients and the ability to operate on dry feeds eliminating the need for humidifiers. Additionally, the design lends itself well to a modular design concept. (c) 2005 Elsevier B.V. All rights reserved.

A unified classification of manufacturing strategies and design processes

This article categorises manufacturing strategy design processes and presents the characteristics of resulting strategies. This work will therefore assist practitioners to appreciate the implications of planning activities. The article presents a framework for classifying manufacturing strategy processes and the resulting strategies. Each process and respective strategy is then considered in detail. In this consideration the preferred approach is presented for formulating a world class manufacturing strategy. Finally, conclusions and recommendations for further work are given.

Market-driven strategies and the design of flexible production systems: evidence from the electronics industry

Links the concept of market-driven business strategies with the design of production systems. It draws upon the case of a firm which, during the last decade, changed its strategy from being “technology led” to “market driven”. The research, based on interdisciplinary fieldwork involving long-term participant observation, investigated the factors which contribute to the successful design and implementation of flexible production systems in electronics assembly. These investigations were conducted in collaboration with a major computer manufacturer, with other electronics firms being studied for comparison. The research identified a number of strategies and actions seen as crucial to the development of efficient flexible production systems, namely: effective integration of subsystems, development of appropriate controls and performance measures, compatibility between production system design and organization structure, and the development of a climate conducive to organizational change. Overall, the analysis suggests that in the electronics industry there exists an extremely high degree of environmental complexity and turbulence. This serves to shape the strategic, technical and social structures that are developed to match this complexity, examples of which are niche marketing, flexible manufacturing and employee harmonization.

Fibrous Aerial Robotics: study of spiderweb strategies for the design of architectural envelopes using swarms of drones and inflatable formworks

La tesi approccia in modo transdisciplinare biologia, architettura e robotica, con la finalità di indagare e applicare principi costruttivi attraverso l’interazione tra sciami di droni che depositano materiale fibroso su strutture gonfiabili di supporto. L’attenzione principale è nello sviluppo (attraverso un workflow computazionale che gestisce sciami di agenti costruttori) di una tettonica che integra struttura, spazio e ornamento all’interno dello stesso processo progettuale, il quale si sviluppa coerentemente dall’ideazione fino alla fabbricazione. Sono stati studiati modelli biologici quali le colonie di ragni sociali, i quali costruiscono artefatti di grandi dimensioni relativamente a quelle del singolo individuo grazie ad un’organizzazione coordinata ed emergente e alle proprietà dei sistemi fibrosi. L’auto-organizzazione e la decentralizzazione, insieme alle caratteristiche del sistema materiale, sono stati elementi indispensabili nell’estrapolazione prima e nella codificazione poi di un insieme di regole adatte allo sviluppo del sistema costruttivo. Parallelamente alla simulazione digitale si è andati a sviluppare anche un processo fisico di fabbricazione che, pur tenendo conto dei vincoli economici e tecnici, potesse dimostrarsi una prova di concetto e fattibilità del sistema costruttivo. Sono state investigate le possibilità che un drone offre nel campo della fabbricazione architettonica mediante il rilascio di fili su elementi gonfiabili in pressione. Il processo può risultare vantaggioso in scenari in cui non è possibile allestire infrastrutture costruttive tradizionali (es. gole alpine, foreste). Tendendo conto dei vincoli e delle caratteristiche del sistema di fabbricazione proposto, sono state esplorate potenzialità e criticità del sistema studiato.

Communication Architecture Design for Real-Time Networked Control Systems

Networked control over data networks has received increasing attention in recent years. Among many problems in networked control systems (NCSs) is the need to reduce control latency and jitter and to deal with packet dropouts. This paper introduces our recent progress on a queuing communication architecture for real-time NCS applications, and simple strategies for dealing with packet dropouts. Case studies for a middle-scale process or multiple small-scale processes are presented for TCP/IP based real-time NCSs. Variations of network architecture design are modelled, simulated, and analysed for evaluation of control latency and jitter performance. It is shown that a simple bandwidth upgrade or adding hierarchy does not necessarily bring benefits for performance improvement of control latency and jitter. A co-design of network and control is necessary to maximise the real-time control performance of NCSs

An Investigation of Cognitive, Emotional and Negative Behavioural Responses to Service Recovery Strategies

Despite the best intentions of service providers and organisations, service delivery is rarely error-free. While numerous studies have investigated specific cognitive, emotional or behavioural responses to service failure and recovery, these studies do not fully capture the complexity of the services encounter. Consequently, this research develops a more holistic understanding of how specific service recovery strategies affect the responses of customers by combining two existing models—Smith & Bolton’s (2002) model of emotional responses to service performance and Fullerton and Punj’s (1993) structural model of aberrant consumer behaviour—into a conceptual framework. Specific service recovery strategies are proposed to influence consumer cognition, emotion and behaviour. This research was conducted using a 2x2 between-subjects quasi-experimental design that was administered via written survey. The experimental design manipulated two levels of two specific service recovery strategies: compensation and apology. The effect of the four recovery strategies were investigated by collecting data from 18-25 year olds and were analysed using multivariate analysis of covariance and multiple regression analysis. The results suggest that different service recovery strategies are associated with varying scores of satisfaction, perceived distributive justice, positive emotions, negative emotions and negative functional behaviour, but not dysfunctional behaviour. These finding have significant implications for the theory and practice of managing service recovery.