Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genomewide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.

Optimising QoE distribution for video applications through LTE-WiFi interworking

Mobile WiFi devices are becoming increasingly popular in non-seamless and user-controlled mobile traffic offloading alongside the standard WiFi hotspots. Unlike the operator-controlled hotspots, a mobile WiFi device relies on the capacity of the macro-cell for the data rate allocated to it. This type of devices can help offloading data traffic from the macro-cell base station and serve the end users within a closer range, but will change the pattern of resource distributions operated by the base station. We propose a resource allocation scheme that aims to optimize user quality of experience (QoE) when accessing video services in the environment where traffic offloading is taking place through interworking between a mobile communication system and low range wireless LANs. In this scheme, a rate redistribution algorithm is derived to perform scheduling which is controlled by a no-reference quality assessment metric in order to achieve the desired trade-offs between efficiency and fairness. We show the performance of this algorithm in terms of the distribution of the allocated data rates throughout the macro-cell investigated and the service coverage offered by the WiFi access point.

Traffic congestion control in communication networks

Next generation networks are characterized by ever increasing complexity, intelligence, heterogeneous technologies and increasing user expectations. Telecommunication networks in particular have become truly global, consisting of a variety of national and regional networks, both wired and wireless. Consequently, the management of telecommunication networks is becoming increasingly complex. In addition, network security and reliability requirements require additional overheads which increase the size of the data records. This in turn causes acute network traffic congestions. There is no single network management methodology to control the various requirements of today's networks, and provides a good level of Quality of Service (QoS), and network security. Therefore, an integrated approach is needed in which a combination of methodologies can provide solutions and answers to network events (which cause severe congestions and compromise the quality of service and security). The proposed solution focused on a systematic approach to design a network management system based upon the recent advances in the mobile agent technologies. This solution has provided a new traffic management system for telecommunication networks that is capable of (1) reducing the network traffic load (thus reducing traffic congestion), (2) overcoming existing network latency, (3) adapting dynamically to the traffic load of the system, (4) operating in heterogeneous environments with improved security, and (5) having robust and fault tolerance behavior. This solution has solved several key challenges in the development of network management for telecommunication networks using mobile agents. We have designed several types of agents, whose interactions will allow performing some complex management actions, and integrating them. Our solution is decentralized to eliminate excessive bandwidth usage and at the same time has extended the capabilities of the Simple Network Management Protocol (SNMP). Our solution is fully compatible with the existing standards.

Controlled growth of carbon nanotubes for high performance nanoelectronics

Unique electrical and mechanical properties of single-walled carbon nanotubes (SWNTs) have made them one of the most promising candidates for next-generation nanoelectronics. Efficient utilization of the exceptional properties of SWNTs requires controlling their growth direction (e.g., vertical, horizontal) and morphologies (e.g., straight, junction, coiled). ^ In this dissertation, the catalytic effect on the branching of SWNTs, Y-shaped SWNTs (Y-SWNTs), was investigated. The formation of Y-shaped branches was found to be dependent on the composition of the catalysts. Easier carbide formers have a strong tendency to attach to the sidewall of SWNTs and thus enhance the degree of branching. Y-SWNTs based field-effect transistors (FETs) were fabricated and modulated by the metallic branch of the Y-SWNTs, exhibiting ambipolar characteristics at room temperature. A subthreshold swing of 700 mV/decade and an on/off ratio of 105 with a low off-state current of 10-13 A were obtained. The transport phenomena associated with Y- and cross-junction configurations reveals that the conduction mechanism in the SWNT junctions is governed by thermionic emission at T > 100 K and by tunneling at T < 100 K. ^ Furthermore, horizontally aligned SWNTs were synthesized by the controlled modification of external fields and forces. High performance carbon nanotube FETs and logic circuit were demonstrated utilizing the aligned SWNTs. It is found that the hysteresis in CNTFETs can be eliminated by removing absorbed water molecules on the CNT/SiO2 interface by vacuum annealing, hydrophobic surface treatment, and surface passivation. SWNT “serpentines” were synthesized by utilization of the interaction between drag force from gas flow and Van der Waals force with substrates. The curvature of bent SWNTs could be tailored by adjusting the gas flow rate, and changing the gas flow direction with respect to the step-edges on a single-crystal quartz substrate. Resistivity of bent SWNTs was observed to increase with curvature, which can be attributed to local deformations and possible chirality shift at curved part. ^ Our results show the successful synthesis of SWNTs having controllable morphologies and directionality. The capability of tailoring the electrical properties of SWNTs makes it possible to build an all-nanotube device by integrating SWNTs, having different functionalities, into complex circuits. ^

Efficient asynchronous scheduling algorithms for cost-effective buffered crossbar switches

Buffered crossbar switches have recently attracted considerable attention as the next generation of high speed interconnects. They are a special type of crossbar switches with an exclusive buffer at each crosspoint of the crossbar. They demonstrate unique advantages over traditional unbuffered crossbar switches, such as high throughput, low latency, and asynchronous packet scheduling. However, since crosspoint buffers are expensive on-chip memories, it is desired that each crosspoint has only a small buffer. This dissertation proposes a series of practical algorithms and techniques for efficient packet scheduling for buffered crossbar switches. To reduce the hardware cost of such switches and make them scalable, we considered partially buffered crossbars, whose crosspoint buffers can be of an arbitrarily small size. Firstly, we introduced a hybrid scheme called Packet-mode Asynchronous Scheduling Algorithm (PASA) to schedule best effort traffic. PASA combines the features of both distributed and centralized scheduling algorithms and can directly handle variable length packets without Segmentation And Reassembly (SAR). We showed by theoretical analysis that it achieves 100% throughput for any admissible traffic in a crossbar with a speedup of two. Moreover, outputs in PASA have a large probability to avoid the more time-consuming centralized scheduling process, and thus make fast scheduling decisions. Secondly, we proposed the Fair Asynchronous Segment Scheduling (FASS) algorithm to handle guaranteed performance traffic with explicit flow rates. FASS reduces the crosspoint buffer size by dividing packets into shorter segments before transmission. It also provides tight constant performance guarantees by emulating the ideal Generalized Processor Sharing (GPS) model. Furthermore, FASS requires no speedup for the crossbar, lowering the hardware cost and improving the switch capacity. Thirdly, we presented a bandwidth allocation scheme called Queue Length Proportional (QLP) to apply FASS to best effort traffic. QLP dynamically obtains a feasible bandwidth allocation matrix based on the queue length information, and thus assists the crossbar switch to be more work-conserving. The feasibility and stability of QLP were proved, no matter whether the traffic distribution is uniform or non-uniform. Hence, based on bandwidth allocation of QLP, FASS can also achieve 100% throughput for best effort traffic in a crossbar without speedup.

Biomimetic modeling of the nitrogen-centered radical postulated to occur during the inhibition of ribonucleotide reductases by 2'-azido-2'-deoxynucleotides

Ribonucleotide reductases (RNR) are essential enzymes that catalyze the reduction of ribonucleotides to 2'-deoxyribonucleotides, which is a critical step that produces precursors for DNA replication and repair. The inactivation of RNR, logically, would discontinue producing the precursors of the DNA of viral or cancer cells, which then would consequently end the cycle of DNA replication. Among different compounds that were found to be inhibitors of RNR, 2'-azido-2'-deoxynucleotide diphosphates (N3NDPs) have been investigated in depth as potent inhibitors of RNR. Decades of investigation has suggested that the inactivation of RNR by N3NDPs is a result of the formation of a nitrogen-centered radical (N·) that is covalently attached to the nucleotide at C3' and cysteine molecule C225 [3'-C(R-S-N·-C-OH)]. Biomimetic simulation reactions for the generation of the nitrogen-centered radicals similar to the one observed during the inactivation of the RNR by azionuclotides was investigated. The study included several modes: (i) theoretical calculation that showed the feasibility of the ring closure reaction between thiyl radicals and azido group; (ii) synthesis of the model azido nucleosides with a linker attached to C3' or C5' having a thiol or vicinal dithiol functionality; (iii) generation of the thiyl radical under both physiological and radiolysis conditions whose role is important in the initiation on RNR cascades; and (iv) analysis of the nitrogen-centered radical species formed during interaction between the thiyl radical and azido group by electron paramagnetic resonance spectroscopy (EPR). Characterization of the aminyl radical species formed during one electron attachment to the azido group of 2'-azido-2'-deoxyuridine and its stereospecifically labelled 1'-, 2'-, 3'-, 4'- or 5,6-[2H 2]-analogues was also examined. This dissertation gave insight toward understanding the mechanism of the formation of the nitrogen-centered radical during the inactivation of RNRs by azidonucleotides as well as the mechanism of action of RNRs that might provide key information necessary for the development of the next generation of antiviral and anticancer drugs.

Lightweight middleware for SDR inter-components communication

The ability to use Software Defined Radio (SDR) in the civilian mobile applications will make it possible for the next generation of mobile devices to handle multi-standard personal wireless devices and ubiquitous wireless devices. The original military standard created many beneficial characteristics for SDR, but resulted in a number of disadvantages as well. Many challenges in commercializing SDR are still the subject of interest in the software radio research community. Four main issues that have been already addressed are performance, size, weight, and power. ^ This investigation presents an in-depth study of SDR inter-components communications in terms of total link delay related to the number of components and packet sizes in systems based on Software Communication Architecture (SCA). The study is based on the investigation of the controlled environment platform. Results suggest that the total link delay does not linearly increase with the number of components and the packet sizes. The closed form expression of the delay was modeled using a logistic function in terms of the number of components and packet sizes. The model performed well when the number of components was large. ^ Based upon the mobility applications, energy consumption has become one of the most crucial limitations. SDR will not only provide flexibility of multi-protocol support, but this desirable feature will also bring a choice of mobile protocols. Having such a variety of choices available creates a problem in the selection of the most appropriate protocol to transmit. An investigation in a real-time algorithm to optimize energy efficiency was also performed. Communication energy models were used including switching estimation to develop a waveform selection algorithm. Simulations were performed to validate the concept.^

Tubular and sector heat pipes with interconnected branches for gas turbine and/or compressor cooling

Designing turbines for either aerospace or power production is a daunting task for any heat transfer scientist or engineer. Turbine designers are continuously pursuing better ways to convert the stored chemical energy in the fuel into useful work with maximum efficiency. Based on thermodynamic principles, one way to improve thermal efficiency is to increase the turbine inlet pressure and temperature. Generally, the inlet temperature may exceed the capabilities of standard materials for safe and long-life operation of the turbine. Next generation propulsion systems, whether for new supersonic transport or for improving existing aviation transport, will require more aggressive cooling system for many hot-gas-path components of the turbine. Heat pipe technology offers a possible cooling technique for the structures exposed to the high heat fluxes. Hence, the objective of this dissertation is to develop new radially rotating heat pipe systems that integrate multiple rotating miniature heat pipes with a common reservoir for a more effective and practical solution to turbine or compressor cooling. In this dissertation, two radially rotating miniature heat pipes and two sector heat pipes are analyzed and studied by utilizing suitable fluid flow and heat transfer modeling along with experimental tests. Analytical solutions for the film thickness and the lengthwise vapor temperature distribution for a single heat pipe are derived. Experimental tests on single radially rotating miniature heat pipes and sector heat pipes are undertaken with different important parameters and the manner in which these parameters affect heat pipe operation. Analytical and experimental studies have proven that the radially rotating miniature heat pipes have an incredibly high effective thermal conductance and an enormous heat transfer capability. Concurrently, the heat pipe has an uncomplicated structure and relatively low manufacturing costs. The heat pipe can also resist strong vibrations and is well suited for a high temperature environment. Hence, the heat pipes with a common reservoir make incorporation of heat pipes into turbo-machinery much more feasible and cost effective.

Background traffic modeling for large-scale network simulation

Network simulation is an indispensable tool for studying Internet-scale networks due to the heterogeneous structure, immense size and changing properties. It is crucial for network simulators to generate representative traffic, which is necessary for effectively evaluating next-generation network protocols and applications. With network simulation, we can make a distinction between foreground traffic, which is generated by the target applications the researchers intend to study and therefore must be simulated with high fidelity, and background traffic, which represents the network traffic that is generated by other applications and does not require significant accuracy. The background traffic has a significant impact on the foreground traffic, since it competes with the foreground traffic for network resources and therefore can drastically affect the behavior of the applications that produce the foreground traffic. This dissertation aims to provide a solution to meaningfully generate background traffic in three aspects. First is realism. Realistic traffic characterization plays an important role in determining the correct outcome of the simulation studies. This work starts from enhancing an existing fluid background traffic model by removing its two unrealistic assumptions. The improved model can correctly reflect the network conditions in the reverse direction of the data traffic and can reproduce the traffic burstiness observed from measurements. Second is scalability. The trade-off between accuracy and scalability is a constant theme in background traffic modeling. This work presents a fast rate-based TCP (RTCP) traffic model, which originally used analytical models to represent TCP congestion control behavior. This model outperforms other existing traffic models in that it can correctly capture the overall TCP behavior and achieve a speedup of more than two orders of magnitude over the corresponding packet-oriented simulation. Third is network-wide traffic generation. Regardless of how detailed or scalable the models are, they mainly focus on how to generate traffic on one single link, which cannot be extended easily to studies of more complicated network scenarios. This work presents a cluster-based spatio-temporal background traffic generation model that considers spatial and temporal traffic characteristics as well as their correlations. The resulting model can be used effectively for the evaluation work in network studies.

Zinc regeneration in rechargeable zinc-air fuel cells:a review

Zinc-air fuel cells (ZAFCs) present a promising energy source with a competing potential with the lithium-ion battery and even with proton-exchange membrane fuel cells (PEMFCs) for applications in next generation electrified transport and energy storage. The regeneration of zinc is essential for developing the next-generation, i.e., electrochemically rechargeable ZAFCs. This review aims to provide a comprehensive view on both theoretical and industrial platforms already built hitherto, with focus on electrode materials, electrode and electrolyte additives, solution chemistry, zinc deposition reaction mechanisms and kinetics, and electrochemical zinc regeneration systems. The related technological challenges and their possible solutions are described and discussed. A summary of important R&D patents published within the recent 10 years is also presented.

Nanostructured Metal Oxide Coatings for Electrochemical Energy Conversion and Storage Electrodes

The realization of an energy future based on safe, clean, sustainable, and economically viable technologies is one of the grand challenges facing modern society. Electrochemical energy technologies underpin the potential success of this effort to divert energy sources away from fossil fuels, whether one considers alternative energy conversion strategies through photoelectrochemical (PEC) production of chemical fuels or fuel cells run with sustainable hydrogen, or energy storage strategies, such as in batteries and supercapacitors. This dissertation builds on recent advances in nanomaterials design, synthesis, and characterization to develop novel electrodes that can electrochemically convert and store energy.

Chapter 2 of this dissertation focuses on refining the properties of TiO2-based PEC water-splitting photoanodes used for the direct electrochemical conversion of solar energy into hydrogen fuel. The approach utilized atomic layer deposition (ALD); a growth process uniquely suited for the conformal and uniform deposition of thin films with angstrom-level thickness precision. ALD’s thickness control enabled a better understanding of how the effects of nitrogen doping via NH3 annealing treatments, used to reduce TiO2’s bandgap, can have a strong dependence on TiO2’s thickness and crystalline quality. In addition, it was found that some of the negative effects on the PEC performance typically associated with N-doped TiO2 could be mitigated if the NH3-annealing was directly preceded by an air-annealing step, especially for ultrathin (i.e., < 10 nm) TiO2 films. ALD was also used to conformally coat an ultraporous conductive fluorine-doped tin oxide nanoparticle (nanoFTO) scaffold with an ultrathin layer of TiO2. The integration of these ultrathin films and the oxide nanoparticles resulted in a heteronanostructure design with excellent PEC water oxidation photocurrents (0.7 mA/cm2 at 0 V vs. Ag/AgCl) and charge transfer efficiency.

In Chapter 3, two innovative nanoarchitectures were engineered in order to enhance the pseudocapacitive energy storage of next generation supercapacitor electrodes. The morphology and quantity of MnO2 electrodeposits was controlled by adjusting the density of graphene foliates on a novel graphenated carbon nanotube (g-CNT) scaffold. This control enabled the nanocomposite supercapacitor electrode to reach a capacitance of 640 F/g, under MnO2 specific mass loading conditions (2.3 mg/cm2) that are higher than previously reported. In the second engineered nanoarchitecture, the electrochemical energy storage properties of a transparent electrode based on a network of solution-processed Cu/Ni cores/shell nanowires (NWs) were activated by electrochemically converting the Ni metal shell into Ni(OH)2. Furthermore, an adjustment of the molar percentage of Ni plated onto the Cu NWs was found to result in a tradeoff between capacitance, transmittance, and stability of the resulting nickel hydroxide-based electrode. The nominal area capacitance and power performance results obtained for this Cu/Ni(OH)2 transparent electrode demonstrates that it has significant potential as a hybrid supercapacitor electrode for integration into cutting edge flexible and transparent electronic devices.

Selective Preparation of Semiconducting Single-Walled Carbon Nanotubes: From Fundamentals to Applications

Aligned single-walled carbon nanotubes (SWNTs) synthesized by the chemical vapor deposition (CVD) method have exceptional potential for next-generation nanoelectronics. However, there are considerable challenges in the preparation of semiconducting (s-) SWNTs with controlled properties (e.g., density, selectivity, and diameter) for their application in solving real-world problems. This dissertation describes research that aims to overcome the limitations by novel synthesis strategies and post-growth treatment. The application of as-prepared SWNTs as functional devices is also demonstrated. The dissertation includes the following parts: 1) decoupling the conflict between density and selectivity of s-SWNTs in CVD growth; 2) investigating the importance of diameter control for the selective synthesis of s-SWNTs; 3) synthesizing highly conductive SWNT thin film by thiophene-assisted CVD method; 4) eliminating metallic pathways in SWNT crossbars by gate-free electrical breakdown method; 5) enhancing the density of SWNT arrays by strain-release method; 6) studying the sensing mechanism of SWNT crossbar chemical sensors.

Other Than a Citizen: Vernacular Poetics in Postwar America

Few symbols of 1950s-1960s America remain as central to our contemporary conception of Cold War culture as the iconic ranch-style suburban home. While the house took center stage in the Nixon/Khrushchev kitchen debates as a symbol of modern efficiency and capitalist values, its popularity depended largely upon its obvious appropriation of vernacular architecture from the 19th century, those California haciendas and Texas dogtrots that dotted the American west. Contractors like William Levitt modernized the historical common houses, hermetically sealing their porous construction, all while using the ranch-style roots of the dwelling to galvanize a myth of an indigenous American culture. At a moment of intense occupational bureaucracy, political uncertainty and atomized social life, the rancher gave a self-identifying white consumer base reason to believe they could master their own plot in the expansive frontier. Only one example of America’s mid-century love affair with commodified vernacular forms, the ranch-style home represents a broad effort on the part of corporate and governmental interest groups to transform the vernacular into a style that expresses a distinctly homogenous vision of American culture. “Other than a Citizen” begins with an anatomy of that transformation, and then turns to the work of four poets who sought to reclaim the vernacular from that process of standardization and use it to countermand the containment-era strategies of Cold War America.

In four chapters, I trace references to common speech and verbal expressivity in the poetry and poetic theory of Charles Olson, Robert Duncan, LeRoi Jones/Amiri Baraka and Gwendolyn Brooks, against the historical backdrop of the Free-Speech Movement and the rise of mass-culture. When poets frame nonliterary speech within the literary page, they encounter the inability of writing to capture the vital ephemerality of verbal expression. Rather than treat this limitation as an impediment, the writers in my study use the poem to dramatize the fugitivity of speech, emphasizing it as a disruptive counterpoint to the technologies of capture. Where critics such as Houston Baker interpret the vernacular strictly in terms of resistance, I take a cue from the poets and argue that the vernacular, rooted etymologically at the intersection of domestic security and enslaved margin, represents a gestalt form, capable at once of establishing centralized power and sparking minor protest. My argument also expands upon Michael North’s exploration of the influence of minstrelsy and regionalism on the development of modernist literary technique in The Dialect of Modernism. As he focuses on writers from the early 20th century, I account for the next generation, whose America was not a culturally inferior collection of immigrants but an imperial power, replete with economic, political and artistic dominance. Instead of settling for an essentially American idiom, the poets in my study saw in the vernacular not phonetic misspellings, slang terminology and fragmented syntax, but the potential to provoke and thereby frame a more ethical mode of social life, straining against the regimentation of citizenship.

My attention to the vernacular argues for an alignment among writers who have been segregated by the assumption that race and aesthetics are mutually exclusive categories. In reading these writers alongside one another, “Other than a Citizen” shows how the avant-garde concepts of projective poetics and composition by field develop out of an interest in black expressivity. Conversely, I trace black radicalism and its emphasis on sociality back to the communalism practiced at the experimental arts college in Black Mountain, North Carolina, where Olson and Duncan taught. In pressing for this connection, my work reveals the racial politics embedded within the speech-based aesthetics of the postwar era, while foregrounding the aesthetic dimension of militant protest.

Not unlike today, the popular rhetoric of the Cold War insists that to be a citizen involves defending one’s status as a rightful member of an exclusionary nation. To be other than a citizen, as the poets in my study make clear, begins with eschewing the false certainty that accompanies categorical nominalization. In promoting a model of mutually dependent participation, these poets lay the groundwork for an alternative model of civic belonging, where volition and reciprocity replace compliance and self-sufficiency. In reading their lines, we become all the more aware of the cracks that run the length of our load-bearing walls.

Semantic markup in discussion fora

Discussion tools in existing LEs have few or no integrated tools to analyse student learning. This paper proposes tools not only for integrating social network analytics, but also why we need to semantically tag and track key concepts within posts in order to make student learning in discussions visible. This paper will argue for the importance of semantic markup in discussion tools using screenshots of existing LEs and UI mockups of semantically aware discussion tools to argue the case for this element of next generation LEs