Synthesis and Aggregation Behavior of Pluronic F87/Poly(acrylic acid) Block Copolymer with Doxorubicin

Poly(acrylic acid) (PAA) was grafted onto both termini of Pluronic F87 (PEO₆₇-PPO₃₉-PEO₆₇) via atom transfer radical polymerization to produce a novel muco-adhesive block copolymer PAA₈₀-b-F₈₇-b-PAA₈₀. It was observed that PAA₈₀-F₈₇-PAA₈₀ forms stable complexes with weakly basic anti-cancer drug, Doxorubicin. Thermodynamic changes due to the drug binding to the copolymer were assessed at different pH by isothermal titration calorimetry (ITC). The formation of the polymer/drug complexes was studied by turbidimetric titration and dynamic light scattering. Doxorubicin and PAA-b-F87-b-PAA block copolymer are found to interact strongly in aqueous solution via non-covalent interactions over a wide pH range. At pH>4.35, drug binding is due to electrostatic interactions. Hydrogen-bond also plays a role in the stabilization of the PAA₈₀-F₈₇-PAA₈₀/DOX complex. At pH 7.4 (α=0.8), the size and stability of polymer/drug complex depend strongly on the doxorubicin concentration. When CDOX <0.13mM, the PAA₈₀-F₈₇-PAA₈₀ copolymer forms stable inter-chain complexes with DOX (110 ~ 150 nm). When CDOX >0.13mM, as suggested by the light scattering result, the reorganization of the polymer/drug complex is believed to occur. With further addition of DOX (CDOX >0.34mM), sharp increase in the turbidity indicates the formation of large aggregates, followed by phase separation. The onset of a sharp enthalpy increase corresponds to the formation of a stoichiometric complex.

ADAM: A Decentralized Parallel Computer Architecture Featuring Fast Thread and Data Migration and a Uniform Hardware Abstraction

The furious pace of Moore's Law is driving computer architecture into a realm where the the speed of light is the dominant factor in system latencies. The number of clock cycles to span a chip are increasing, while the number of bits that can be accessed within a clock cycle is decreasing. Hence, it is becoming more difficult to hide latency. One alternative solution is to reduce latency by migrating threads and data, but the overhead of existing implementations has previously made migration an unserviceable solution so far. I present an architecture, implementation, and mechanisms that reduces the overhead of migration to the point where migration is a viable supplement to other latency hiding mechanisms, such as multithreading. The architecture is abstract, and presents programmers with a simple, uniform fine-grained multithreaded parallel programming model with implicit memory management. In other words, the spatial nature and implementation details (such as the number of processors) of a parallel machine are entirely hidden from the programmer. Compiler writers are encouraged to devise programming languages for the machine that guide a programmer to express their ideas in terms of objects, since objects exhibit an inherent physical locality of data and code. The machine implementation can then leverage this locality to automatically distribute data and threads across the physical machine by using a set of high performance migration mechanisms. An implementation of this architecture could migrate a null thread in 66 cycles -- over a factor of 1000 improvement over previous work. Performance also scales well; the time required to move a typical thread is only 4 to 5 times that of a null thread. Data migration performance is similar, and scales linearly with data block size. Since the performance of the migration mechanism is on par with that of an L2 cache, the implementation simulated in my work has no data caches and relies instead on multithreading and the migration mechanism to hide and reduce access latencies.

Self-Assembly of Stimuli-Responsive Water-Soluble [60]Fullerene End-Capped Ampholytic Block Copolymer

Well-defined, water-soluble, pH and temperature stimuli-responsive [60]fullerene (C₆₀) containing ampholytic block copolymer of poly((methacrylic acid)-block-(2-(dimethylamino)ethyl methacrylate))-block–C₆₀ (P(MAA-b-DMAEMA)-b-C₆₀) was synthesized by the atom transfer radical polymerization (ATRP) technique. The self-assembly behaviour of the C₆₀ containing polyampholyte in aqueous solution was characterized by dynamic light scattering (DLS), and transmission electron microscopy. This amphiphilic mono-C₆₀ end-capped block copolymer shows enhanced solubility in aqueous medium at room and elevated temperatures and at low and high pH but phase-separates at intermediate pH of between 5.4 and 8.8. The self assembly of the copolymer is different from that of P(MAA-b-DMAEMA). Examination of the association behavior using DLS revealed the co-existence of unimers and aggregates at low pH at all temperatures studied, with the association being driven by the balance of hydrophobic and electrostatic interactions. Unimers and aggregates of different microstructures are also observed at high pH and at temperatures below the lower critical solution temperature (LCST) of PDMAEMA. At high pH and at temperatures above the LCST of PDMAEMA, the formation of micelles and aggregates co-existing in solution is driven by the combination of hydrophobic, electrostatic, and charge-transfer interactions.

Applying the Lessons of “Lean Now” to Transform the US Aerospace Enterprise

Lean is common sense and good business sense. As organizations grow and become more successful, they begin to lose insight into the basic truths of what made them successful. Organizations have to deal with more and more issues that may not have anything to do with directly providing products or services to their customers. Lean is a holistic management approach that brings the focus of the organization back to providing value to the customer. In August 2002, Mrs. Darleen Druyun, the Principal Deputy to the Assistant Secretary of the Air Force for Acquisition and government co-chairperson of the Lean Aerospace Initiative (LAI), decided it was time for Air Force acquisitions to embrace the concepts of lean. At her request, the LAI Executive Board developed a concept and methodology to employ lean into the Air Force’s acquisition culture and processes. This was the birth of the “Lean Now” initiative. An enterprise-wide approach was used, involving Air Force System Program Offices (SPOs), aerospace industry, and several Department of Defense agencies. The aim of Lean Now was to focus on the process interfaces between these “enterprise” stakeholders to eliminate barriers that impede progress. Any best practices developed would be institutionalized throughout the Air Force and the Department of Defense (DoD). The industry members of LAI agreed to help accelerate the government-industry transformation by donating lean Subject Matter Experts (SMEs) to mentor, train, and facilitate the lean events of each enterprise. Currently, the industry SMEs and the Massachusetts Institute of Technology are working together to help the Air Force develop its own lean infrastructure of training courses and Air Force lean SMEs. The first Lean Now programs were the F/A-22, Global Hawk, and F-16. Each program focused on specific acquisition processes. The F/A-22 focused on the Test and Evaluation process; the Global Hawk focused on Evolutionary Acquisitions; and the F-16 focused on improving the Contract Closeout process. Through lean, each enterprise made many significant improvements. The F/A-22 was able to reduce its Operational Flight Plan (OFP) Preparation and Load process time of 2 to 3 months down to 7 hours. The Global Hawk developed a new production plan that increases the annual production of its Integrated Sensor Suite from 3 per year to 6 per year. The F-16 enterprise generated and is working 12 initiatives that could result in a contract closeout cycle time reduction of 3 to 7 years. Each enterprise continues to generate more lean initiatives that focus on other areas and processes within their respective enterprises.