Improving the selectivity of engineered protease inhibitors: Optimizing the P2 prime residue using a versatile cyclic peptide library

Standard mechanism inhibitors are attractive design templates for engineering reversible serine protease inhibitors. When optimizing interactions between the inhibitor and target protease, many studies focus on the nonprimed segment of the inhibitor's binding loop (encompassing the contact β-strand). However, there are currently few methods for screening residues on the primed segment. Here, we designed a synthetic inhibitor library (based on sunflower trypsin inhibitor-1) for characterizing the P2′ specificity of various serine proteases. Screening the library against 13 different proteases revealed unique P2′ preferences for trypsin, chymotrypsin, matriptase, plasmin, thrombin, four kallikrein-related peptidases, and several clotting factors. Using this information to modify existing engineered inhibitors yielded new variants that showed considerably improved selectivity, reaching up to 7000-fold selectivity over certain off-target proteases. Our study demonstrates the importance of the P2′ residue in standard mechanism inhibition and unveils a new approach for screening P2′ substitutions that will benefit future inhibitor engineering studies.

Book Review: "The Interface: IBM and the Transformation of Corporate Design, 1945-1975", John Harwood, Minneapolis: University of Minnesota Press, 2011

Within the history of twentieth-century design, there are a number of well-known objects and stories that are invoked time and time again to capture a pivotal moment or summarize a much broader historical transition. For example, Marcel Breuer’s Model B3 chair is frequently used as a stand-in for the radical investigations of form and new industrial materials occurring at the Bauhaus in the mid-1920s. Similarly, Raymond Loewy’s streamlined pencil sharpener has become historical shorthand for the emergence of modern industrial design in the 1930s. And any discussion of the development of American postwar “organic design” seems incomplete without reference to Charles and Ray Eames’s molded plywood leg splint of 1942. Such objects and narratives are dear to historians of modern design. They are tangible, photogenic subjects that slot nicely into exhibitions, historical surveys, and coffee-table best sellers...

Power Optimal Network-on-Chip Interconnect Design

A large part of today's multi-core chips is interconnect. Increasing communication complexity has made essential new strategies for interconnects, such as Network on Chip. Power dissipation in interconnects has become a substantial part of the total power dissipation. Techniques to reduce interconnect power have thus become a necessity. In this paper, we present a design methodology that gives values of bus width for interconnect links, frequency of operation for routers, in Network on Chip scenario that satisfy required throughput and dissipate minimal switching power. We develop closed form analytical expressions for the power dissipation, with bus width and frequency as variables and then use Lagrange multiplier method to arrive at the optimal values. We present a 4 port router in 90 nm technology library as case study. The results obtained from analysis are discussed.

High performance VLSI architecture design for H.264 CAVLC decoder

H.264 video standard achieves high quality video along with high data compression when compared to other existing video standards. H.264 uses context-based adaptive variable length coding (CAVLC) to code residual data in Baseline profile. In this paper we describe a novel architecture for CAVLC decoder including coeff-token decoder, level decoder total-zeros decoder and run-before decoder UMC library in 0.13 mu CMOS technology is used to synthesize the proposed design. The proposed design reduces chip area and improves critical path performance of CAVLC decoder in comparison with [1]. Macroblock level (including luma and chroma) pipeline processing for CAVLC is implemented with an average of 141 cycles (including pipeline buffering) per macroblock at 250MHz clock frequency. To compare our results with [1] clock frequency is constrained to 125MHz. The area required for the proposed architecture is 17586 gates, which is 22.1% improvement in comparison to [1]. We obtain a throughput of 1.73 * 10(6) macroblocks/second, which is 28% higher than that reported in [1]. The proposed design meets the processing requirement of 1080HD [5] video at 30frames/seconds.

Effective drug dosage design for treatment of infectious diseases using dynamic inversion

A generic nonlinear mathematical model describing the human immunological dynamics is used to design an effective automatic drug administration scheme. Even though the model describes the effects of various drugs on the dynamic system, this work is confined to the drugs that kill the invading pathogen and heal the affected organ. From a system theoretic point of view, the drug inputs can be interpreted as control inputs, which can be designed based on control theoretic concepts. The controller is designed based on the principle of dynamic inversion and is found to be effective in curing the �nominal model patient� by killing the invading microbes and healing the damaged organ. A major advantage of this technique is that it leads to a closed-form state feedback form of control. It is also proved from a rigorous mathematical analysis that the internal dynamics of the system remains stable when the proposed controller is applied. A robustness study is also carried out for testing the effectiveness of the drug administration scheme for parameter uncertainties. It is observed from simulation studies that the technique has adequate robustness for many �realistic model patients� having off-nominal parameter values as well.

Design of linear systems for decoupling and disturbance rejection

The question of achieving decoupling and asymptotic disturbance rejection in time-invariant linear multivariable systems subject to unmeasurable arbitrary disturbances of a given class is discussed. A synthesis procedure which determines a feedback structure, incorporating an integral compensator, is presented.

Mechanism design problems in carbon economics

Reduction of carbon emissions is of paramount importance in the context of global warming and climate change. Countries and global companies are now engaged in understanding systematic ways of solving carbon economics problems, aimed ultimately at achieving well defined emission targets. This paper proposes mechanism design as an approach to solving carbon economics problems. The paper first introduces carbon economics issues in the world today and next focuses on carbon economics problems facing global industries. The paper identifies four problems faced by global industries: carbon credit allocation (CCA), carbon credit buying (CCB), carbon credit selling (CCS), and carbon credit exchange (CCE). It is argued that these problems are best addressed as mechanism design problems. The discipline of mechanism design is founded on game theory and is concerned with settings where a social planner faces the problem of aggregating the announced preferences of multiple agents into a collective decision, when the actual preferences are not known publicly. The paper provides an overview of mechanism design and presents the challenges involved in designing mechanisms with desirable properties. To illustrate the application of mechanism design in carbon economics,the paper describes in detail one specific problem, the carbon credit allocation problem.

Dioxomolybdenum reagents in organic synthesis: utility of redox capability to design reduction and oxidation

The usefulness of dioxomolybdenum reagents in oxo-transfer reactions have been reviewed. The redox ability of dioxomolybdenum reagent has been utilized in designing several synthetic methods, which are useful in organic synthesis. Several reactions such as oxidation of alcohols, sulfides, amines, azides olefins etc are accomplished by using dioxomolybdenum reagents. Similarly, it is also demonstrated that dioxomolybdenum complex is useful in performing reduction of aldehydes, ketones, esters, azides etc. A fine tuning of reaction conditions provides suitable conditions to perform either oxidation or reduction by using catalytic amount of reagents. The oxidation reactions are further simplified by employing the polymer supported molybdenum reagents.

Simulation-driven design of helmets for head impact protection using an injury-based criterion

The current paper suggests a new procedure for designing helmets for head impact protection for users such as motorcycle riders. According to the approach followed here, a helmet is mounted on a featureless Hybrid 3 headform that is used in assessing vehicles for compliance to the FMVSS 201 regulation in the USA for upper interior head impact safety. The requirement adopted in the latter standard, i.e. not exceeding a threshold HIC(d) limit of 1000, is applied in the present study as a likely criterion for adjudging the efficacy of helmets. An impact velocity of 6 m/s (13.5 mph) for the helmet-headform system striking a rigid target can probably be acceptable for ascertaining a helmet's effectiveness as a countermeasure for minimizing the risk of severe head injury. The proposed procedure is demonstrated with the help of a validated LS-DYNA model of a featureless Hybrid 3 headform in conjunction with a helmet model comprising an outer polypropylene shell to the inner surface of which is bonded a protective polyurethane foam padding of a given thickness. Based on simulation results of impact on a rigid surface, it appears that a minimum foam padding thickness of 40 mm is necessary for obtaining an acceptable value of HIC(d).

Binding of Gemini Bisbenzimidazole Drugs with Human Telomeric G-Quadruplex Dimers: Effect of the Spacer in the Design of Potent Telomerase Inhibitors

The study of anticancer agents that act via stabilization of telomeric G-quadruplex DNA (G4DNA) is important because such agents often inhibit telomerase activity. Several types of G4DNA binding ligands are known. In these studies, the target structures often involve a single G4 DNA unit formed by short DNA telomeric sequences. However, the 3'-terminal single-stranded human telomeric DNA can form higher-order structures by clustering consecutive quadruplex units (dimers or nmers). Herein, we present new synthetic gemini (twin) bisbenzimidazole ligands, in which the oligo-oxyethylene spacers join the two bisbenzimidazole units for the recognition of both monomeric and dimeric G4DNA, derived from d(T2AG3)4 and d(T2AG3) 8 human telomeric DNA, respectively. The spacer between the two bisbenzimidazoles in the geminis plays a critical role in the G4DNA stability. We report here (i) synthesis of new effective gemini anticancer agents that are selectively more toxic towards the cancer cells than the corresponding normal cells; (ii) formation and characterization of G4DNA dimers in solution as well as computational construction of the dimeric G4DNA structures. The gemini ligands direct the folding of the single-stranded DNA into an unusually stable parallel-stranded G4DNA when it was formed in presence of the ligands in KCl solution and the gemini ligands show spacer length dependent potent telomerase inhibition properties.

Evaluating FuncSION: A software for automated synthesis of design solutions for stimulating ideation during mechanical conceptual design

The goal of the work reported in this paper is to use automated, combinatorial synthesis to generate alternative solutions to be used as stimuli by designers for ideation. FuncSION, a computational synthesis tool that can automatically synthesize solution concepts for mechanical devices by combining building blocks from a library, is used for this purpose. The objectives of FuncSION are to help generate a variety of functional requirements for a given problem and a variety of concepts to fulfill these functions. A distinctive feature of FuncSION is its focus on automated generation of spatial configurations, an aspect rarely addressed by other computational synthesis programs. This paper provides an overview of FuncSION in terms of representation of design problems, representation of building blocks, and rules with which building blocks are combined to generate concepts at three levels of abstraction: topological, spatial, and physical. The paper then provides a detailed account of evaluating FuncSION for its effectiveness in providing stimuli for enhanced ideation.

A Review of Theories and Models of Design

This paper intends to provide an overview of the rich legacy of models and theories that have emerged in the last fifty years of the relatively young discipline of design research, and identifies some of the major areas of further research. It addresses the following questions: What are the major theories and models of design? How are design theory and model defined, and what is their purpose? What are the criteria they must satisfy to be considered a design theory or model? How should a theory or model of design be evaluated or validated? What are the major directions for further research?

Pond construction: design and layout of ponds

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