An approach for sensitivity-reduced design of linear regulators

A now procedure for the design of sensitivity-reduced control for linear regulators is described. The control is easily computable and implementable since it requires neither the solution of an increased-order augmented system nor the generation and feedback of a trajectory sensitivity vector. The method provides a trade-off between reduction in sensitivity measure and increase in performance index.

Applying urban morphology theory to design practice

The aim of this paper is to investigate the relationship between research and design through an applied example of how architects can approach the design for a building guided by data derived from morphological research. An Expert Focus Group consisting of nine leading architects and urban designers from Brisbane, Australia was given the task of testing this proposition. Analysis of the workshop outcomes are examined, and the design drawings of each participant are assessed to determine the relative congruence of the design proposals within the morphological commodity of the specific context. In addition, qualitative data, captured through verbal and written feedback is assessed highlighting the participants' observations and experiences of the workshop. This paper makes a contribution to the current debate within the field on the opportunities of integrating research with practice.

Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis

Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organ ` isms. Our findings suggest that compound 10 ``locks'' DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.

Gabapentin: A Stereochemically Constrained gamma Amino Acid Residue in Hybrid Peptide Design

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino adds, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino adds with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino add residue that contains a cyclohexyl ring at the C-beta carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C-7 and C-9 hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alpha gamma sequences, district C-12 hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones.

Modeling of heat and mass transfer for solid state fermentation process in tray bioreactor

A mathematical model is developed to simulate oxygen consumption, heat generation and cell growth in solid state fermentation (SSF). The fungal growth on the solid substrate particles results in the increase of the cell film thickness around the particles. The model incorporates this increase in the biofilm size which leads to decrease in the porosity of the substrate bed and diffusivity of oxygen in the bed. The model also takes into account the effect of steric hindrance limitations in SSF. The growth of cells around single particle and resulting expansion of biofilm around the particle is analyzed for simplified zero and first order oxygen consumption kinetics. Under conditions of zero order kinetics, the model predicts upper limit on cell density. The model simulations for packed bed of solid particles in tray bioreactor show distinct limitations on growth due to simultaneous heat and mass transport phenomena accompanying solid state fermentation process. The extent of limitation due to heat and/or mass transport phenomena is analyzed during different stages of fermentation. It is expected that the model will lead to better understanding of the transport processes in SSF, and therefore, will assist in optimal design of bioreactors for SSF.

Bombs away: Visual thinking and students’ engagement in design studios contexts

In design studio, sketching or visual thinking is part of processes that assist students to achieve final design solutions. At QUT’s First and Third Year industrial design studio classes we engage in a variety of teaching pedagogies from which we identify ‘Concept Bombs’ as instrumental in the development of students’ visual thinking and reflective design process, and also as a vehicle to foster positive student engagement. In First year studios our Concept Bombs’ consist of 20 minute individual design tasks focusing on rapid development of initial concept designs and free-hand sketching. In Third Year studios we adopt a variety of formats and different timing, combining individual and team based tasks. Our experience and surveys tell us that students value intensive studio activities especially when combined with timely assessment and feedback. While conventional longer-duration design projects are essential for allowing students to engage with the full depth and complexity of the design process, short and intensive design activities introduce variety to the learning experience and enhance student engagement. This paper presents a comparative analysis of First and Third Year students’ Concept Bomb sketches to describe the types of design knowledge embedded in them, a discussion of limitations and opportunities of this pedagogical technique, as well as considerations for future development of studio based tasks of this kind as design pedagogies in the midst of current university education trends.

Design, Synthesis, and DNA Binding Properties of Photoisomerizable Azobenzene−Distamycin Conjugates: An Experimental and Computational Study

Here, we present the synthesis, photochemical, and DNA binding properties of three photoisomerizable azobenzene−distamycin conjugates in which two distamycin units were linked via electron-rich alkoxy or electron-withdrawing carboxamido moieties with the azobenzene core. Like parent distamycin A, these molecules also demonstrated AT-specific DNA binding. Duplex DNA binding abilities of these conjugates were found to depend upon the nature and length of the spacer, the location of protonatable residues, and the isomeric state of the conjugate. The changes in the duplex DNA binding efficiency of the individual conjugates in the dark and with their respective photoirradiated forms were examined by circular dichroism, thermal denaturation of DNA, and Hoechst displacement assay with poly[d(A-T).d(T-A)] DNA in 150 mM NaCl buffer. Computational structural analyses of the uncomplexed ligands using ab initio HF and MP2 theory and molecular docking studies involving the conjugates with duplex d[(GC(AT)10CG)]2 DNA were performed to rationalize the nature of binding of these conjugates.

Design of mechanism-based inhibitors of transthyretin amyloidosis:Studies with biphenyl ethers and new structural templates

Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (> 90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.

Design of a climate-responsive BIPV research facility in Bangalore

This paper describes the design and erection of a climate-responsive Building Integrated Photovoltaic (BIPV) structure in Bangalore, (12.58 N, 77.38 E) in the state of Karnataka, India. Building Integrated Photovoltaics integrate solar panels as part of a building structure (roofs and walls) with an aim to achieve self-sufficiency in the operation and occupant-comfort energy requirements. A joint collaboration between the Centre for Sustainable Technologies, Indian Institute of Science (IISc) and Bharat Heavy Electricals Limited (BHEL) is setting up a 70,000 US$ facility for research in BIPV structures. The structure utilizes low energy building materials like Stabilized Mud Blocks (SMB) integrated with a PV roof. Numerous challenges were overcome in the design of the BIPV roof including mechanisms for natural thermal comfort in response to Bangalore's climatic conditions. The paper presents the challenges overcome in the design and construction of a low energy, climate-responsive BIPV structure.

Process makes perfect: High-performance design creates healthy environments for high-performance learning

Considering the staggering benefits of high-performance schools, it seems an obvious choice to “go green.” High-performance schools offer an exceptionally cost-effective means to enhance student learning, using on average 33 percent less energy than conventionally designed schools, and provide substantial health gains, including reduced respiratory problems and absenteeism. According to the 2006 study, Greening America's Schools, Costs and Benefits, co-sponsored by the American Institute of Architects (AIA) and Capital E, a green building consulting firm, high-performance lighting is a key element of healthy learning environments, contributing to improved test scores, reduced off-task behavior, and higher achievement among students. Few argue this point more convincingly than architect Heinz Rudolf, of Portland-Oregon-based Boora Architects, who has designed sustainable schools for more than 80 school districts in Oregon, Washington, Colorado, and Wyoming, and has pioneered the high-performance school movement. Boora's recently completed project, the Baker Prairie Middle School in Canby, Oregon is one of the most sustainable K-12 facilities in the state, and illustrates Rudolf's progressive and research-intensive approach to school design.

Dynamics of free-running, pump-modulated and coupled semiconductor and solid-state lasers

The output of a laser is a high frequency propagating electromagnetic field with superior coherence and brightness compared to that emitted by thermal sources. A multitude of different types of lasers exist, which also translates into large differences in the properties of their output. Moreover, the characteristics of the electromagnetic field emitted by a laser can be influenced from the outside, e.g., by injecting an external optical field or by optical feedback. In the case of free-running solitary class-B lasers, such as semiconductor and Nd:YVO4 solid-state lasers, the phase space is two-dimensional, the dynamical variables being the population inversion and the amplitude of the electromagnetic field. The two-dimensional structure of the phase space means that no complex dynamics can be found. If a class-B laser is perturbed from its steady state, then the steady state is restored after a short transient. However, as discussed in part (i) of this Thesis, the static properties of class-B lasers, as well as their artificially or noise induced dynamics around the steady state, can be experimentally studied in order to gain insight on laser behaviour, and to determine model parameters that are not known ab initio. In this Thesis particular attention is given to the linewidth enhancement factor, which describes the coupling between the gain and the refractive index in the active material. A highly desirable attribute of an oscillator is stability, both in frequency and amplitude. Nowadays, however, instabilities in coupled lasers have become an active area of research motivated not only by the interesting complex nonlinear dynamics but also by potential applications. In part (ii) of this Thesis the complex dynamics of unidirectionally coupled, i.e., optically injected, class-B lasers is investigated. An injected optical field increases the dimensionality of the phase space to three by turning the phase of the electromagnetic field into an important variable. This has a radical effect on laser behaviour, since very complex dynamics, including chaos, can be found in a nonlinear system with three degrees of freedom. The output of the injected laser can be controlled in experiments by varying the injection rate and the frequency of the injected light. In this Thesis the dynamics of unidirectionally coupled semiconductor and Nd:YVO4 solid-state lasers is studied numerically and experimentally.

Privacy architectures in social networks’ state-of-the-art survey

The use of social networking has exploded, with millions of people using various web- and mobile-based services around the world. This increase in social networking use has led to user anxiety related to privacy and the unauthorised exposure of personal information. Large-scale sharing in virtual spaces means that researchers, designers and developers now need to re-consider the issues and challenges of maintaining privacy when using social networking services. This paper provides a comprehensive survey of the current state-of-the-art privacy in social networks for both desktop and mobile uses and devices from various architectural vantage points. The survey will assist researchers and analysts in academia and industry to move towards mitigating many of the privacy issues in social networks.

Performance of Quantized Equal Gain Transmission With Noisy Feedback Channels

In this paper, new results and insights are derived for the performance of multiple-input, single-output systems with beamforming at the transmitter, when the channel state information is quantized and sent to the transmitter over a noisy feedback channel. It is assumed that there exists a per-antenna power constraint at the transmitter, hence, the equal gain transmission (EGT) beamforming vector is quantized and sent from the receiver to the transmitter. The loss in received signal-to-noise ratio (SNR) relative to perfect beamforming is analytically characterized, and it is shown that at high rates, the overall distortion can be expressed as the sum of the quantization-induced distortion and the channel error-induced distortion, and that the asymptotic performance depends on the error-rate behavior of the noisy feedback channel as the number of codepoints gets large. The optimum density of codepoints (also known as the point density) that minimizes the overall distortion subject to a boundedness constraint is shown to be the same as the point density for a noiseless feedback channel, i.e., the uniform density. The binary symmetric channel with random index assignment is a special case of the analysis, and it is shown that as the number of quantized bits gets large the distortion approaches the same as that obtained with random beamforming. The accuracy of the theoretical expressions obtained are verified through Monte Carlo simulations.

Disulfide conformation and design at helix N-termini

To understand structural and thermodynamic features of disulfides within an alpha-helix, a non-redundant dataset comprising of 5025 polypeptide chains containing 2311 disulfides was examined. Thirty-five examples were found of intrahelical disulfides involving a CXXC motif between the N-Cap and third helical positions. GLY and PRO were the most common amino acids at positions 1 and 2, respectively. The N-Cap residue for disulfide bonded CXXC motifs had average values of (-112 +/- 25.2 degrees, 106 +/- 25.4 degrees). To further explore conformational requirements for intrahelical disulfides, CYS pairs were introduced at positions N-Cap-3; 1,4; 7,10 in two helices of an Escherichia coli thioredoxin mutant lacking its active site disulfide (nSS Trx). In both helices, disulfides formed spontaneously during purification only at positions N-Cap-3. Mutant stabilities were characterized by chemical denaturation studies (in both oxidized and reduced states) and differential scanning calorimetry (oxidized state only). All oxidized as well as reduced mutants were destabilized relative to nSS Trx. All mutants were redox active, but showed decreased activity relative to wild-type thioredoxin. Such engineered disulfides can be used to probe helix start sites in proteins of unknown structure and to introduce redox activity into proteins. Conversely, a protein with CYS residues at positions N-Cap and 3 of an alpha-helix is likely to have redox activity.

Design of mechanism-based inhibitors of transthyretin amyloidosis: Studies with biphenyl ethers and new structural templates

Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (> 90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.