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Future Design (future + design)
Selected AbstractsTemplated assembly of the pH-sensitive membrane-lytic peptide GALACHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2004D.H. Haas Abstract:, Delivery of protein or nucleic acid therapeutics into intracellular compartments may require facilitation to allow these macromolecules to cross otherwise impermeant cellular membranes. Peptides capable of forming membrane-spanning channels hold promise as just such facilitators, although the requirement for peptide oligomerization to form these channels may limit their effectiveness. Synthetic molecules containing multiple copies of membrane-active peptides attached to a template molecule in a pre-oligomerized form have attracted interest for drug-delivery applications. Using three template designs, we synthesized multimeric versions of the pH-sensitive lytic peptide GALA and compared their performance to monomeric GALA. Template assembly stabilized helix formation: templated GALA retained , -helical structure even at neutral pH, unlike monomeric GALA. In membrane leakage assays, templated GALA retained the pH sensitivity of the monomer, with improved leakage for dimeric GALA. Surprisingly, trimeric GALA was less effective, particularly when synthesized with a larger and more flexible spacer. Surface plasmon resonance analysis indicated that reversible binding of templated GALA to lipid surfaces at acidic conditions was greatly reduced compared with monomeric GALA, but that the amount of irreversibly bound material was similar. We interpreted these results to indicate that templated peptides may cyclize into ,self-satisfied' oligomeric structures, incapable of further aggregation and subsequent pore formation. Future design of templated peptides must be carefully performed to avoid this unwanted consequence. [source] How many cisplatin administration protocols does your department use?EUROPEAN JOURNAL OF CANCER CARE, Issue 1 2010A.P. GREYSTOKE bsc, mbchb, registrar medical oncology GREYSTOKE A.P., JODRELL D.I., CHEUNG M., RIVANS I. & MACKEAN M.J. (2009) European Journal of Cancer Care19, 80,90 How many cisplatin administration protocols does your department use? The introduction, 30 years ago, of the co-administration of appropriate hydration and ensuring a diuresis occurs during the administration of cisplatin was important in its development, allowing clinically significant doses to be given with acceptable rates of toxicity. The clinical usage of cisplatin has increased and hydration protocols have been amended to increase patient comfort and reduce resource utilization. We suspected that this had led to unnecessary variations in practice both in clinical trials and subsequently in the clinic. Therefore, we reviewed practice in the Edinburgh Cancer Centre and discovered that 25 different hydration protocols were in use, with wide variation in dilution of cisplatin, total fluid administered, use of electrolyte (potassium and magnesium) supplementation and diuretics. These differences are a reflection of adoption of variations in hydration regimes published in pivotal clinical trials. A review of the available evidence relating to cisplatin associated hydration regimens was performed and recommendations will be made for the future design of evidence-based protocols. [source] Reproducible pattern of microRNA in normal human skinEXPERIMENTAL DERMATOLOGY, Issue 8 2010Line Marie Holst Please cite this paper as: Reproducible pattern of microRNA in normal human skin. Experimental Dermatology 2010; 19: e201,e205. Abstract:, MicroRNAs (miRNAs) regulate cell growth, differentiation and apoptosis via specific targeting of messenger RNA (mRNA). Aberrant mRNA expression contributes to pathological processes such as carcinogenesis. To take advantage of miRNA profiling in skin disease it is essential to investigate miRNA expression pattern in normal human skin. Here we investigated miRNA expression profiles from skin biopsies of 8 healthy volunteers taken from sun protected and mildly photo damaged skin using the modified protocol for miRNA extraction. We were able to show a constant pattern of miRNA expression between different individuals. We did not find any significant differences in miRNA expression between sun protected and mildly photodamaged skin. These results may be valuable for future design of studies on miRNA expression in skin disease. [source] Heterologous expression of a Clostridium minicellulosome in Saccharomyces cerevisiaeFEMS YEAST RESEARCH, Issue 8 2009Mariska Lilly Abstract The yeast Saccharomyces cerevisiae was genetically modified to assemble a minicellulosome on its cell surface by heterologous expression of a chimeric scaffoldin protein from Clostridium cellulolyticum under the regulation of the phosphoglycerate kinase 1 (PGK1) promoter and terminator regulatory elements, together with the ,-xylanase 2 secretion signal of Trichoderma reesei and cell wall protein 2 (Cwp2) of S. cerevisiae. Fluorescent microscopy and Far Western blot analysis confirmed that the Scaf3p is targeted to the yeast cell surface and that the Clostridium thermocellum cohesin domain is functional in yeast. Similarly, functionality of the C. thermocellum dockerin domain in yeast is shown by binding to the Scaf3 protein in Far Western blot analysis. Phenotypic evidence for cohesin,dockerin interaction was also established with the detection of a twofold increase in tethered endoglucanase enzyme activity in S. cerevisiae cells expressing the Scaf3 protein compared with the parent strain. This study highlights the feasibility to future design of enhanced cellulolytic strains of S. cerevisiae through emulation of the cellulosome concept. Potentially, Scaf3p-armed yeast could also be developed into an alternative cell surface display strategy with various tailor-made applications. [source] Ultrafast Hole-Transfer Dynamics in Polymer/PCBM Bulk HeterojunctionsADVANCED FUNCTIONAL MATERIALS, Issue 10 2010Artem A. Bakulin Abstract Ultrafast dynamics of the hole-transfer process from methanofullerene to a polymer in a polymer/PCBM bulk heterojunction are directly resolved. Injection of holes into MDMO-PPV is markedly delayed with respect to [60]PCBM excitation. The fastest component of the delayed response is attributed to the PCBM,polymer hole-transfer process (30,±,10,fs), while the slower component (,150,fs) is provisionally assigned to energy transfer and/or relaxation inside PCBM nanoclusters. The charge generation through the hole transfer is therefore as fast and efficient as through the electron-transfer process. Exciton harvesting efficiency after PCBM excitation crucially depends on the concentration of the methanofullerene in the blend, which is related to changes in the blend morphology. Ultrafast charge generation is most efficient when the characteristic scale of phase separation in the blend does not exceed ,20,nm. At larger-scale phase separation, the exciton harvesting dramatically declines. The obtained results on the time scales of the ultrafast charge generation after PCBM excitation and their dependence on blend composition and morphology are instrumental for the future design of fullerene-derivative-based photovoltaic devices. [source] A CdSe Nanowire/Quantum Dot Hybrid Architecture for Improving Solar Cell PerformanceADVANCED FUNCTIONAL MATERIALS, Issue 9 2010Yanghai Yu Abstract Incorporating colloidal CdSe quantum dots (QDs) into CdSe nanowire (NW)-based photoelectrochemical solar cells increases their incident-photon-to-carrier conversion efficiencies (IPCE) from 13% to 25% at 500,nm. While the effect could, in principle, stem from direct absorption and subsequent carrier generation by QDs, the overall IPCE increase occurs across the entire visible spectrum, even at wavelengths where the dots do not absorb light. This beneficial effect originates from an interplay between NWs and QDs where the latter fill voids between interconnected NWs, providing electrically accessible conduits, in turn, enabling better carrier transport to electrodes. The presence of QDs furthermore reduces the residual polarization anisotropy of random NW networks. Introducing QDs therefore addresses an important limiting constraint of NW photoelectrochemical solar cells. The effect appears to be general and may aid the future design and implementation of other NW-based photovoltaics. [source] Hybrid Microstructures: One-Dimensional Microwires Formed by the Co-Assembly of Complementary Aromatic Donors and Acceptors (Adv. Funct.ADVANCED FUNCTIONAL MATERIALS, Issue 11 2009Mater. A complementary donor-acceptor pair of truxene derivatives, Tr3 and its oxidized counterpart TrO3, are presented by Pei et al. on page 1746, and used to build a foundation for the investigation of aromatic donor,acceptor interaction. Two-component one-dimensional microstructures are realized by a simple solution process reliant on this interaction. Such a hybrid material opens new possibilities in the future design of multicomponent organic nano- and microstructures. [source] Subtype selective kainic acid receptor agonists: Discovery and approaches to rational designMEDICINAL RESEARCH REVIEWS, Issue 1 2009Lennart Bunch Abstract (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (mGluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all,to our knowledge,published KA receptor agonists. In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 1, 3,28, 2009 [source] Molecular rectification in metal,bridge molecule,metal junctionsPHYSICA STATUS SOLIDI (A) APPLICATIONS AND MATERIALS SCIENCE, Issue 4 2010Yaqing Liu Abstract Molecular bridged nanocontacts allow direct electrical addressing of electroactive molecules, which is of interest for the development of molecular based electronic devices. In the present paper, the electroactive molecule 6-ferrocenyl-1-hexanethiol (Fc-HT) was integrated into metal,bridge,metal (MBM) junctions assembled in a scanning tunneling microscope (STM) setup. A diode-like behavior was observed from the current/bias (It/Vb) signal through Au (substrate)/Fc-HT/Au (tip) junction, which presented an asymmetric current response due to the resonant tunneling between metal electrode and ferrocenylthiol molecules. With gate electrode modulation, the enhancement of the tunneling current can be controlled, which allows to tune the direction of the current rectification. Our investigations demonstrated that ferrocenylthiol bridged MBM nanostructure has potential applications in the future design of higher-order heterojunctions components in combination with electrochemical logic gates. [source] Triad of polar residues implicated in pH specificity of acidic mammalian chitinasePROTEIN SCIENCE, Issue 3 2009Andrea M. Olland Abstract Acidic mammalian chitinase (AMCase) is a mammalian chitinase that has been implicated in allergic asthma. One of only two active mammalian chinases, AMCase, is distinguished from other chitinases by several unique features. Here, we present the novel structure of the AMCase catalytic domain, both in the apo form and in complex with the inhibitor methylallosamidin, determined to high resolution by X-ray crystallography. These results provide a structural basis for understanding some of the unique characteristics of this enzyme, including the low pH optimum and the preference for the ,-anomer of the substrate. A triad of polar residues in the second-shell is found to modulate the highly conserved chitinase active site. As a novel target for asthma therapy, structural details of AMCase activity will help guide the future design of specific and potent AMCase inhibitors. [source] Comparative proteomics profile of osteoblasts cultured on dissimilar hydroxyapatite biomaterials: An iTRAQ-coupled 2-D LC-MS/MS analysisPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 20 2008Jinling Xu Dr. Abstract Hydroxyapatite (HA) and its derived bioceramic materials have been widely used for skeletal implants and/or bone repair scaffolds. It has been reported that carbon nanotube (CNT) is able to enhance the brittle ceramic matrix without detrimental to the bioactivity. However, interaction between osteoblasts and these bioceramics, as well as the underlying mechanism of osteoblast proliferation on these bioceramic surfaces remain to be determined. Using iTRAQ-coupled 2-D LC-MS/MS analysis, we report the first comparative proteomics profiling of human osteoblast cells cultured on plane HA and CNT reinforced HA, respectively. Cytoskeletal proteins, metabolic enzymes, signaling, and cell growth proteins previous associated with cell adhesion and proliferation were found to be differentially expressed on these two surfaces. The level of these proteins was generally higher in cells adhered to HA surface, indicating a higher level of cellular proliferation in these cells. The significance of these findings was further assessed by Western blot analysis. The differential protein profile in HA and CNT strengthened HA established in our study should be valuable for future design of biocompatible ceramics. [source] Exploring the Appeal of Product Design: A Grounded, Value-Based Model of Key Design Elements and Relationships,THE JOURNAL OF PRODUCT INNOVATION MANAGEMENT, Issue 5 2010Charles H. Noble Product design is increasingly being recognized as an important source of sustainable competitive advantage. Until recently, the domain of design has been loosely categorized as "form and function" issues. However, as this paper will explore, product design deals with a much richer range of issues, many of which have not been considered in the marketing literature. To explore the domain and elements of design, the paper begins with two major goals: (1) to elicit the key dimensions of design and to develop an enriched language for the understanding and study of design; and (2) to integrate the design dimensions within a broader model that ties initial design goals to eventual psychological and behavioral responses from consumers. To achieve these ends, grounded theory development is used by conducting an extensive literature review, in-depth interviews, and an interactive object elicitation technique. Drawing from this rich source of qualitative information as well as diverse literature fields, a framework is proposed for the creation of design value in consumer products. This framework not only explores the domain of design but also highlights the important elements of design that go well beyond the clichéd form and function issues. The resulting model reflects specific marketplace and organizational constraints that may help or impede the conversion of designer goals to so-called design levers. These levers are used to convey three types of values to consumers: rational, kinesthetic, and emotional. The framework then explains how and when these different values may be perceived by the consumer. Within this framework, testable research propositions and specific directions for future design-based research are also offered. Beyond its potential to spur marketing and new product development (NPD) management thought, the framework offered here represents a significant contribution to the field of design, which has historically been represented as a highly fragmented body of knowledge. Formalizing this framework should help overcome perhaps the largest obstacle to date to marketing-related and NPD-related research in this area,the lack of a detailed and consistent nomological view of the scope of design dimensions including testable linkages. Design has become an important tool that can be used by managers to develop dominant brands with lasting advantages. This research lends the NPD manager and the marketing manager better insights in into how this increasingly popular focus can be used to influence consumer behavior and firm success. "Design may be our top unexploited competitive edge." Tom Peters, 2004 (cover review of Norman, 2004) "We don't have a good language to talk about [design]. In most people's vocabularies, design means veneer., But to me, nothing could be further from the meaning of design. Design is the fundamental soul of a man-made creation." Steve Jobs, Apple Computers [source] Antimetabolite incorporation into DNA: Structural and thermodynamic basis for anticancer activityBIOPOLYMERS, Issue 3 2002William H. Gmeiner Abstract Antimetabolites are a class of effective anticancer drugs that structurally resemble naturally occurring biochemicals and interfere in essential biochemical processes. In this review, the recent literature describing investigations of the structural and thermodynamic basis for the anticancer activity of three antipyrimidines [1-,- D -arabinofuranosyl cytidine (AraC). 2,,2,-difluoro deoxycytidine (dFdC), and 5-fluoro-2,-deoxyuridine (FdUrd)] is summarized. Our laboratory, and others, have shown that misincorporation of any of these three antipyrimidines into DNA perturbs the structure and decreases the stability of duplex DNA. These data are useful for rationalizing the effects of antipyrimidine misincorporation on the activities of proteins required for DNA replication and repair such as DNA topoisomerase 1 and DNA polymerases. The studies completed to date and summarized in this review demonstrate the utility of investigations into the structure,function relationships between antipyrimidine-substituted DNA complexed with DNA-modifying proteins for the purpose of understanding the basis for effective antipyrimidine cancer chemotherapy and the future design of novel anticancer drugs. © 2002 Wiley Periodicals, Inc. Biopolymers (Nucleic Acid Sci) 65: 180,189, 2002 [source] Conversing with pedagogical agents: A phenomenological exploration of interacting with digital entitiesBRITISH JOURNAL OF EDUCATIONAL TECHNOLOGY, Issue 6 2008George Veletsianos In this paper, we examine the meaning of conversing with pedagogical agents. Previous research has focused on examining cause and effect relationships, failing to take into account the meaning of the experiences individuals have when holding a dialogue with conversational agents for educational purposes. To understand these experiences, we have conducted a phenomenological examination of what it means to converse with a pedagogical agent. In phenomenological terms, findings suggest the experience is complex, engrossing, virtual yet real, human-like, and social. Implications for the future design, implementation, and research of conversational agents in educational and other settings are discussed. [source] Consistent Bioactive Conformation of the Neu5Ac,(2,3)Gal Epitope Upon Lectin BindingCHEMBIOCHEM, Issue 18 2008Anirban Bhunia Dr. Get to NOE MAG: Partial structures of GQ1b,, the natural ligand of the myelin-associated glycoprotein (MAG), have been synthesized and subjected to NOE experiments to determine their bioactive conformations. The experiments show that the flexible ,(2,3)-glycosidic linkage between N -acetylneuraminic acid and galactose present in all ligands adopts a "sialyl Lewisx -type" binding mode. This information is valuable for the future design of conformationally preorganized MAG inhibitors. [source] Cooperative 2:1 Binding of a Bisphenothiazine to Duplex DNACHEMBIOCHEM, Issue 6 2008Frédéric Rosu Dr. DNA,drug dimers: Drugs based on the phenothiazine scaffold have a wide variety of therapeutic applications and are also used as DNA photosensitizers. Highly cooperative formation of a 2:1 complex was revealed by electrospray mass spectrometry experiments, and a structural model is proposed. This bisphenothiazine scaffold can therefore be exploited for future design of new minor groove binding agents having photosensitizing properties. [source] Combined in Silico and Experimental Approach for Drug Design: The Binding Mode of Peptidic and Non-Peptidic Inhibitors to Hsp90 N-Terminal DomainCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2010Simona Tomaselli Heat shock protein 90 (Hsp90) is a prime target for antitumor therapies. The information obtained by molecular dynamics (MD) simulations is combined with NMR data to provide a cross-validated atomic resolution model of the complementary interactions of heat shock protein 90 with a peptidic (shepherdin) and a non-peptidic (5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside, AICAR) inhibitor, showing antiproliferative and proapoptotic activity in multiple tumor cell lines. This approach highlights the relevant role of imidazolic moiety in the interaction of both antagonist molecules. In 5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside bound state, one conformation of those present in solution is selected, where imidazolic, H4 and H5 protons have a key role in defining a non-polar region contacting heat shock protein 90 surface. The dynamic equilibrium between N-type and S-type puckered forms of 5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside moiety is shown to be functional to inhibitor binding. The first experimental structural data on these inhibitors are presented and discussed as hints for future design of improved molecules. [source] Age dependence of cataract induced by ultraviolet radiation-B in miceACTA OPHTHALMOLOGICA, Issue 2007Y ZHANG Purpose: To investigate for the C57BL/6 mouse if there is an age dependence of the dose-response function for in vivo UVR-300 nm induced forward light scattering in the lens. Methods: Each of four age groups of 25 mice aged 3, 6, 12, or 24 weeks were randomly distributed on five age group specific UVR-B dose levels. The dose levels selected for each age group were derived from the expected maximum tolerable dose (MTD). Expected MTDs were set to 1.9, 3.2, 4.8, and 6.0 kJ/m^2 for the 3, 12, and 24 weeks mice, respectively, based on published data for the albino Sprague Dawley rat. Each animal was unilaterally exposed to UVR-B to the pre-determined dose, delivered during 15 minutes. All mice were sacrificed two days after exposure and both lenses were extracted for; macroscopic imaging in incident illumination against a grid and in dark-field illumination, and measurement of intensity of forward light scattering. The difference of intensity of forward light scattering between the exposed and the contralateral not exposed lens was fitted against dose received using regression based on a second order polynomial model. Results: Two days after exposure, subcapsular opacities were observed in the exposed lenses from all dose groups except at 0 kJ/m^2. In all age groups, the difference of intensity of forward light scattering increased with increasing UVR-B dose. The increase was age dependent. Conclusions: In the pigmented C57BL/6 mouse, an increasing in vivo dose of UVR-300 nm induces an increasing intensity of forward light scattering that is age dependent in the age interval 3-24 weeks. This finding should be considered in future design of experiments on UVR-effects to the mouse lens. [source] Identification, SAR Studies, and X-ray Co-crystallographic Analysis of a Novel Furanopyrimidine Aurora Kinase,A InhibitorCHEMMEDCHEM, Issue 2 2010Mohane Selvaraj Coumar Dr. Abstract Herein we reveal a simple method for the identification of novel Aurora kinase,A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in-house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC50 values ranging from ,300,nM to ,15,,M, by testing only 133 compounds from a database of ,125,000 compounds. Structure,activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC50 value of 309,nM toward Aurora kinase,A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors. [source] A TEST AND REVIEW OF THE ROLE OF EFFECTIVE POPULATION SIZE ON EXPERIMENTAL SEXUAL SELECTION PATTERNSEVOLUTION, Issue 7 2009Rhonda R. Snook Experimental evolution, particularly experimental sexual selection in which sexual selection strength is manipulated by altering the mating system, is an increasingly popular method for testing evolutionary theory. Concerns have arisen regarding genetic diversity variation across experimental treatments: differences in the number and sex ratio of breeders (effective population size; Ne) and the potential for genetic hitchhiking, both of which may cause different levels of genetic variation between treatments. Such differences may affect the selection response and confound interpretation of results. Here we use both census-based estimators and molecular marker-based estimates to empirically test how experimental evolution of sexual selection in Drosophila pseudoobscura impacts Ne and autosomal genetic diversity. We also consider effects of treatment on X-linked Nes, which have previously been ignored. Molecular autosomal marker-based estimators indicate that neither Ne nor genetic diversity differs between treatments experiencing different sexual selection intensities; thus observed evolutionary responses reflect selection rather than any confounding effects of experimental design. Given the increasing number of studies on experimental sexual selection, we also review the census Nes of other experimental systems, calculate X-linked Ne, and compare how different studies have dealt with the issues of inbreeding, genetic drift, and genetic hitchhiking to help inform future designs. [source] | |||||||||||||||||||||||||