Books by Subject
- pt. A-B, 2007. Springerpt. B, 2007 SpringerFrank A. Carey and Richard J. Sundberg.pt. A. Structure and mechanisms -- pt. B. Reactions and synthesis.
- 2007 CRCnetBASEJohn L. Holmes, Christiane Aubry, and Paul M. Mayer.
- 2013 SpringerJosef Flammer, Maneli Mozaffarieh, Hans Bebie.What Is Light? -- The Interaction Between Light and Matter -- Light Sources -- Examinations with Light -- Ultrasound Diagnostics -- Further Imaging Procedures -- Interventions with Laser Light -- Some History of Chemistry -- Oxygen -- Water -- Carbon Dioxide (CO2) -- Nitric Oxide -- Redox Reactions -- DNA -- RNA -- Proteins -- Lipids -- Matter: Using Water as an Example -- If You Are Interested in More ... -- Appendix: Units and Constants.
- 2012 Wileyedited by Nathan Brown.
- 2010 WileyAbraham, Donald J.; Burger, Alfred; Rotella, David P."... provides an established, recognized, authoritative and comprehensive source on medicinal chemistry and drug discovery and development. This flagship reference for medicinal chemists and pharmaceutical professions has been thoroughly updated and expanded across 8 volumes to incorporate the entire process of drug development (preclinical testing, clinical trials, etc.) alongside the traditional strengths in medicinal chemistry and drug discovery"--Provided by publisher.
- 2007 WileyKang Li.Chapter 1 Ceramic Membranes and Membrane Processes, p. 1-20 -- Chapter 2. Preparation of Ceramic Membranes, p. 21-57 -- Chapter 3. Characterization of Ceramic Membranes, p. 59-95 -- Chapter 4. Transport and Separation of Gases in Porous Ceramic Membranes, p. 97-134 -- Chapter 5. Ceramic Hollow Fibre Membrane Contactors for Treatment of Gases/Vapours, p. 135-168 -- Chapter 6 Mixed Conducting Ceramic Membranes for Oxygen Separation, p. 169-215 -- Chapter 7. Mixed Conducting Ceramic Membranes for Hydrogen Permeation, p. 217-243 -- Chapter 8. Ceramic Membrane Reactors, p. 245-298.
- 2005 SpringerG. Festel ... [et al.].
- 2013 CRCnetBASEAlan Rodgman and Thomas A. Perfetti.Ch. 1. Hydrocarbons -- ch. 2. Alcohols and phytosterols -- ch. 3. Aldehydes and ketones -- ch. 4. Carboxylic acids -- ch. 5. Esters -- ch. 6. Lactones -- ch. 7. Anhydrides -- ch. 8. Carbohydrates and their derivatives -- ch. 9. Phenols and quinones -- ch. 10. Ethers -- ch. 11. Nitriles -- ch. 12. Acyclic amines -- ch. 13. Amides -- ch. 14. Imides -- ch. 15. N-nitrosamines -- ch. 16. Nitroalkanes, nitroarenes, and nitrophenols -- ch. 17. Nitrogen heterocyclic components -- ch. 18. Miscellaneous components -- ch. 19. Fixed and variable gases -- ch. 20. Metallic and nonmetallic elements, isotopes, ions, and salts -- ch. 21. Pesticides and growth regulators -- ch. 22. Genes, nucleotides, and enzymes -- ch. 23. Hoffmann analytes -- ch. 24. Tobacco and/or tobacco smoke components used as tobacco ingredients -- ch. 25. Pyrolysis -- ch. 26. Carcinogens, tumorigens, and mutagens vs. anticarcinogens, inhibitors, and antimutagens -- ch. 27. Free radicals -- ch. 28. Summary.
- 2006 Ebrary2006 MyiLibraryedited by Marcel Dicke and Willem Takken.
- 2005 ScienceDirectedited by John T. Romeo.
- 2011 Springer Protocolsedited by Joe Zhongxiang Zhou.Historical overview of chemical library design / Roland E. Dolle -- Chemoinformatics and library design / Joe Zongxiang Zhou -- Molecular library design using multi-objective optimization methods / Christos A. Nicolaou and Christos C. Kannas -- A scalable approach to combinatorial library design / Puneet Sharma, Srinivasa Salapaka, and Carolyn Beck -- Application of Free-Wilson selectivity analysis for combinatorial library design / Simone Sciabola ... [et al.] -- Application of QSAR and shape pharmacophore modeling approaches for targeted chemical library design / Jerry O. Ebalunode, Weifan Zheng, and Alexander Tropsha -- Combinatorial library design from reagent pharmacophore fingerprints / Hongming Chen, Ola Engkvist, and Niklas Blomberg -- Docking methods for structure-based library design / Claudio N. Cavasotto and Sharangdhar S. Phatak -- Structure-based library design in efficient discovery of novel inhibitors / Shunqi Yan and Robert Selliah -- Structure-based and property-compliant library design of 11[beta]-HSD1 adamantyl amide inhibitors / Genevieve D. Paderes ... [et al.] -- Design of screening collections for successful fragment-based lead discovery / James Na and Qiyue Hu -- Fragment-based drug design / Eric Feyfant ... [et al.] -- LEAP into the Pfizer Global Virtual Library (PGVL) space : creation of readily synthesizable design ideas automatically / Qiyue Hu ... [et al.] -- The design, annotation, and application of a kinase-targeted library / Hualin Xi and Elizabeth A. Lunney -- PGVL hub : an integrated desktop tool for medicinal chemists to streamline design and synthesis of chemical libraries and singleton compounds / Zhengwei Peng ... [et al.] -- Design of targeted libraries against the human Chk1 kinase using PGVL hub / Xengwei Peng and Qiyue Hu -- GLARE : a tool for product-oriented design of combinatorial libraries / Jean-François Truchon -- CLEVER : a general design tool for combinatorial libraries / Tze Hau Lam ... [et al.].
- 2008 CRCnetBASEedited by James A. Romano, Jr., Brian J. Lukey, Harry Salem.Brief history and use of chemical warfare agents in warfare and terrorism / Harry Salem, Andrew L. Ternay, Jr., and Jeffery K. Smart -- The chemistry of chemical warfare agents / Peter Kikilo, Vitaly Fedorenko, and Andrew L. Ternay, Jr. -- Chemical warfare agent threat to drinking water / Harry Salem ... [et al.] -- Health effects of low-level exposure to nerve agents / John H. McDonough and James A. Romano, Jr. -- Toxicokinetics of nerve agents / Marcel J. van der Schans, Hendrik P. Benschop, and Christopher E. Whalley -- Application of genomic, proteomic, and metabolomic technologies to the development of countermeasures against chemical warfare agents / Jennifer Sekowski and James Dillman -- Novel approaches to medical protection against chemical warfare nerve agents / Ashima Saxena ... [et al.] -- Nerve agent bioscavengers : progress in development of a new mode of protection against organophosphorus exposure / David E. Lenz ... [et al.] -- Butyrylcholinesterase and its synthetic C-terminal peptide confer in-vitro suppression of amyloid fibrils formation / Erez Podoly ... [et al.] -- A novel medical countermeasure for organophosphorus intoxication : connection to Alzheimer's disease and dementia / Edna F. R. Pereira ... [et al.] -- Inhalation toxicology of nerve agents / Paul A. Dabisch ...[et al.] -- Vesicants and oxidative stress / Milton G. Smith ...[et al.] -- Health effects of exposure to vesicant agents / Charles G. Hurst and William J. Smith -- Cyanides : toxicology, clinical presentation, and medical management / Bryan Ballantyne and Harry Salem -- Chemicals used for riot control and personal protection / Harry Salem, Bryan Ballantyne, and Sydney Katz -- Mechanism of action of botulinum neurotoxin and overview of medical countermeasure development for intoxication / Michael Adler ... [et al.] -- Ricin and related toxins : review and perspective / Charles B. Millard and Ross D. LeClaire -- Screening smokes : applications, toxicology, clinical considerations and medical management / Bryan Ballantyne and Harry Salem -- Clinical detection of exposure to chemical warfare agents / Benedict R. Capacio ... [et al.] -- Personal protective equipment (ppe) : practical and theoretical considerations / Michael R. Jones -- Chemical warfare agent decontamination from skin / Brian J. Lukey ... [et al.] -- Chemical warfare, chemical terrorism, and traumatic stress responses : an assessment of psychological impact / James A. Romano, Jr. ... [et al.] -- Emergency response to a chemical warfare agent incident : domestic preparedness, first response, and public health considerations / David H. Moore and Barbara Saunders-Price -- Emergency medical response to a chemical terrorist attack / Stephen A. Pulley and Michael R. Jones.
- 2002 CRCnetBASEselected and arranged by Carl C. Gaither and Alma E. Cavazos-Gaither ; illustrated by Andrew Slocombe.Abstraction -- Accident -- Accuracy -- Acid -- Adsorption -- Aesthetic -- Affinity -- Age -- Air -- Alchemy -- Ambition -- Analogy -- Analysis -- Analyst -- Answer -- Apparatus -- Approximate -- Atom -- Atomic weight -- Authority -- Average -- Balance -- Beauty -- Biochemistry -- Book -- Bubble -- Calculation -- Candle -- Cause and effect -- Central limit theorem -- Chance -- Chaos -- Chemical -- Chemical affinities -- Chemical engineer -- Chemical limericks -- Chemical mnemonics -- Chemist -- Chemistry -- Chemistry and life -- Chemistry and medicine -- Chemistry songs -- Classroom emanations -- Commandments -- Common sense -- Communication -- Compound -- Concept -- Confusion -- Cosmochemistry -- Creativity -- Criticism -- Crystal -- Crystallography -- Curiosity -- Data -- Definition -- Demonstration -- Difference -- Discovery -- Disorder -- Distill -- Electron -- Element -- Energy -- Energy state -- Enzyme -- Error -- Ethics -- Experience -- Experiment -- Experimenter -- Explain -- Fact -- Faith -- Fermentation -- Filter -- Fire -- Fluorochemistry -- Force -- Forecast -- Formula -- Fractal -- Gas -- Generality -- Genius -- Geochemistry -- Glassware -- God -- Graph -- Guess -- Heat -- History -- Hypothesis -- Idea -- Ignorance -- Imagination -- Impossible -- Improbable -- Independence -- Inference -- Information -- Inorganic -- Instrument -- Ion -- Knowledge -- Laboratory -- Language -- Law -- Learn -- Life -- Literature -- Little Willie -- Magic -- Mathematics -- Matter -- Measurement -- Mechanics -- Metal -- Metaphor -- Metaphysics -- Method -- Microscope -- Model -- Molecule -- Motion -- Mystery -- Naivete -- Name -- Nature -- Nomenclature -- Notation -- Null hypothesis -- Numbers -- Observation -- Occam's razor -- Opinion -- Order -- Organic -- Outlier -- Paradox -- Periodic law -- Philosophy -- Physical science -- Plagerism -- Pollution -- Postulate -- Prayer -- Precision -- Prediction -- Probability -- Problem -- Progress -- Proposition -- Publication -- Purity -- Purpose -- Question -- Radical -- Random -- Reaction -- Reason -- Research -- Results -- Rust -- Salt -- Science -- Scientific -- Scientist -- Silver trees -- Simplicity -- Solid -- Soluble -- Solution -- Speculation -- Statistical -- Statistician -- Statistics -- Symbol -- Symmetry -- Synthesis -- Teaching -- Terminology -- Theorist -- Theory -- Thermodynamics -- Thought -- Trial and error -- Truth -- Uncertainty -- Understand -- Unexpected -- Unknown -- Vacuum -- Vision -- Volume -- Water -- Wisdom -- Word -- Work -- Writing -- X-rays.
- 2013 CRCnetBASEedited by Goutam Brahmachari."Natural products play crucial roles in modern drug development and constitute a prolific source of novel lead compounds or pharmacophores for ongoing drug discovery programs. Chemistry and Pharmacology of Naturally Occurring Bioactive Compounds presents cutting-edge research in the chemistry of bioactive natural products and demonstrates how natural product research continues to make significant contributions in the discovery and development of new medicinal entities."--Page  of cover.
- 2014 Wileyedited by Dr. Ravin Narain.General methods of bioconjugation -- Covalent and noncovalent bioconjugation strategies -- Polymer bioconjugates -- Bioconjugates based on poly(ethylene glycol)s and polyglycerols -- Synthetic polymer bioconjugate systems -- Natural polymer bioconjugate systems -- Dendrimer bioconjugates: synthesis and applications -- Organic nanoparticles based bioconjugates -- Bioconjugation strategies: lipids, liposomes, polymersomes, and microbubbles -- Organic nanoparticle bioconjugate: micelles, cross-linked micelles, and nanogels -- Carbon nanotubes and fullerene C60 bioconjugates -- Inorganic nanomaterials bioconjugates (metals, metal oxides--quantum dots, iron-oxide) -- Gold nanomaterials bioconjugates -- Methods for magnetic nanoparticle synthesis and functionalization -- Quantum dots bioconjugates -- Silica nanoparticle bioconjugates -- Polyhedral oligomeric silsesquioxanes (POSS) bioconjugates -- Cell-based, hydrogels/microgels and glyco-bioconjugates -- Cell-based bioconjugates -- Bioresponsive hydrogels and microgels -- Conjugation strategies used for the preparation of carbohydrate-conjugate vaccines -- Characterization, physico-(bio)chemical properties, and applications of bioconjugates -- Properties and characterization of bioconjugates -- Physico-chemical and biochemical properties of bioconjugates -- Applications of bioconjugates.
- 2006 CRCnetBASEN. Leo Benoiton.Chapter 1. Fundamentals of Peptide Synthesis -- Chapter 2. Methods for the Formation of Peptide Bonds -- Chapter 3. Protectors and Methods of Deprotection -- Chapter 4. Chirality in Peptide Synthesis -- Chapter 5. Solid-Phase Synthesis -- Chapter 6. Reactivity, Protection and Side Reactions -- Chapter 7. Ventilation of Activated Forms and Coupling Methods -- Chapter 8. Miscellaneous.
- 2007 SpringerB.A. Bunin, B. Siesel, G.A. Morales, J. Bajorath.
- 2008 CRCnetBASEeditors, Gordon Rees Jones, Anthony G. Deakin, Joseph W. Spencer.
- 2005 CRCnetBASEDobiáš, B.; Stechemesser, Hansjoachim.
- Lide, David R.; Weast, Robert C.Also available: Print – 2002/03.
- 2006 CRCnetBASEauthors, Thomas J. Bruno, Paris D.N. Svoronos.
- 2008 CRCnetBASEedited by Anil K. Bhowmick.
- 2011Christina Barnes Cooley.My graduate studies have focused on the design, synthesis, and biological evaluation of novel probe and drug delivery technologies. This research has explored the development of new molecular transporter scaffolds with a focus on step economy and translational costs as well as evaluation of their uptake and delivery properties in cells and animals. Chapter 1 provides a historical context and overview of guanidinium-rich molecular transporter technology. Chapter 2 describes the development of a new family of guanidinium-rich oligocarbonate molecular transporter which are flexibly and efficiently assembled by a one-step oligomerization strategy. These novel oligocarbonate transporters were shown to exhibit excellent uptake properties both in cells and animal models. Chapter 3 is directed at the utility of an oligomerization approach to generate molecular transporters by the design, synthesis, and evaluation of new aphipathic co-oligomers for the delivery of siRNA, an oligonucleotide cargo of intense therapeutic interest. Amphipathic carbonate co-oligomers were prepared by an oligomerization strategy and demonstrated to effectively package, deliver, and release functional siRNA in cells. Chapter 4 describes the effects of a branched guanidinium array on the transport and delivery efficiency of releasable dendrimeric guanidinium-rich transporters. These transporters were synthesized and demonstrated to deliver and release a small molecule for turnover by its intracellular target enzyme by bioluminescence assays in cells and transgenic animal models. Chapter 5 describes the design, synthesis, and preliminary biological evaluation of lipidated molecular transporter derivatives of the immunosuppressant drug rapamycin for topical delivery.
- 2011Minsub Chung.Many cellular processes including cell-cell communications and regulated membrane transport are mediated by membrane proteins and depend upon the ability of lipid membranes to be a differentially permeable barrier. However, the roles and function of membrane proteins are often difficult to study due to the complexity of the native membranes and lack of reliable and flexible artificial model lipid membranes. Supported lipid bilayers (SLB) have been used as a model system to study biological membrane behavior and the structure and function of membrane proteins and receptors in a simpler context apart from the complex cellular environment. Although SLBs have the advantages of simple formation, easy handling and are well-suited for investigation by a suite of surface sensitive methods due to their planar geometry, the close proximity of the lower leaflet to the solid support often leads to unfavorable interactions with integral membrane proteins. This causes distortion of the protein conformation and possible loss of its reactivity and function. Moreover, this interaction with the substrate often traps proteins and reduces their mobility in the membranes. Recognizing this limitation, we have developed a new model membrane architecture in which the DNA-tethered lipid bilayer is either to fixed DNA on a surface or to laterally mobile DNA displayed on a supported bilayer. This separates the lipid membranes from surface interactions and provides a more favorable environment for integral membrane protein with large globular domains. With mobile DNA hybrid tethers, stable tethered bilayers were made with specific lipid composition, while those with fixed tethers are stable regardless of membrane composition. The mobile tethers between a tethered and a supported lipid bilayer offer a particularly interesting architecture for studying the dynamics of membrane-membrane interactions. By careful choice of composition, improved stability was obtained and we can investigate the lateral segregation of DNA hybrids when different lengths are present. Based on a theoretical model, the effects of population, length and affinity of DNA complexes are simulated and described. This model system captures some of the essential physics of synapse formation and is a step toward understanding lipid membrane behavior in a cell-to-cell junction. To demonstrate the excellent environment provided by DNA-tethered membranes for studying transmembrane proteins free from any surface interactions, the behavior of a transmembrane protein, the photosynthetic reaction center, reconstituted in the DNA-tethered membranes is investigated. Inspired by DNA-mediated membrane fusion studies of our group, we applied the DNA-machinery to achieve fusion of small (~ 100 nm) proteoliposomes for delivery of membrane proteins to either giant vesicles or DNA-tethered planar lipid membrane patches. The diffusion behavior of delivered proteins is measured and compared with those in supported bilayers. Also, the protein activity and orientation before and after fusion is analyzed. This will offer a feasible method to incorporate intact membrane proteins to already formed model membranes. In addition, the behavior of proteins during the fusion event will provide insight into the mechanism of DNA-mediated lipid membrane fusion. The geometry of our model membrane system directly mimics that of a neuronal synapse. We expect that this architecture will be readily transferable to other model membrane fusion systems, including systems using reconstituted SNARE proteins. Consequently, it will be of considerable interest to a wide range of researchers.
- 2012Tracy Curtis Holmes, II.Developing novel therapies for gram-negative bacterial infections and glioblastoma multiforme I. cloning and characterization of the guadinomine biosynthetic gene cluster II. developing a novel chemo-sensitizing agent to treat glioblastoma. This thesis explores the development of novel therapies for the treatment of two complicated problems: Gram-negative bacterial infections and glioblastoma multiforme, the most aggressive form of brain cancer. Part I of the thesis summarizes the current body of knowledge regarding guadinomines, their biosynthesis and implications for developing novel anti-infective agents. Part II of the thesis summarizes the development of the small molecule, ERW1227B, and its ability to sensitize glioblastoma cells to standard therapies. Part I. Guadinomines are a recently discovered family of anti-infective compounds produced by Streptomyces sp. K01-0509. They are the first microbial metabolites shown to inhibit the Type III Secretion System (TTSS) of Gram-negative bacteria. The TTSS is required for the virulence of many pathogenic Gram-negative bacteria including Escherichia coli, Salmonella spp., Yersinia spp., Chlamydia spp., Vibrio spp., and Pseudomonas spp. Inhibition of the TTSS can mitigate virulence which is important considering that Gram-negative bacteria infect millions each year, leading to considerable morbidity and mortality. The guadinomine (gdn) biosynthetic gene cluster has been sequenced, and encodes a chimeric multimodular polyketide synthase -- nonribosomal peptide synthetase spanning 26 open reading frames and 51.2 kb. It also encodes enzymes responsible for the biosynthesis of the unusual aminomalonyl-ACP extender unit and the signature carbamoylated cyclic guanidine. Its identity was established by genetic inactivation of the cluster, as well as heterologous expression and analysis of enzymes in the biosynthetic pathway. Identifying the guadinomine gene cluster provides critical insight into the biosynthesis of these biologically important compounds. Part II. Glioblastomas display variable phenotypes that include increased drug-resistance associated with enhanced migratory and anti-apoptotic characteristics. These shared characteristics contribute to failure of clinical treatment regimens. Identification of novel compounds that both promote cell death and impair cellular motility is a logical strategy to develop more effective clinical protocols. Previously, we described the ability of the small molecule, KCC009, a tissue transglutaminase inhibitor, to sensitize glioblastoma cells to chemotherapy. In the current study, we synthesized a series of related compounds that show variable ability to promote cell death and impair motility in glioblastomas, irrespective of their ability to inhibit TG2. Each compound has a 3-bromo-4,5-dihydroisoxazole component that presumably reacts with a nucleophilic cysteine thiol residue in one (or more) target protein(s) that have affinity for the small molecule. Our studies focused on the effects of the compound, ERW1227B. Treatment of glioblastoma cells with ERW1227B was associated with both down-regulation of the PI-3 kinase/Akt pathway, which enhanced cell death; as well as disruption of focal adhesions and intracellular actin fibers, which impaired cellular mobility. Bioassays as well as time-lapse photography of glioblastoma cells treated with ERW1227B showed cell death and rapid loss of cellular motility. Mice studies with in vivo glioblastoma models demonstrated the ability of ERW1227B to sensitize tumor cells to cell death after treatment with either chemotherapy or radiation. The above findings identify ERW1227B as a potential novel therapeutic agent in the treatment of glioblastomas.
- 2011Ilya Anatoliy Shestopalov.Embryonic development is a remarkable program of cell proliferation, migration, and differentiation that transforms a single fertilized egg into a complex multicellular organism. This process depends on spatial and temporal control of gene function, and deciphering the molecular mechanisms that underlie pattern formation requires novel methods for perturbing gene expression with similar precision. Synthetic reagents can help meet this demand, and in this thesis I describe the development and application of caged morpholino (cMO) oligonucleotides for inactivating genes in zebrafish and other optically transparent organisms with spatiotemporal control simply by irradiating embryonic tissues with a focused light beam. In chapter 1 I provide an overview of the zebrafish model system of vertebrate development and survey the capabilities and limitations of various oligonucleotide-based technologies for perturbing RNA function and tracking RNA expression in zebrafish. I examine various light-gated oligonucleotide technologies that exploit the optical transparency of zebrafish embryos, including cMOs, for achieving spatiotemporal control of RNA function. In chapter 2 we describe the initial synthesis of a cMO targeting expression of the no tail a (ntla) transcription factor. By permitting spatiotemporal gene regulation in zebrafish embryos, the ntla cMO was used to make initial observations into the time-dependent role of this gene in notochord formation. In chapter 3 we report optimized methods for the design and synthesis of hairpin cMOs, incorporating a dimethoxynitrobenzyl (DMNB)-based bifunctional linker that permits cMO assembly in only three steps from commercially available reagents. Using this simplified procedure, we have systematically prepared cMOs with differing structural configurations and investigated how the in vitro thermodynamic properties of these reagents correlate with their in vivo activities. Through these studies, I have established general principles for cMO design and successfully applied them to several developmental genes. Our optimized synthetic and design methodologies have also enabled us to prepare a next-generation cMO that contains a bromohydroxyquinoline (BHQ)-based linker for two-photon uncaging. Collectively, these advances established the generality of cMO technologies to facilitate the application of these chemical probes in vivo for functional genomic studies. Finally, in chapter 4 we illustrate the utility of the cMO technology in isolating spatiotemporally-distinct functions of transcription factors -- genes that play diverse roles during embryonic development, with each controlling multiple cellular states in a spatially and temporally defined manner. Resolving the dynamic transcriptional profiles that underlie these patterning processes is essential for understanding embryogenesis at the molecular level; however, probing in vivo gene function with comparable spatiotemporal precision has been a technological challenge. To address this need, I have integrated cMOs with similarly caged fluorophores, fluorescence-activated cell sorting (FACS), and microarray technologies. Using this approach, I have dynamically profiled the No tail-a (Ntla)-dependent transcriptome at different stages of zebrafish mesoderm development, discovering discrete sets of genes that are associated with either notochord cell fate commitment or subsequent changes in cell function. Our studies elucidated the roles of several Ntla-regulated genes in notochord development and demonstrated the activation of multiple transcriptomes within a cell lineage by a single transcription factor.
- 2011Jungjoon Kempthorne Lee.The development of live cell RNA imaging techniques will lead to the unraveling of many important biological processes. To achieve this goal, there have been three different strategies developed. They are the development of small molecule probes, nucleic acid probes, and green fluorescent protein (GFP) probes. In the following thesis, the pros and cons of each approach are discussed, followed by a proposal to resolve the limitations. In the small molecule case, a probe was developed that utilized a quenched sulforhodamine dye. It was designed so that its structure can be rationally modified from the initial lead compound. An aptamer sequence that activates the sulforhodamine probe with micro molar affinity was found by in vitro Systematic Evolution of Ligands by Exponential Enrichment (SELEX), followed by fluorescence screening in E.coli. The rational modification of the structure of the initial sulforhodamine probe resulted in an overall 33-fold increase in binding affinity compared to the initial lead compound. Instead of the chemical modification of the lead compound, the small molecule's cell permeability and binding affinity to the target could be improved by linking to cell penetrating peptides (CPP). A CPP is a short peptide sequence composed of poly arginine amino acids which shows excellent cell uptake and affinity to RNA. However, the use of the CPP-linked dye in live cell imaging has been limited by strong signals in the endosome region. An attempt was made to overcome this difficulty by linking a quencher molecule to the dye-CPP via a disulfide bond, which only breaks when it enters the cytosol. For the nucleic acid probe, the major problem was its low cell permeability and low signal-to-background ratio due to the low copy number of mRNA targets within the cell. We made mutant Hammerhead ribozymes and embedded them in a non-coding region of the GFP expression vector that can be transfected to mammalian cells. This modified Hammerhead ribozyme acts as a logic gate, and the signal is amplified by the expression of GFP in the presence of the target mRNA. In vitro and in vivo results are discussed. Finally, a fragmented GFP system, the fluorescence of which could be recovered by binding to a specific RNA tag, was developed. The major problem for the GFP-mediated RNA imaging system was the low signal-to-background ratio from the GFP probe that is not bound to the RNA tag. To find the non-fluorescent GFP, the GFP was truncated from the C-terminus such that it loses its fluorescence with minimum loss of amino acids. An RNA sequence that has high affinity to this GFP was found by in vitro SELEX. The subsequent E.coli screening found an RNA sequence that reactivates the fluorescence of the GFP probe.
- Development of techniques for three-dimensional super-resolution fluorescence microscopy and their application to biological systems2011Michael Anthony Thompson.Fluorescence microscopy is one of the most widely used tools in cell biology due its intrinsically high detection sensitivity coupled with the ability to genetically label proteins and other cellular structures with fluorescent tags. However, the resolution of fluorescence microscopy has historically been limited to about 200 nm laterally and 800 nm axially because of the diffraction limit of visible light. In the past five years, imaging below the diffraction limit ("super-resolution imaging") by localizing single fluorophores, one at a time (1-3), has opened a wide a variety of new biological systems for study. This Dissertation is a collection of both techniques for two and three dimensional super-resolution imaging as well as applications in bacterial and yeast imaging. References 1. Betzig E, et al (2006) Imaging intracellular fluorescent proteins at nanometer resolution. Science 313: 1642-1645. 2. Hess ST, Girirajan TPK & Mason MD (2006) Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. Biophys J 91: 4258-4272. 3. Rust MJ, Bates M & Zhuang X (2006) Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat Methods 3: 793-795.
- 2006 CRCnetBASEedited by Peter M. Collins.
- 2011Andrew Everett Howery.CLC chloride channels and transporters play diverse physiological roles in processes ranging from regulating bone-density, muscle excitability, and blood pressure, to facilitating extreme-acid survival of pathogenic bacteria. Defects in CLC proteins cause human disorders in these processes. Small-molecule inhibitors of the CLCs would be useful as drugs for treating a variety of CLC-related human diseases and also to investigate CLC physiology. In addition, inhibitors are powerful tools for studying molecular mechanisms of Cl-- gating. Trapping channels or transporters in particular conformational states with high-affinity ligands could potentially advance our understanding of the structural basis for CLC activity. Despite their usefulness, specific small-molecule inhibitors for CLC proteins are scarce. To address this shortfall, we have exploited the 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) scaffold to develop two novel classes of CLC inhibitors. DIDS has been used as an anion-transport inhibitor for decades and was first used to inhibit CLCs over 30 years ago. However, experiments to determine the compound's mode of inhibition led us to discover that minor contaminants in the DIDS solutions inhibit CLC proteins more effectively than DIDS itself. The contaminants were found to derive from hydrolysis of the labile isothiocyanate moieties. The structures of five major hydrolysis products were determined by 1H NMR, HRMS analysis, and chemical synthesis to be DIDS-based polythioureas. These compounds bind directly to the CLC proteins, as evidenced by the fact that they inhibit purified, reconstituted ClC-ec1 and that inhibition of ClC-Ka can be prevented by the point mutation N68D. These polythioureas are the highest affinity inhibitors known for the CLCs and provide a new class of chemical probes for dissecting the molecular mechanisms of chloride transport. The second class of identified CLC inhibitors combines the DIDS core structure with alkyl chain carboxylic acids. The most potent inhibitor identified, 4,4'-octanamidostilbene-2,2'-disulfonic acid (OADS), inhibits ClC-ec1 with an apparent affinity of 29 [Mu]M. As a means to identify the inhibitor-binding site, we synthesized photo-reactive diazirine derivatives of OADS and showed that these photo-affinity reagents specifically inhibit ClC-ec1. Experiments to identify the binding site using 'top-down' mass spectrometry, in which the protein is cleaved into peptide fragments via electron-capture dissociation, have identified an intracellular binding region encompassing 76 amino acids, or 16% of the protein. Current efforts using protease digestion procedures are focused on further refinement of the binding region. Once located, protein/inhibitor interactions gleaned from the labeling of ClC-ec1 could allow us to rationally design more potent inhibitors of CLC transporters and channels.
- Dissertation]. Part I, Unnatural thymidine analogs and shape mimics as substrates for human thymidine kinases. Part II, Fluorescent size-expanded DNA analogs as efficient substrates for a template-independent DNA polymerase2011Sarah King Jarchow-Choy.This thesis is composed of two separate studies involving unnatural nucleoside (DNA) analogs in two different types of enzymes: human thymidine kinases 1 and 2 and terminal deoxynucleotidyl transferase (TdT). The ability of two types of unnatural DNA analogs, nonpolar nucleoside analogs and expanded nucleoside analogs, to act as efficient substrates in enzymes will be described. Nonpolar nucleoside analogs lacking the ability to hydrogen bond were synthesized to systematically vary in size and shape, and then used to probe the ability of two types of human thymidine kinases (TK1 and TK2) to recognize and phosphorylate these analogs. The results establish that nucleoside recognition mechanisms for these two classes of thymidine kinase are very different. On the basis of this data, nonpolar nucleosides are likely to be active in the nucleotide salvage pathway in human cells, suggesting new designs for bioactive molecules. Another class of nucleoside analogs, expanded nucleoside (xDNA) analogs, maintain the ability to hydrogen-bond to their respective natural bases, but have enhanced pi-stacking due to their larger size, allowing the molecule to have greater stability in a DNA duplex, and unique fluorescent properties. It was found that terminal deoxynucleotidyl transferase (TdT), a template-independent DNA polymerase, can accept multiple xDNA nucleotide analogs as substrates with efficiencies close to that of natural nucleotides. In addition, the expanded adenine (xA) and cytosine (xC) analogs show a visible and spectral change in fluorescence when TdT incorporates multiple analogs. The ease of enzymatic synthesis of these analogs and their inherent fluorescence suggest their use in nucleic acid labeling and hybridization studies. The comparable efficiencies which nonpolar nucleoside analogs and xDNA nucleotide analogs have to natural bases in thymidine kinases and TdT give new information about the steric and electronic requirements of these enzymes, and will be useful for potential therapeutic and biotechnological applications.
- 2012Bettina Van Lengerich.Vesicle fusion is a central process in transport and communication in biology. In neuronal transmission, synaptic vesicles carrying neurotransmitters dock and fuse to the plasma membrane of the neuron, a process mediated by a combination of several membrane anchored and soluble proteins. Fusion results in the merger of the two apposing lipid bilayers, leading to the exchange of both the lipidic and aqueous components. The fusion reaction is thought to proceed through several stages: first, the membranes are brought into close proximity (docking), second, the outer leaflets mix, but the inner leaflets and contents remain separate (hemi-fusion), and finally, the inner leaflet and contents exchange (full fusion). Due to the complex nature of the fusion reaction and the multitude of proteins involved, the mechanism of the fusion reaction is not well understood. Simplified model systems for vesicle fusion can bring insight into the mechanism by studying the fusion reaction in a more defined and controllable system. This thesis describes a DNA-based model for the protein fusion machinery. Previously, DNA-lipids were used to tether lipid vesicles to glass-supported lipid bilayers. These vesicles could be observed by fluorescence microscopy, and are laterally mobile along the plane parallel to the supported bilayer. DNA-mediated docking between vesicles was characterized, but fusion was not observed due to the fact that the DNA partners were both coupled at the 5' end, so antiparallel hybridization holds the membranes apart. In this work, a new synthesis of DNA-lipid conjugates is described which allows coupling at both the 3' and 5' end of the DNA. Incorporation of complementary DNA-lipids coupled at opposite ends mediates fusion between lipid vesicles. Vesicle fusion was measured in bulk fluorescence assays (Chapter 2 and 3), by both lipid mixing and content mixing assays. The rate of vesicle fusion showed a strong dependence on the number of DNA per vesicle, as well as the sequence of the DNA. Consistent with previous results measured for the docking reaction, fusion was faster for a repeating DNA sequence than for a non-repeating sequence that required full overlap of the strands for hybridization. The role of membrane proximity on the rate of vesicle fusion was investigated in Chapter 3 by insertion of a short spacer sequence at the membrane-proximal end of fusion sequences. The length of the spacer sequence was varied between two and 24 bases, corresponding to length scales of approximately 1-12 nm. Fusion, as measured in bulk assays by lipid and content mixing, decreases systematically as the membranes are held progressively further apart, demonstrating a clear dependence of the rate of the fusion reaction on membrane proximity. While the bulk vesicle fusion assays showed that DNA-lipids can mediate vesicle fusion, these ensemble measurements convolve the multiple steps (docking, hemifusion, and full fusion) of the fusion reaction, complicating any kinetic analysis. In order to image individual vesicle fusion events between tethered vesicles, a new tethering strategy was developed (Chapter 4). This strategy exploits the dependence of DNA hybridization on salt by covalently attaching lipid vesicles to a glass-supported lipid bilayer, then triggering DNA-mediated docking and fusion by spiking the salt concentration. The kinetics of individual vesicle fusion events were subsequently measured using a FRET-based lipid mixing assay for many vesicles (Chapter 6). An analysis of the distribution of waiting times from docking to fusion indicated that this transition occurs in a single step. A second model membrane architecture was used to study individual fusion events between vesicles and a planar bilayer (Chapters 5 and 6). This architecture uses a DNA-tethered planar free-standing bilayer as the target membrane. The kinetics of individual vesicle fusion events to this membrane patch were also consistent with a single step process, as for vesicle to vesicle fusion. In this system, it was also possible to observe content transfer of vesicles containing a self-quenched aqueous dye (Chapter 5). By analyzing the diffusion profile of the dye, it was shown that the dye indeed is transferred into the region below the planar membrane patch, and is not released into the solution above the patch due to vesicle rupture or leakage.
- 2008 HighWireInternational Commission on Radiation Units and Measurements.
- 2001- WileyContains a database of approximately 70,000 reactions and 4000 of the most frequently consulted reagents. Fully searchable by structure and sub-structure, reagent, reaction type, experimental conditions, and keyword. Also includes a searchable interface: Acronym finder (an interface for Scientific and technical acronyms, symbols, and abbreviations).
- Effects of matrix anisotropy and shear flow on endothelial cells : developing a small-diameter vascular graft to regulate endothelial function2012Edwina S. Lai.The development of atherosclerosis, a chronic inflammatory disease of the arteries, can usually be attributed to specific regions of the blood vessel. In the straight segments of an artery, endothelial cells (ECs) align with the unidirectional blood flow which commonly occurs in these simple geometries. The elongated and aligned ECs are generally found to have a healthy, athero-resistant phenotype. In contrast, branches or curved vessel geometries have regions of disturbed flow, characterized by low shear stress and high shear stress gradients. In these regions of complicated flow patterns, ECs are non-aligned and have a cobblestone cellular morphology. The non-aligned ECs elicit biological properties that promote atherosclerosis, as the location of atherosclerotic fatty plaque is often found at these bends, branches, or bifurcations. Therefore, this correlation highly suggests that the morphology and biological function are inextricably linked in ECs. The ability to regulate both EC morphology and motility, with the aim to influence EC biology, might be highly beneficial in the prevention or treatment of vascular disease. In this dissertation, anisotropic matrices of collagen nanofibrils were fabricated with a simple flow processing technique and used to investigate fundamental cell-matrix interactions with ECs. The aligned fibrils were able to regulate both the morphology and biology of ECs, thereby suggesting the nanofibrillar collagen can be a useful tool to maintain vascular homeostasis. The ECs elongated and organized their actin cytoskeleton along the direction of the aligned collagen fibrils, as demonstrated by organized actin, microtubule networks, and focal adhesions. The nanofibrillar collagen also promoted increased cellular migration along the direction of the nanofibrils. The quantification of monocyte adhesion and expression level of adhesion molecules, known testing indicators of atherosclerosis development, suggested the aligned nanofibrils also promoted an athero-resistant phenotype in the ECs. ECs are subject to biophysical cues in vivo, either in the form of surface topography (provided by the basement membrane of the ECM) or the hemodynamic effects of blood flow. The combination of these cues regulate the organization and immunogenicity of ECs and is representative of the in vivo environment. Therefore, we also investigated the endothelial behavior when both types of cues (topography and flow) were simultaneously present. At physiological levels of high shear stress (14-17 dynes/cm2), the matrix-aligned ECs were able to resist reorientation despite shear flow perpendicular to the matrix direction. The anisotropic collagen matrix could preserve the alignment and elongation of ECs as well as promote an athero-resistant phenotype after exposure to antagonistic perpendicular flow. The ability of the anisotropic nanofibrillar collagen to regulate cell morphology and especially EC immunogenicity highlights its potential in the treatment of vascular diseases. Therefore, an aligned conduit of collagen nanofibrils was fabricated to address the need for a small-diameter vascular graft capable of regulating cellular function. The vascular graft was designed to have a mechanical integrity comparable to that of native vessels and was able to regulate EC attachment, morphology, and phenotype. In addition, the aligned collagen grafts could support an anti-thrombogenic surface modification, providing short-term patency in the carotid artery model of Sprague-Dawley rats.
- Efficient access to bryostatin and functional bryostatin analogs : design, synthesis and evaluation of potent bryostatin analogs and the total synthesis of bryostatin 9 using B-ring annulative macrocyclization strategies2011Adam James Schrier.The bryostatins are a family of structurally complex natural products isolated from the marine bryozoan Bugula neritina. Bryostatin 1 is currently being investigated for cancer, Alzheimer's and HIV/AIDS indications. Despite these remarkable activities, research on the bryostatins is hampered by their low natural abundance. Efficient access by total chemical synthesis has been in large part precluded by the bryostatins' structural complexity. This dissertation describes the design, synthesis, and preliminary biological evaluation of functional bryostatin analogs that possess biological activities comparable or superior to the natural product. These fully synthetic analogs were convergently assembled in a uniquely step-economical manner using novel macrocyclization strategies, including macroacetalization and Prins-driven macrocyclization approaches. Bryostatin analogs were identified that possess unique affinities (subnanomolar) and selectivities for protein kinase C (PKC). Synthetic bryostatin analogs also exhibit subnanomolar antileukemic activity in in vitro assays. The convergent total synthesis of bryostatin 9, a highly potent congener of the natural product family, is also described.
- 2006 CRCnetBASEedited by Johan Sjoblom.
- v. 1-2, 2005 CRCnetBASEedited by Jack Cazes.
- 1998 Wileyeditor-in-chief, Paul von Ragué Schleyer.
- 2007 CRCnetBASEAlan E. Comyns.
- 2012Jay Thomas Fitzgerald.Polyketides are a large class of structurally diverse natural products which posses a wide range of biological activities. Unfortunately, despite the potential utility of these compounds in the clinic, large scale production of many of these natural products from their native hosts remains a challenge. Additionally, due to their complexity, engineering better pharmacokinetic properties by traditional synthetic means is often challenging. A better understanding of the biosynthetic machinery which produces polyketides allows for optimization of their production and paves the way for bioactivity-based pathway reengineering. This work begins with an introduction detailing attempts to unravel the biosynthetic underpinnings of two key natural product families, the tetracyclines and the thiostreptons, with an eye toward ultimately reengineering the pathways. Then, our efforts to reconstruct and reengineer the biosynthesis and biological activity of the type II polyketides frenolicin and A-74528 are detailed. Successful reconstruction of a chimeric biosynthetic pathway to frenolicin B and subsequent reengineering of that pathway to produce novel frenolicin analogs is described. Then, the biological activity of these compounds both in vitro against the parasites Toxoplasma gondii and Plasmodium falciparum is discussed. Additional studies against Plasmodium berghi in mice show that frenolicin B is an effective antiparastic agent in vivo. Following this, engineering of a biosynthetic pathway to the novel antiviral agent A-74528 from S. sp. SANK 61196 is presented and the impact of various tailoring enzymes on metabolite production are explored.
- 2005 CRCnetBASECazes, Jack; Ewing, Galen Wood.
- [v.3], 2014Jonathan Orsay.
- 2006 CRCnetBASEedited by Øyvind M. Andersen, Kenneth R. Markham.
- Fluorophores for single-molecule imaging in living cells : characterizing and optimizing DCDHF photophysics2010Samuel Joseph Lord.The number of reports per year on single-molecule imaging experiments has grown roughly exponentially since the first successful efforts to optically detect a single molecule were completed over two decades ago. Single-molecule spectroscopy has developed into a field that includes a wealth of experiments at room temperature and inside living cells. The fast growth of single-molecule biophysics has resulted from its benefits in probing heterogeneous populations, one molecule at a time, as well as from advances in microscopes and detectors. There is a need for new fluorophores that can be used for single-molecule imaging in biological media, because imaging in cells and in organisms require emitters that are bright and photostable, red-shifted to avoid pumping cellular autofluorescence, and chemically and photophysically tunable. To this end, we have designed and characterized fluorescent probes based on a class of nonlinear-optical chromophores termed DCDHFs. This dissertation describes various physical and optical studies on these emitters, from sensing local environment to photoactivation. Chapter 1 is a general introduction to fluorescence and single-molecule spectroscopy and imaging. Single-molecule experiments in living cells are discussed and probes used for such experiments are summarized and compared. Chapter 2 explores the basic photophysics of the DCDHF fluorophores and some general methods of measuring relevant spectroscopic parameters, including photostability. Chapter 3 discusses the various approaches we have taken to modify particular properties by changing the fluorophore's structure. We have redesigned the DCDHF fluorophore into a photoactivatable fluorogen -- a chromophore that is nonfluorescent until converted to a fluorescent form using light -- described in Chapter 4. Finally, a different, chemical route to fluorescence activation is presented in Chapter 5. The remainder of the Dissertation is the Appendix and a full Bibliography. The Appendix includes a table of photophysical parameter for DCDHF fluorophore, various protocols used in the experiments discussed, MatLab codes, and NMR spectra.
- 2007 CRCnetBASEeditor, Carmen Socaciu.
- 2003 WileyCarraher, Charles E.; Seymour, Raymond B.ch. 1. The Building Blocks of Our World, p. 1-30 -- ch. 2. Small Organic Molecules, p. 31-55 -- ch. 3. Introduction to the Science of Giant Molecules, p. 57-93 -- ch. 4. Relationships Between the Properties and Structure of Giant Molecules, p. 95-112 -- ch. 5. Physical and Chemical Testing of Polymers, p. 113-132 -- ch. 6. Thermoplastics, p. 133-181 -- ch. 7. Engineering Plastics, p. 183-208 -- ch. 8. Thermosets, p. 209-227 -- ch. 9. Fibers, p. 229-250 -- ch. 10. Rubbers (Elastomers, p. 251-274 -- ch. 11. Paints, Coatings, Sealants, and Adhesives, p. 275-291 -- ch. 12. Composites, p. 293-305 -- ch. 13. Nature's Giant Molecules: The Plant Kingdom, p. 307-327 -- ch. 14. Nature's Giant Molecules: The Animal Kingdom, p. 329-363 -- ch. 15. Derivatives of Natural Polymers, p. 365-378 -- ch. 16. Inorganic Polymers, p. 379-403 -- ch. 17. Specialty Polymers, p. 405-423 -- ch. 18. Additives and Starting Materials, p. 425-444 -- ch. 19. The Future of Giant Molecules, p. 445-453 -- Appendix 1. Studying Giant Molecules, p. 455-457 --. Appendix 2. Electronic Web Sites, p. 459-461.
- Handbook for DNA-encoded chemistry : theory and applications for exploring chemical space and drug discovery2014 Wileyedited by Robert A. Goodnow, Jr.Just enough knowledge? -- A brief history of the development of combinatorial chemistry and the emerging need for DNA-encoded chemistry -- A history of DNA-encoding -- DNA-compatible chemistry -- Foundations of a DNA-encoded library (DEL) -- Practices for synthesizing DNA-encoded libraries -- Chemical gene design for DNA-encoded libraries -- Analytical challenges for DNA-encoded library systems -- Information technology: functionality and architectures for DNA-encoding -- Theoretical considerations of the application of DNA-encoded libraries to drug discovery -- Begin with the end in mind : the hit-to-lead process -- Enumeration and visualization of large combinatorial chemical libraries -- Screening large compound collections -- Reported applications of DNA-encoded library chemistry -- Dual-pharmacophore DNA-encoded chemical libraries -- Hit identification and hit follow-up -- Using DNA to program chemical synthesis, discover new reactions, and detect ligand binding -- An outlook and the changing feasibility and economics of chemical diversity exploration with DNA-encoded combinatorial approaches -- Keeping the promise? an outlook on dna chemical library technology.
- 2008 CRCnetBASER.W. Sabnis.
- 2006 CRCnetBASEedited by David S. Hage.
- 2003 CRCnetBASESamuel H. Yalkowsky, Yan He.
- 2005 CRCnetBASEB.L. Goodwin.
- 2008 CRCnetBASEedited by James P. Landers.
- 2007 CRCnetBASEedited by John Regalbuto.
- 2008 CRCnetBASED. Hank Ellison.
- 2010 CRCnetBASEedited by Jean-Loup Faulon, Andreas Bender.Chapter 1. Representing Two-Dimensional (2D) Chemical Structures with Molecular Graphs / Ovidiu Ivanciuc -- Chapter 2. Algorithms to Store and Retrieve Two-Dimensional (2D) Chemical Structures / Milind Misra, Jean-Loup Faulon -- Chapter 3. Three-Dimensional (3D) Molecular Representations / Egon L. Willighagen -- Chapter 4. Molecular Descriptors / Nikolas Fechner, Georg Hinselmann, Jor̈g Kurt Wegner -- Chapter 5. Ligand- and Structure-Based Virtual Screening / Robert D. Clark, Diana C. Roe -- Chapter 6. Predictive Quantitative Structure-Activity Relationships Modeling: Data Preparation and the General Modeling Workflow / Alexander Tropsha, Alexander Golbraikh -- Chapter 7. Predictive Quantitative Structure-Activity Relationships Modeling: Development and Validation of QSAR Models / Alexander Tropsha, Alexander Golbraikh -- Chapter 8. Structure Enumeration and Sampling / Markus Meringer -- Chapter 9. Computer-Aided Molecular Design / Donald P. "Visco, Jr." -- Chapter 10. Computer-Aided Molecular Design / Diana C. Roe -- Chapter 11. Reaction Network Generation / Jean-Loup Faulon, Pablo Carbonell -- Chapter 12. Open Source Chemoinformatics Software and Database Technologies / Rajarshi Guha -- Chapter 13. Sequence Alignment Algorithms / Tatsuya Akutsu -- Chapter 14. Machine Learning-Based Bioinformatics Algorithms / Shawn Martin -- Chapter 15. Using Systems Biology Techniques to Determine Metabolic Fluxes and Metabolite Pool Sizes / Fangping Mu, Amy L. Bauer, James R. Faeder, William S. Hlavacek.
- 2003 CRCnetBASEGennady P. Manchenko.
- 2008 CRCnetBASEedited by Donald A. Burns, Emil W. Ciurczak.
- 2006 CRCnetBASEMontalti, Marco; Murov, Steven L.
- 2008 CRCnetBASERobert C. Klingender.Chapter 1. Polychloroprene Rubber (CR) / by Rudiger Musch & Hans Magg -- Chapter 2. Acrylonitrile Butadiene Rubber (NBR) / by Robert Klingender -- Chapter 3. Hydrogenated Nitrile Rubber (HNBR) / by Dr. Robert Keller -- Chapter 4. Fluoroelastomers, FKM, and FEPM / by Pascal Ferrandez -- Chapter 5. Polyacrylate Elastomers Properties and Applications / by Robert Klingender -- Chapter 6. Ethylene Acrylic (AEM) Elastomer Formulation Design / by Lawrence C. Muschiatti, Yun-Tai Yu, Edward McBride and Klaus Kammerer -- Chapter 7. Polyepichlorohydrin Elastomer / by Robert Klingender -- Chapter 8. Compounding with Chlorinated Polyethylene / by Ray Laakso -- Chapter 9. Chlorosulfonated Polyethylene (CSM) and Aklylated Chlorosulfonated Polyethylene (ACSM) / by Robert Klingender -- Chapter 10. Ethylene Vinyl Acetate Elastomer (EVM) (ASTM designation AEM) / by Drs. H. Meisenheimer & A. Zens -- Chapter 11. Polysulfide Elastomers / by Stephen K. Flanders & Robert Klingender - Submitted -- Chapter 12. Plasticizers, Process Oils, Vulcanized Vegetable Oils / by Peter Rand -- Chapter 13. Vulcanization Agents for Specialty Elastomers / by Robert Ohm -- Chapter 14. Antioxidants for Specialty Elastomers by Russell Mazzeo -- Chapter 15. Processing Aids for Specialty Elastomers / by Jerry M. Sherritt -- Chapter 16. Considerations in the design of a rubber formulation / by Robert Klingender -- 16A. Oil Field elastomeric Products / by Robert C. Klingender -- 16B. Life Prediction / by John Vicic -- 16C. Compression, Transfer, and Injections Molding of Specialty Elastomers / by Robert W. Keller.
- 2003 Wileyedited by G. Gauglitz and T. Vo-Dinh.v. 1. -- Part I. Sample preparation and sample pretreatment -- ch. 1. Collection and preparation of gaseous samples / Douglas A. Lane -- ch. 2. Sample collection and preparation of liquid and solids / Brian M. Cullum, Tuan Vo-Dinh -- Part II. Methods 1: Optical spectroscopy -- ch. 3. Basics of optical spectroscopy / Martin Hof -- ch. 4. Instrumentation / Valdas Sablinskas -- ch. 5. Measurement techniques / Gerald Steiner -- ch. 6. Applications / Valdas Sablinskas, Gerald Steiner, Martin Hof -- Part III. Methods 2: Nuclear magnetic resonance spectroscopy -- ch. 7. An Introduction to solution, solid-state, and imaging NMR spectroscopy / Leslie G. Butler -- ch. 8. Solution NMR spectroscopy / Gary E. Martin, Chad E. Hadden, David J. Russell -- ch. 9. Solid-state NMR / Steven P. Brown, Lyndon Emsley -- Part IV. Methods 3: Mass spectrometry -- ch. 10. Mass spectrometry / Michael Przybylski, Wolfgang Weinmann, Thilo A. Fligge -- Part V. Methods 4: Elemental analysis -- ch. 11. X-ray fluorescence analysis / K. Janssens -- ch. 12. Atomic absorption spectrometry (AAS) and atomic emission spectrometry (AES) / Erwin Rosenberg, Ulrich Panne -- Part VI. Methods 5: Surface analysis techniques -- ch. 13. Surface analysis techniques / A. Macková, S.A. Morton, C.G.H. Walker, K. Volka -- v. 2. -- Part VII. Applications 1: Bioanalysis -- ch. 14. Bioanalysis / Willem M. Albers, Arto Annila, Nicholas J. Goddard, Gabor Patonay, Erkki Soini -- Part VIII. Applications 2: Environmental analysis -- ch. 15. LC-MS in environmental analysis / H.Fr. Schröder -- ch. 16. Gas chromatography/ion trap mass spectrometry (GC/ITMS) for environmental analysis / Michel Sablier, Toshihiro Fujii -- Part IX. Application 3: Process control -- ch. 17. Optical spectroscopy / John Green -- ch. 18. NMR / Loring A. Weisenberger -- ch. 19. Process mass spectrometry / Christian Hassell -- ch. 20. Elemental analysis / J.S. Crighton -- Part X. Hyphenated techniques -- ch. 21. Hyphenated techniques for chromatographic detection / John C. Fetzer -- Part XI. General data treatment: data bases/spectral libraries -- ch. 22. Optical spectroscopy / Steffen Thiele, Reiner Salzer -- ch. 23. Nuclear magnetic resonance spectroscopy / Wolfgang Robien -- ch. 24. Mass spectrometry / Antony N. Davies.
- 2003 CRCnetBASEedited by Joseph Sherma, Bernard Fried.
- 2007 CRCnetBASEedited by Leo M.L. Nollet.
- 2003 CRCnetBASEedited by Scott M. Auerbach, Kathleen A. Carrado, Prabir K. Dutta.
- 2002 Knovelrevised by Richard J. Lewis, Sr.Abbreviations -- Condensed chemical dictionary -- Appendix I: Origin of some chemical terms -- Appendix II: Highlights in the history of chemistry -- Appendix III: Manufacturers of trademarked products (alphabetical list).
- 2009 CRCnetBASEedited by Perry G. Wang.High throughput sample preparation techniques and their application to bioanalytical protocols and purification of combinatorial libraries / Krishna Kallury -- High-throughput quantitative bioanalysis / Katty X. Wan -- Optimizing LCMS equipment to increase throughput in pharmaceutical analysis / Michael G. Frank and Douglas E. Mcintyre -- Throughput improvement of bioanalytical LC-MS/MS by sharing of detector between HPLC systems / Min Shuan Chang and Tawakol El-Shourbagy -- High throughput strategies for metabolite identification in drug discovery / Patrick J. Rudewicz, Qin Yue, and Young Shin -- Utilizing micro parallel liquid chromatography for high-throughput analyses in the pharmaceutical industry / Sergio A. Guazzotti -- Strategies and techniques for higher throughput ADME/PK assays / Walter Korfmacher -- High-throughput analysis in drug metabolism during early drug discovery / Yau Yi Lau -- High-throughput analysis in the support of process chemistry and formulation research & development in the pharmaceutical industry / Zhong Li -- On-line SPE LC/MS/MS for high throughput bioanalytical analysis / Dong Wei and Liyu Yang -- Applications of high-throughput analysis in therapeutic drug monitoring / Quanyun A. Xu and Timothy L. Madden -- High-throughput quantitative pharmaceutical analysis in drug metabolism and pharmacokinetics (DMPK) using liquid crhomatrography-mass spectrometry / Xiaohui Xu -- Designing high throughput HPLC assays for small and biological molecules / Roger K. Gilpin and Wanlong Zhou -- The advances in capillary and nano-HPLC technology for drug discovery and development / Frank J. Yang and Richard Yu -- High-throughput analysis of complex protein mixtures by mass spectrometry / Kojo S.J. Elenitoba-Johnson.
- 2005 ScienceDirectedited by Swapan K. Chowdhury.
- 2005 CRCnetBASESangeeta, D.; LaGraff, John R.
- 2006 SpringerPaul Lecoq ... [et al.].
- 2003 ScienceDirectedited by John T. Romeo.The enzymatic basis of flavonoid biodiversity / Ragai K. Ibrahim and Dominique Anzellotti -- Structural, functional and evolutionary basis for methylation of plant small molecules / Joseph P. Noel ... [et al.] -- Regulation of anthocyanin pigmentation / Niloufer G. Irani, J. Marcela Hernandez and Erich Grotewold -- Localization of plant myrosinases and glucosinolates / Erik Andreasson and Lise Bolt Jorgensen -- Glucosinolate hydrolysis and its impact on generalist and specialist insect herbivores / Ute Wittstock ... [et al.] -- A novel myrosinase-glucosinolate defense system in cruciferous specialist aphids / John T. Rossiter, Alexnadra M. Jones and Atle M. Bones -- Multiple levels of control in the regulation of alkaloid biosynthesis / Peter J. Facchini ... [et al.] -- Biochemistry and molecular biology of indole alkaloid biosynthesis : the implication of recent discoveries / Vincenzo de Luca -- Chemical ecology of alkaloids exemplified with the pyrrolizidines / Dietrich Ober -- The chemical wizardry of isoprenoid metabolism in plants / Bryan T. Greenhagen ... [et al.] -- The sabath family of MTS in Arabidopsis Thaliana and other plant species / John C. D'Auria, Feng Chen, Eran Pichersky -- Xochipilli updated, terpenes from Mexican plants / Edmundo Lozoya-Gloria.
- 2012 WileyT.D.H. Bugg.From Jack Beans to designer genes -- All enzymes are proteins -- Enzymes are wonderful catalysts -- Methods for studying enzymatic reactions -- Enzymatic hydrolysis and group transfer reactions -- Enzymatic redox chemistry -- Enzymatic carbon-carbon bond formation -- Enzymatic addition/elimination reactions -- Enzymatic transformations of amino acids -- Isomerases -- Radicals in enzyme catalysis -- Non-enzymatic biological catalysis.
- 2012 WileySteen Hansen, Stig Pedersen-Bjergaard, Knut Rasmussen.Introduction to pharmaceutical analysis -- International pharmacopoeias, regulations and guidelines -- Fundamental chemical properties, buffers and pH -- Fundamentals of pharmaceutical analysis -- Titrimetric methods -- Introduction to spectroscopic methods -- UV-spectrophotometry -- IR-spectrophotometry -- Atomic spectrometry -- Fundamentals of chromatography -- Chromatographic separation principles -- Thin-layer chromatography -- High-performance liquid chromatography -- Gas chromatography -- Capillary electrophoresis -- Mass spectrometry -- Miscellaneous chemical techniques -- Sample preparation -- Analytical chemical characteristics of selected drug substances -- Quantification and quality of analytical data -- Chemical analysis of drug substances -- Chemical analysis of final pharmaceutical products -- Bioanalysis.
- 2006 CRCnetBASEedited by Amnon Kohen, Hans-Heinrich Limbach.
- 2007 NLMprepared for publication by John H. Duffus, Monica Nordberg, Douglas M. Templeton.
- Jokichi Takamine : the man who gave "adrenaline" to the world : English translation of the panels exhibited at the National Science Museum, Tokyo, Japan, December 10, 2004-January 10, 2005 in commemoration of the 150th anniversary of Takamine's birth.2007Ishida, Mitsuo; Nakatsugawa, Tsutomu.
- 2005- WileyKirk, Raymond E.; Othmer, Donald F.Includes risk management, enterprise resource planning, outsourcing, combinatorial synthesis and technology, functional foods, process automation, electronic chemicals, specialty silicones, mergers and acquisitions, nanoparticles, bioinformatics, ISO 14000, micron-scale chemical analysis, medical applications of biodegradable materials, product development, strategies, drug discovery strategies, chemistry of aging, single-site catalysis, custom manufacturing, and global chemical market analysis.
- Lead optimization for medicinal chemists : pharmacokinetic properties of functional groups and organic compounds2012 WileyFlorencio Zaragoza Dorwald.Part I : Introduction. The drug discovery process ; lead optimization -- Part II : The pharmacokinetic properties of compound classes. Alkanes ; Alkenes and alkynes ; Arenes ; Halides ; Azides ; Nitro compounds ; Azo compounds ; Triazenes ; Nitrates and nitrites ; N-nitroso compounds ; N-oxides ; Alcohols ; Phenols ; Ethers ; Epoxides ; Peroxides ; Thiols ; Thioethers ; Sulfoxides ; Sulfones ; Aliphatic amines ; Quaternary ammonium salts ; Amidines ; Guanidines, acylguanidines, and biguanides ; Anilines ; Hydrazines, acylhydrazines, and hydrazones ; Aldehydes ; Ketones ; Carboxylic acids ; Carboxylic esters ; Amides ; Lactams and imides ; Nitriles ; Carbonates ; Carbamates ; Ureas ; Thiocarbonyl compounds ; Sulfonic acids ; Sulfonic esters ; Sulfates And sulfamic acids ; Phosphonic acids ; Phosphoric acid derivatives ; N-(aminoalkyl)benzamides, -benzoates, and related compounds ; Arylalkylamines ; Phenethylamines (2-phenylethylamines) ; Aminoalkylindoles and indole alkaloids ; Phenothiazines ; Dibenzazepines and related tricyclic compounds ; 3-aryloxy-2-hydroxypropylamines (b-adrenergic antagonists; 'b-blockers') ; Opiates ; N-(carboxyalkyl)-a-amino acid amides (prils) ; Anilides and amides of glycine ; Peptides, peptidomimetics, and related oligoamides ; Oligoarylamines, oligoarylamides, oligoarylcarbamates, and oligoarylureas ; Imidazoles ; Triazoles ; Pyridines, pyrimidines, and related compounds ; Quinolines ; Nucleoside analogs ; Dihydropyridines ; Arenesulfonamides ; Sulfonylureas ; Benzodiazepines ; Steroids ; Anthracyclines ; Arylacetic, benzoic, and related carboxylic acids (NSAIDS) ; Quinolonecarboxylic acids (gyrase inhibitors) ; B-lactams ; Prostaglandin analogs ; Sartans ; Statins ; Folic acid analogs (antifolates) ; Taxanes ; Macrocyclic compounds.
- 2014 Wileyeditor, Tim Storr.Introduction to ligand design in medicinal inorganic chemistry -- Platinum-based anticancer agents -- Coordination chemistry and ligand design in the development of metal based radiopharmaceuticals -- Ligand design in D-block optical imaging agents and sensors -- Luminescent lanthanoid probes -- Metal complexes of carbohydrate-targeted ligands in medicinal inorganic chemistry -- Design of Schiff base-derived ligands: applications in therapeutics and medical diagnosis -- Metal-based antimalarial agents -- Therapeutic gold compounds -- Ligand design to target and modulate metal-protein interactions in neurodegenerative diseases -- Rational design of copper and iron chelators to treat Wilson's disease and hemochromatosis -- MRI contrast agents -- Photoactivatable metal complexes and their use in biology and medicine -- Metalloprotein inhibitors -- Ruthenium anticancer compounds with biologically-derived ligands.
- 2007 CRCnetBASEedited by Frank D. Gunstone, John L. Harwood, Albert J. Dijkstra.
- 2006 CRCnetBASENiessen, W. M. A.
- 2003 CRCnetBASEChristopher G. Herbert, Robert A.W. Johnstone.
- [v. 5], 2016edited by Alexander Stone Macnow, MD.Atomic Structure -- The Periodic Table -- Bonding and Chemical Interactions -- Compounds and Stoichiometry -- Chemical Kinetics -- Equilibrium -- Thermochemistry -- The Gas Phase -- Solutions -- Acids and Bases -- Oxidation-Reduction Reactions -- Electrochemistry.
- [v. 6], 2016edited by Alexander Stone Macnow, MD.Nomenclature -- Isomers -- Bonding -- Analyzing Organic Reactions -- Alcohols -- Aldehydes and Keotones I: Electrophilicity and Oxidation--Reduction -- Aldehyde and Keo tones II: Enolates -- Carboxylic Acids -- Carboxylic Acid Derivatives -- Nitrogen- and Phosphorus-Containing Compounds -- Spectroscopy -- Separations and Purifications.
- MCR 2009 : proceedings of the 4th International Conference on Multi-Component Reactions and Related Chemistry, Ekaterinburg, Russia2011 SpringerMaxim A. Mironov, editor.Catalysis and multi-component reactions -- Multi-component reactions in heterocyclic chemistry -- Multi-component reactions in drug discovery -- Novel reagents for multi-component reactions -- Design of multi-component reactions -- Multi-component reactions in supramolecular chemistry and material science.Also available: Print – 2011
- 2006 CambridgeSoftMaryadele J. O'Neil, editor ... [et al.].Also available: Print – 2006
- 2013Maryadele J. O'Neil, editor-in-chief ; Patricia E. Heckelman, senior associate editor ; Peter H. Dobbelaar, associate editor ; Kristin J. Roman, assistant editor ; Catherine M. Kenny, senior editorial assistant ; Linda S. Karaffa, technical assistant.
- 2007 CRCnetBASEMohammad Niyaz Khan.
- 2006 CRCnetBASEPaul C.H. Li.
- 2003 ScienceDirectV.S. Sastri ... [et al.].Preface -- . Introduction -- 2. General aspects -- 3. Stability of complexes -- 4. Lanthanide and macrocyclic complexes -- 5. Structural chemistry of lanthanide complexes -- 6. Organometallic complexes -- 7. Kinetics and mechanisms of rare earth complexation -- 8. Spectroscopy of lanthanide complexes -- 9. Photoelectron spectroscopy of rare earths -- 10. Lanthanide NMR shift reagents -- 11. Environmental, ecological, biological aspects -- 12. Applications -- Subject index.
- 2005 CRCnetBASEeditor, William Craig Byrdwell.
- Modulated temperature differential scanning calorimetry : theoretical and practical applications in polymer characterisation2006 Springeredited by Mike Reading and Douglas J. Hourston.
- Molecular design : part I, synthesis of cyclooctatetraenes as ligands for catalysis; part II, studies on the C1B binding domain of protein kinase C2012Adam B. Lesser.The concepts of molecular analysis and design bring together structure, mechanism, and synthesis into a useful whole by allowing them to work toward a common goal. This thesis explores these concepts in two major subject areas: New Reactions and Protein/Ligand Interactions. In the first subject area, this work explores a major goal of organic synthesis, the realization of functional value of a molecular target via step economy. Indeed step economy dictates all other economies and costs including time, waste stream, and environmental goals. Improving known reactions is an important part of advancing synthesis. Of even greater consequence is the introduction of new reactions as they change how we think about bond construction. New reactions offer new ways to reduce step count and more effective and environmentally sound process options. This thesis work focuses on new reactions, new scaffolds, novel ligands for catalysis, and computational studies on these to advance this first subject area. In the second subject area, this work investigates protein/ligand interactions in the context of a cooperative project involving protein kinase C ligands. Molecular design and analysis have been fundamental in the development and implementation of this new project. This exciting area of impactful research is expected to provide numerous opportunities for further exploration. In Chapter 1, cyclooctatetraenes (COTs) are introduced as a fascinating class of molecules with great potential utility as building blocks for synthesis, scaffolds for drug discovery, ligands for catalysis, components for molecular detection devices, and novel materials. After discussing the synthesis, properties and applications of COTs, a discussion on metal-bound COTs is presented. This discussion is followed by a comprehensive critical review of the literature involving 1,2,5,6-4 COT ligands in transition metal complexes. This chapter provides background and justification for the further studies on the synthesis and use of COTs explored in Chapters 2-4. Chapter 2 describes the development of the Ni(0)-catalyzed [2+2+2+2] cycloaddition from tethered diynes that has made possible the synthesis of functionalized COTs. The initial design and development work is addressed, including the impact of important reaction variables. This is followed by an exploration of the substrate scope, including the syntheses of highly substituted COTs from non-terminal diynes to give highly substituted COTs. Studies on the physical properties and structure of these molecules are also addressed in the form of NMR experiments and X-ray crystallographic studies. Lastly, an approach toward the COT-containing natural product caulerpin utilizing the methodology is presented. This chapter provides the foundation for the COTs utilized in Chapters 3 and 4. Chapter 3 explores the use of the method developed in Chapter 2 toward metal binding ligands. A rational analysis of the COT scaffold is presented, with an emphasis on the synthesis of C2-symmetric ligands for metals. This is followed by the discussion of the synthesis and evaluation of two different ligand families encompassing 4 ligands in total. Important structural aspects of these ligands are investigated including advanced NMR and crystallographic studies. These ligands represent the first examples of topologically chiral racemic COTs used to coordinate metals through appended functionality. Initial successes and modeling studies in this area of metal-ligand binding led to the inspiration for the COTs and strategy utilized in Chapter 4. Chapter 4 is focused on the development of novel dinaphthocyclooctatetraene (dnCOT) Rh catalysts, and the resulting [5+2] cycloaddition studies. Initial unsuccessful results with COTs from Chapter 2 prompted a detailed analysis of factors involved in COT-metal bonding, including the development of a theoretical method for the prediction of COT geometries. This design-related work in turn guided the efficient synthesis of the dnCOT ligand. In addition, an expedient route to diversified dnCOTs was developed via a common bromide intermediate. The further development of dnCOT as a ligand for Rh included extensive characterization of the ligand and resulting Rh complexes in the form of crystallographic and NMR studies. Following these studies, the use of the Rh/dnCOT complex as a catalyst is examined in the context of the [5+2] cycloaddition. It was found that this species is an excellent catalyst for the reaction featuring superior reactivity in several cases when compared with other catalysts. The behavior of this catalyst was also investigated with respect to regioselectivities. The use of the Rh/dnCOT complex has also been briefly explored as a catalyst for other reactions. Finally, Chapter 5 examines the design and early implementation of a collaborative project involving protein kinase C (PKC) C1b domain ligands and REDOR NMR techniques. An introduction to PKC, bryostatin and REDOR NMR is given, followed by the overall project strategy. The design of NMR-labeled analogs of bryostatin is discussed in detailed, including computational studies used to help guide synthetic efforts. Preliminary work on elucidating the structure of the PKC/bryostatin complex is discussed in the form of docking studies to be integrated with experimental NMR data. The successful synthesis of one of the key labeled analogs designed in the previous sections, labellog 8, is described. Lastly, future directions for this promising project are explored.
- 2006 Springeredited by Richard G. Weiss and Pierre Terech.
- 2003 WileyMakoto Komiyama ... [et al.].ch. 1. Introduction, p. 1-8 -- ch. 2. Fundamentals of Molecular Imprinting, p. 9-19 -- ch. 3. Experimental Methods (1 - Procedures of Molecular Imprinting, p. 21-45 -- ch. 4. Experimental Methods (2 - Evaluation of Imprinting Efficiency, p. 47-52 -- ch. 5. Spectroscopic Anatomy of Molecular Imprinting Reactions, p. 53-64 -- ch. 6. Flow Chart of a Typical Molecular Imprinting, p. 65-73 -- ch. 7. Applications of Molecularly Imprinted Polymers, p. 75-118 -- ch. 8. Recent Challenges and Progress, p. 119-139 -- ch. 9. Conclusions and Prospects, p. 141.
- 2011Sarah Paige Sherlock.In recent years there has been a growing interest in utilizing nanomaterials for drug delivery and biomedical imaging applications. This work focuses on the development of two multifunctional graphitic-carbon based nanomaterials capable of acting as both drug delivery agents and as contrast agents for either magnetic resonance imaging or near-infrared fluorescence imaging. Both of these agents heat under near-infrared light and are capable of loading chemotherapy drugs making them multifunctional in nature. The first material discussed is a FeCo-graphitic carbon nanocrystal loaded with doxorubicin. Addition of near-infrared photothermal therapy significantly increases the cellular toxicity of these nanocrystals in vitro. Treatment of breast cancer tumors in mice using combined nanocrystal drug delivery and photothermal therapy resulted in complete tumor regression in 45% of mice. The imaging capability of these nanocrystals is demonstrated through high-resolution magnetic resonance imaging of microvessels in rabbits. The potential long-term biodistribution and safety of this material is evaluated. The second graphitic-carbon nanomaterial used in this work is single-walled carbon nanotubes. This material is developed as a deep-tissue fluorescent imaging agent due to their inherit photoluminescence beyond 1 micron. This light emission is demonstrated to be particularly useful for in vivo imaging by minimizing light scattering by tissues leading to crisp anatomical resolution.
- New cell-free platform for effective site-specific incorporation of non-natural amino acids and screening for orthogonal components2012Cem Albayrak.Proteins in all living systems are composed predominantly of 20 natural amino acids, each of which is incorporated by a processive mechanism involving dedicated transfer RNAs and enzymes called aminoacyl-tRNA synthetases. Despite the diversity in protein structure and function, these natural amino acids provide side chains with only limited reactivity. Site-specific incorporation of non-natural amino acids (nnAAs) expands the chemical reactivity of proteins and enables their precise post-translational modification. These nnAAs are incorporated in a manner analogous to natural amino acids. An orthogonal synthetase specific to the nnAA first couples the nnAA to an orthogonal amber suppressor tRNA (o-tRNA). The aminoacylated o-tRNA then forms a three-molecule complex with Ef-Tu and GTP, enters the ribosome, and at an amber stop codon (UAG) in the mRNA, adds the nnAA to the nascent polypeptide chain. Of the more than 30 nnAAs that have been site-specifically incorporated using Escherichia coli-based protein synthesis systems, the Swartz laboratory has been particularly interested in the nnAAs p-azido-L-phenylalanine (pAzF) and p-propargyloxy-L-phenylalanine (pPaF), since proteins containing these nnAAs can be directly coupled using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. In our laboratory, this technology is used to design unique and effective vaccines and diagnostic agents. Despite the improvements in the versatility and productivity of the cell-free protein synthesis (CFPS) platform, the yields of proteins containing nnAAs (i.e. modified proteins) have been substantially lower than their natural counterparts. The first part of this dissertation summarizes our efforts in improving the current methods for site-specific nnAA incorporation. Supplementing the initial CFPS system with additional o-tRNA doubled the modified protein yields. Titration experiments and turnover calculations suggested that, despite the apparent o-tRNA limitation, the synthetase is the more inefficient orthogonal component. Nonetheless, a convenient and modular method for adequate o-tRNA supply was demonstrated to further improve the efficiency of nnAA incorporation. Using this new method, in which the o-tRNA and the modified protein are produced simultaneously during the CFPS reaction, as much as 1.67 mg/ml full-length and soluble modified super-folder GFP (sfGFP) was obtained. This represents a 6-fold improvement over previous cell-free yields of modified sfGFP. This new method was used then to study nnAA incorporation at twelve different sites in sfGFP using two different o-tRNA sequences. Our results did not confirm the previous trends for the position effect (i.e. variation of modified protein yield with nnAA incorporation position). The use of the o-tRNA that was developed to better recognize the endogenous Ef-Tu decreased the size of the position effect. In addition, the method employing in situ o-tRNA synthesis was extended to the incorporation of the nnAAs into sfGFP at 2 or 3 positions. These proteins were subsequently purified and coupled to synthesize linear and branched protein polymers. After polymerization and removal of the catalyst, the specific activity of the proteins was fully retained. The second part of this dissertation describes our efforts towards developing a new set of orthogonal components from the endogenous tyrosyl tRNA/synthetase pair. A cell-free method was first developed to screen for an orthogonal variant of the E. coli tyrosyl tRNA. 201 potential orthogonal tRNAs were identified out of a library containing 384 tRNA mutants. Eight were more carefully analyzed for orthogonality (i.e. absence of cross-reactivity with E. coli synthetases) and one was identified to be both sufficiently orthogonal and not inhibitory to CFPS. Finally, the in vitro compartmentalization (IVC) method was adapted for the production of sfGFP in emulsion CFPS reactions. A method was also developed to quantify the number of adsorbed genes on a bead by fluorescence using FACS. This protocol promises to be a powerful high-throughput method for screening orthogonal synthetases.
- 2007 ScienceDirectedited by Bruno Tota and Barry Trimmer.
- 2015 SpringerChristopher Ahern, Stephan Pless, editors.Introduction -- Engineered ionized side chains -- Cysteine modification: probing channel structure, function, and conformational change -- Functional site-directed fluorometry -- Bioreactive tethers -- Flipping the photoswitch: ion channels under light control -- Incorporation of non-canonical amino acids -- Index.Also available: Print – 2015
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