Solution structure and proposed binding mechanism of a novel potassium channel toxin kappa-conotoxin PVIIA

Background: kappa-PVIIA is a 27-residue polypeptide isolated from the venom of Conus purpurascens and is the first member of a new class of conotoxins that block potassium channels. By comparison to other ion channels of eukaryotic cell membranes, voltage-sensitive potassium channels are relatively simple and methodology has been developed for mapping their interactions with small-peptide toxins, PVIIA, therefore, is a valuable new probe of potassium channel structure. This study of the solution structure and mode of channel binding of PVIIA forms the basis for mapping the interacting residues at the conotoxin-ion channel interface. Results: The three-dimensional structure of PVIIA resembles the triple-stranded beta sheet/cystine-knot motif formed by a number of toxic and inhibitory peptides. Subtle structural differences, predominantly in loops 2 and 4, are observed between PVIIA and other conotoxins with similar structural frameworks, however. Electrophysiological binding data suggest that PVIIA blocks channel currents by binding in a voltage-sensitive manner to the external vestibule and occluding the pore, Comparison of the electrostatic surface of PVIIA with that of the well-characterised potassium channel blocker charybdotoxin suggests a likely binding orientation for PVIIA, Conclusions: Although the structure of PVIIA is considerably different to that of the alpha K scorpion toxins, it has a similar mechanism of channel blockade. On the basis of a comparison of the structures of PVIIA and charybdotoxin, we suggest that Lys19 of PVIIA is the residue which is responsible for physically occluding the pore of the potassium channel.

Briefing: Factored material properties and limit state loads-unlikely extreme or impossible pretense

In the limit state design (LSD) method each design criterion is formally stated and assessed using a performance function. The performance function defines the relationship between the design parameters and the design criterion. In practice, LSD involves factoring up loads and factoring down calculated strengths and material parameters. This provides a convenient way to carry out routine probabilistic-based design. The factors are statistically calculated to produce a design with an acceptably low probability of failure. Hence the ultimate load and the design material properties are mathematical concepts that have no physical interpretation. They may be physically impossible. Similarly, the appropriate analysis model is also defined by the performance function and may not describe the real behaviour at the perceived physical equivalent limit condition. These points must be understood to avoid confusion in the discussion and application of partial factor LSD methods.

Nanosized polymetallic resorcinarene-based host assemblies that strongly bind fullerenes

Polymetallic nanodimensional assemblies have been prepared via metal directed assembly of dithiocarbamate functionalized cavitand structural frameworks with late transition metals (Ni, Pd, Cu, Au, Zn, and Cd). The coordination geometry about the metal centers is shown to dictate the architecture adopted. X-ray crystallographic studies confirm that square planar coordination geometries result in "cagelike" octanuclear complexes, whereas square-based pyramidal metal geometries favor hexanuclear "molecular loop" structures. Both classes of complex are sterically and electronically complementary to the fullerenes (C-60 and C-70). The strong binding of these guests occurred via favorable interactions with the sulfur atoms of multiple dithiocarbamate moieties of the hosts. In the case of the tetrameric copper(II) complexes, the lability of the copper(II)-dithiocarbamate bond enabled the fullerene guests to be encapsulated in the electron-rich cavity of the host, over time. The examination of the binding of fullerenes has been undertaken using spectroscopic and electrochemical methods, electrospray mass spectrometry, and molecular modeling.

Rhodium-catalyzed carbonylation of allylaminoalcohols: Catalytic synthesis of N-(2-hydroxy-alkyl)-gamma-lactams and bicyclic oxazolidines

Gamma-lactams and bicyclic oxazolidines are important structural frameworks in both synthetic organic chemistry and related pharmacological fields. These heterocycles can be prepared by the rhodium-catalyzed carbonylation of unsaturated amines. In this work, allylaminoalcohols, derived from the aminolysis of cyclohexene oxide, styrene oxide, (R)-(+)-limonene oxide, and ethyl-3-phenyl-glicidate, were employed as substrates. These allylaminoalcohols were carbonylated by employing RhClCO(PPh3)(2) as a precatalyst under varying CO/H-2 mixtures, and moderate to excellent yields were obtained, depending on the substrate used. The results indicated that an increase in the chelating ability of the substrate (-OH and -NHR moieties) decreased the conversion and selectivity of the ensuing reaction. Additionally, the selectivity could be optimized to favor either the gamma-lactams or the oxazolidines by controlling the CO/H-2 ratio. A large excess of CO provided a lactam selectivity of up to 90%, while a H-2-rich gas mixture improved the selectivity for oxazolidines, resulting from hydroformylation/cyclization. Studies of the reaction temperature indicated that an undesirable substrate deallylation reaction occurs at higher temperature (>100 degrees C). Further, kinetic studies have indicated that the oxazolidines and gamma-lactams were formed through parallel routes. Unfortunately, the mechanism for oxazolidines formation is not yet well understood. However, our results have led us to propose a catalytic cycle based on hydroformylation/acetalyzation pathways. The gamma-lactams formation follows a carbonylation route, mediated by a rhodium-carbamoylic intermediate, as previously reported. To this end, we have been able to prepare and isolate the corresponding iridium complex, which could be confirmed by X-ray crystallographic analysis. (C) 2008 Elsevier B.V. All rights reserved.

Copper-organic frameworks assembled from in situ generated 5-(4-pyridyl) tetrazole building blocks: synthesis, structural features, topological analysis and catalytic oxidation of alcohols

Two new metal- organic compounds {[Cu-3(mu(3)-4-(p)tz)(4)(mu(2)-N-3)(2)(DMF)(2)](DMF)(2)}(n) (1) and {[Cu(4ptz) (2)(H2O)(2)]}(n) (2) {4-ptz = 5-(4-pyridyl)tetrazolate} with 3D and 2D coordination networks, respectively, have been synthesized while studying the effect of reaction conditions on the coordination modes of 4-pytz by employing the [2 + 3] cycloaddition as a tool for generating in situ the 5-substituted tetrazole ligands from 4-pyridinecarbonitrile and NaN3 in the presence of a copper(II) salt. The obtained compounds have been structurally characterized and the topological analysis of 1 discloses a topologically unique trinodal 3,5,6-connected 3D network which, upon further simplification, results in a uninodal 8-connected underlying net with the bcu (body centred cubic) topology driven by the [Cu-3(mu(2)-N-3)(2)] cluster nodes and mu(3)-4-ptz linkers. In contrast, the 2D metal-organic network in 2 has been classified as a uninodal 4-connected underlying net with the sql [Shubnikov tetragonal plane net] topology assembled from the Cu nodes and mu(2)-4-ptz linkers. The catalytic investigations disclosed that 1 and 2 act as active catalyst precursors towards the microwave-assisted homogeneous oxidation of secondary alcohols (1-phenylethanol, cyclohexanol, 2-hexanol, 3-hexanol, 2-octanol and 3-octanol) with tert-butylhydroperoxide, leading to the yields of the corresponding ketones up to 86% (TOF = 430 h(-1)) and 58% (TOF = 290 h(-1)) in the oxidation of 1-phenylethanol and cyclohexanol, respectively, after 1 h under low power ( 10 W) microwave irradiation, and in the absence of any added solvent or additive.

Self-assembled Transition Metal Coordination Frameworks of Carbohydrazone and Thiocarbohydrazone Ligands: Structural, Spectral, Magnetic and Anticancer Properties

Chemistry occupies a unique middle position in the scientific arena, between physics and mathematics on the one side and biology, ecology, sociology and economics on the other [1]. Chemistry is the science of matter and of its transformations, and life is its highest expression [2]. According to reductionist thinking biology is reducible into chemistry, chemistry into physics, and ultimately physics into mathematics. Reductionism implies the ease of understanding one level in terms of another.The work presented this thesis comprises synthesis and characterization of suitably substituted thiocarbohydrazone and carbohydrazone ligand building blocks, self-assembled metallosupramolecular square grid complexes as well as some di/multinuclear complexes. The primary aim was the deliberate syntheses of some novel transition metal framework complexes, mainly metallosupramolecular coordination square grids by self-assembly and their physico-chemical characterization. The work presented, however, also include synthesis and characterization of four mononuclear Ni(II) complexes of two thiosemicarbazones, which we carried out as a preliminary and supporting study. Based on the present work we would like to conclude that the carbohydrazones, thiocarbohydrazones and their coordination framework complexes of transition metals are promising systems for wide application in science and technology varied from physics to biotechnology. Novel classes of materials and biologically important potential compounds open up further scope of researches and we hopefully welcome any sort of related research to make this work more valuable.

Synthesis, structural characterization, luminescent properties and theoretical study of three novel lanthanide metal-organic frameworks of Ho(III), Gd(III) and Eu(III) with 2,5-thiophenedicarboxylate anion

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Frameworks for Systemic and Structural Analysis of Financial Innovations in Infrastructure

Financial innovations have emerged globally to close the gap between the rising global demand for infrastructures and the availability of financing sources offered by traditional financing mechanisms such as fuel taxation, tax-exempt bonds, and federal and state funds. The key to sustainable innovative financing mechanisms is effective policymaking. This paper discusses the theoretical framework of a research study whose objective is to structurally and systemically assess financial innovations in global infrastructures. The research aims to create analysis frameworks, taxonomies and constructs, and simulation models pertaining to the dynamics of the innovation process to be used in policy analysis. Structural assessment of innovative financing focuses on the typologies and loci of innovations and evaluates the performance of different types of innovative financing mechanisms. Systemic analysis of innovative financing explores the determinants of the innovation process using the System of Innovation approach. The final deliverables of the research include propositions pertaining to the constituents of System of Innovation for infrastructure finance which include the players, institutions, activities, and networks. These static constructs are used to develop a hybrid Agent-Based/System Dynamics simulation model to derive propositions regarding the emergent dynamics of the system. The initial outcomes of the research study are presented in this paper and include: (a) an archetype for mapping innovative financing mechanisms, (b) a System of Systems-based analysis framework to identify the dimensions of Systems of Innovation analyses, and (c) initial observations regarding the players, institutions, activities, and networks of the System of Innovation in the context of the U.S. transportation infrastructure financing.

Synthesis and structural stability of metal-organic frameworks

Metal-organic frameworks (MOFs) have attracted significant attention during the past decade due to their high porosity, tunable structures, and controllable surface functionalities. Therefore many applications have been proposed for MOFs. All of them however are still in their infancy stage and have not yet been brought into the market place. In this thesis, the background of the MOF area is first briefly introduced. The main components and the motifs of designing MOFs are summarized, followed by their synthesis and postsynthetic modification methods. Several promising application areas of MOFs including gas storage and separation, catalysis and sensing are reviewed. The current status of commercialization of MOFs as new chemical products is also summarized. Examples of the design and synthesis of two new MOF structures Eu(4,4′,4′′,4′′′-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid))·2H2O∙xDMF and Zn4O(azobenzene-4,4’-dicarboxylic acid)3∙xNMP are described. The first one contains free-base porphyrin centers and the second one has azobenzene components. Although the structures were synthesized as designed, unfortunately they did not possess the expected properties. The research idea to use MOFs as template materials to synthesize porous polymers is introduced. Several methods are discussed to grow PMMA into IRMOF-1 (Zn4O(benzene-1,4-dicarboxylate)3, IR stands for isoreticular) structure. High concentration of the monomers resulted in PMMA shell after MOF digestion while with low concentration of monomers no PMMA was left after digestion due to the small iii molecular weight. During the study of this chapter, Kitagawa and co-workers published several papers on the same topic, so this part of the research was terminated thereafter. Many MOFs are reported to be unstable in air due to the water molecules in air which greatly limited their applications. By incorporating a number of water repelling functional groups such as trifluoromethoxy group and methyl groups in the frameworks, the water stability of MOFs are shown to be significantly enhanced. Several MOFs inculding Banasorb-22 (Zn4O(2-trifluoromethoxybenzene-1,4-dicarboxylate)3), Banasorb-24 (Zn4O(2, 5-dimethylbenzene-1,4-dicarboxylate)3) and Banasorb-30 (Zn4O(2-methylbenzene-1,4-dicarboxylate)3) were synthesized and proved to have isostructures with IRMOF-1. Banasorb-22 was stable in boiling water steam for one week and Banasorb-30’s shelf life was over 10 months under ambient condition. For comparison, IRMOF-1’s structure collapses in air after a few hours to several days. Although MOF is a very popular research area nowadays, only a few studies have been reported on the mechanical properties of MOFs. Many of MOF’s applications involve high pressure conditions, so it is important to understand the behavior of MOFs under elivated pressures. The mechanical properties of IRMOF-1 and a new MOF structure Eu2(C12N2O4H6)3(DEF)0.87(H2O)2.13 were studied using diamond anvil cells at Advanced Photon Source. IRMOF-1 experienced an irriversible phase transtion to a nonporous phase followed by amorphization under high pressure. Eu2(C12N2O4H6)3(DEF)0.87(H2O)2.13 showed reversible compression under pressure up to 9.08GPa.

An improved continuous medium technique for structural frame analysis

This paper presents an improved constitutive equation of frame in the context of continuous medium technique. This improved constitutive equation, which is a consistent formulation of column global bending, is applicable to a complete class of frameworks including the ideal shear frame panel, for which the beams are assumed to be rigid, and the associated column system, for which the rigidity of beams is negligible. Global buckling and second-order effects of the frame structure are discussed. The main results can be extended to other types of lateral stiffening elements as built-up columns. A worked example is presented in order to compare the main results with those obtained by the classic matrix method. Copyright (C) 2007 John Wiley & Sons, Ltd.

The Finnish it industries in transition. Defining and Measuring the Finnish Software Product and IT Services Industries by Applying Theoretical Frameworks

The starting point of this study is that the prevailing way to consider the Finnish IT industries and industry information often results in a limited and even skewed picture of the sector. The purpose of the study is to contribute and increase knowledge and understanding of the status, structure and evolution of the Finnish IT industries as well as the Finnish IT vendor field and competition. The focus is on software product and IT services industries which form a crucial part of all ICT industries. This study examines the Finnish IT sector from production (supply) as well as market (demand) perspective. The study is based on empirical information from multiple sources. Three research questions were formulated for the study. The first concerns the status of the Finnish IT industries considered by applying theoretical frameworks. The second research question targets at the basis for the future evolution of the Finnish IT industries and, finally, the third at the ability of the available definitions and indicators to describe the Finnish IT industries and IT markets. Major structural changes like technological changes and related innovations, globalization and new business models are drivers of the evolution of the IT industries. The findings of this study emphasize the significant role of IT services in the Finnish IT sector and in connection to that the ability to combine IT service skills, competences and practices with high level software skills also in the future. According to the study the Finnish IT enterprises and their customers have become increasingly dependent on global ecosystems and platforms, applications and IT services provided by global vendors. As a result, more IT decisions are made outside Finland. In addition, IT companies are facing new competition from other than IT industries bringing into market new substitutes. To respond to the new competition, IT firms seek growth by expanding beyond their traditional markets.. The changing global division of labor accentuates the need for accurate information of the IT sector but, at the same time, also makes it increasingly challenging to acquire the information needed. One of the main contributions of this study is to provide frameworks for describing the Finnish IT sector and its evolution. These frameworks help combine empirical information from various sources and make it easier to concretize the structures, volumes, relationships and interaction of both, the production and market side of the Finnish IT industry. Some frameworks provide tools to analyze the vendor field, competition and the basis for the future evolution of the IT industries. The observations of the study support the argument that static industry definitions and related classifications do not serve the information needs in dynamic industries, such as the IT industries. One of the main messages of this study is to emphasize the importance of understanding the definitions and starting points of different information sources. Simultaneously, in the structure and evolution of Finnish IT industries the number of employees has become a more valid and reliable measure than the revenue based indicators.

Specificity grafting of human antibody frameworks selected from a phage display library: generation of a highly stable humanized anti-CD22 single-chain Fv fragment

A prerequisite for the enrichment of antibodies screened from phage display libraries is their stable expression on a phage during multiple selection rounds. Thus, if stringent panning procedures are employed, selection is simultaneously driven by antigen affinity, stability and solubility. To take advantage of robust pre-selected scaffolds of such molecules, we grafted single-chain Fv (scFv) antibodies, previously isolated from a human phage display library after multiple rounds of in vitro panning on tumor cells, with the specificity of the clinically established murine monoclonal anti-CD22 antibody RFB4. We show that a panel of grafted scFvs retained the specificity of the murine monoclonal antibody, bound to the target antigen with high affinity (6.4-9.6 nM), and exhibited exceptional biophysical stability with retention of 89-93% of the initial binding activity after 6 days of incubation in human serum at 37degreesC. Selection of stable human scaffolds with high sequence identity to both the human germline and the rodent frameworks required only a small number of murine residues to be retained within the human frameworks in order to maintain the structural integrity of the antigen binding site. We expect this approach may be applicable for the rapid generation of highly stable humanized antibodies with low immunogenic potential.

Anion-directed synthesis of metal-organic frameworks based on 2-picolinate Cu(II) complexes: a ferromagnetic alternating chain and two unprecedented ferromagnetic fish backbone chains

Three new polynuclear copper(II) complexes of 2-picolinic acid (Hpic), {[Cu-2(pic)(3)(H2O)]ClO4}(n) (1), {[Cu-2(pic)(3)(H2O)]BF4}(n) (2), and [Cu-2(pic)3(H2O)(2)(NO3)](n) (3), have been synthesized by reaction of the "metalloligand" [Cu-(pic)(2)] with the corresponding copper(II) salts. The compounds are characterized by single-crystal X-ray diffraction analyses and variable-temperature magnetic measurements. Compounds 1 and 2 are isomorphous and crystallize in the triclinic system with space group P (1) over bar, while 3 crystallizes in the monoclinic system with space group P2(1)/n. The structural analyses reveal that complexes 1 and 2 are constructed by "fish backbone" chains through syn-anti (equatorial-equatorial) carboxylate bridges, which are linked to one another by syn-anti (equatorial-axial) carboxylate bridges, giving rise to a rectangular grid-like two-dimensional net. Complex 3 is formed by alternating chains of syn-anti carboxylate-bridged copper(II) atoms, which are linked together by strong H bonds involving coordinated nitrate ions and water molecules and uncoordinated oxygen atoms from carboxylate groups. The different coordination ability of the anions along with their involvement in the H-bonding network seems to be responsible for the difference in the final polymeric structures. Variable-temperature (2-300 K) magnetic susceptibility measurement shows the presence of weak ferromagnetic coupling for all three complexes that have been fitted with a fish backbone model developed for 1 and 2 (J = 1.74 and 0.99 cm(-1); J' = 0.19 and 0.25 cm(-1), respectively) and an alternating chain model for 3 (J = 1.19 cm(-1) and J' = 1.19 cm(-1)).

Helices, chirality and interpenetration: the versatility and remarkable interconversion of silver-copper cyanide frameworks

The structural transformations between cesium silver-copper cyanides under modest conditions, both in solution and in the solid state, are described. Three new cesium silver(I) copper(I) cyanides with three-dimensional (3-D) framework structures were prepared as single crystals from a one-pot reaction initially heated under hydrothermal conditions. The first product to appear, Cs3Ag2Cu3(CN)(8) (I), when left in contact with the supernatant produced CsAgCu(CN)(3) (II) and CsAgCu(CN)(3)center dot 1/3H(2)O (III) over a few months via a series of thermodynamically controlled cascade reactions. Crystals of the hydrate (III) can be dehydrated to polycrystalline CsAgCu(CN)(3) (II) on heating at 100 degrees C in a remarkable solid-state transformation involving substantial breaking and reconnection of metal-cyanide linkages. Astonishingly, the conversion between the two known polymorphs of CsAg2Cu(CN)(4), which also involves a major change in connectivity and topology, occurs at 180 degrees C as a single-crystal to single-crystal transformation. Structural features of note in these materials include the presence of helical copper-cyanide chains in (I) and (II), which in the latter compound produce a chiral material. In (II) and (III), the silver-copper cyanide networks are both self- and interpenetrating, features also seen in the known polymorphs of CsAg2Cu(CN)(4).

Crystal Engineering of an Anti-HIV Drug Based on the Recognition of Assembling Molecular Frameworks

A rational strategy was employed for design of an orthorhombic structure of lamivudine with maleic acid. On the basis of the lamivudine saccharinate structure reported in the literature, maleic acid was chosen to synthesize a salt with the anti-HIV drug because of the structural similarities between the salt formers. Maleic acid has an acid-ionization constant of the anti first proton and an arrangement of their hydrogen bonding functionalities similar to those of saccharin. Likewise, there is a saccharin-like conformational rigidity in maleic acid because of the hydrogen-bonded ring formation and the Z-configuration around the C=C double bond. As was conceivably predicted, lamivudine maleate assembles into a structure whose intermolecular architecture is related to that of saccharinate salt of the drug. Therefore, a molecular framework responsible for crystal assembly into a lamivudine saccharinate-like structure could be recognized in the salt formers. Furthermore, structural correlations and structure-solubility relationships were established for lamivudine maleate and saccharinate. Although there is a same molecular framework in maleic acid and saccharin, these salt formers are Structurally different in some aspects. When compared to saccharin, neither out-of-plane SO(2) oxygens nor a benzene group occur in maleic acid. Both features could be related to higher solubility of lamivudine maleate. Here, we also anticipate that multicomponent molecular crystals of lamivudine with other salt formers possessing the molecular framework responsible for crystal assembly can be engineered successfully.