Structural Determination of an Unusual CuI-Porphyrin-π-Bond in a Hetero-Pacman Cu-Zn-Complex

The synthesis and characterization of a hetero-dinuclear compound is presented, in which a copper(I) trishistidine type coordination unit is positioned directly above a zinc porphyrin unit. The close distance between the two coordination fragments is secured by a rigid xanthene backbone, and a unique (intramolecular) copper porphyrin-π-bond was determined for the first time in the molecular structure. This structural motif was further analyzed by temperature-dependent NMR studies: In solution at room temperature the coordinative bond fluctuates, while it can be frozen at low temperatures. Preliminary reactivity studies revealed a reduced reactivity of the copper(I) moiety towards dioxygen. The results adumbrate why nature is avoiding metal porphyrin-π-bonds by fixing reactive metal centers in a predetermined distance to each other within multimetallic enzymatic reaction centers.     

Probing Hydrogen Bonding to Bound Dioxygen in Synthetic Models for Heme Proteins: The Importance of Precise Geometry

Distal hydrogen bonding in natural dioxygen binding proteins is crucial for the discrimination between different potential ligands such as O₂ or CO. In the present study, we probe the chemical requirements for proper distal hydrogen bonding in a series of synthetic model compounds for dioxygen‐binding heme proteins. The model compounds 1‐Co to 7‐Co bear different distal residues. The hydrogen bonding in their corresponding dioxygen adducts is directly measured by pulse EPR spectroscopy. The geometrical requirements for this interaction to take place were found to be narrow and very specific. Only two model complexes, 1‐Co and 7‐Co , form a hydrogen bond to bound dioxygen, which was characterized in terms of geometry and nature of the bond. The geometry and dipolar nature of this interaction in 1‐Co ‐O₂ is more similar to the one in natural cobalt myoglobin (Co‐Mb), making 1‐Co the best model compound in the entire series.     

Fluorous-based peptide microarrays for protease screening

As ever more protease sequences are uncovered through genome sequencing projects, efficient parallel methods to discover the potential substrates of these proteases becomes crucial. Herein we describe the first use of fluorous-based microarrays to probe peptide sequences and begin to define the scope and limitations of fluorous microarray technologies for the screening of proteases. Comparison of a series of serine proteases showed that their ability to cleave peptide substrates in solution was maintained upon immobilization of these substrates onto fluorous-coated glass slides. The fluorous surface did not serve to significantly inactivate the enzymes. However, addition of hydrophilic components to the peptide sequences could induce lower rates of substrate cleavage with enzymes such as chymotrypsin with affinities to hydrophobic moieties. This work represents the first step to creating robust protease screening platforms using noncovalent microarray interface that can easily incorporate a range of compounds on the same slide.     

Learning concurrently partition granularities and rule bases of Mamdani fuzzy systems in a multi-objective evolutionary framework

In this paper we propose a multi-objective evolutionary algorithm to generate Mamdani fuzzy rule-based systems with different good trade-offs between complexity and accuracy. The main novelty of the algorithm is that both rule base and granularity of the uniform partitions defined on the input and output variables are learned concurrently. To this aim, we introduce the concepts of virtual and concrete rule bases: the former is defined on linguistic variables, all partitioned with a fixed maximum number of fuzzy sets, while the latter takes into account, for each variable, a number of fuzzy sets as determined by the specific partition granularity of that variable. We exploit a chromosome composed of two parts, which codify the variables partition granularities, and the virtual rule base, respectively. Genetic operators manage virtual rule bases, whereas fitness evaluation relies on an appropriate mapping strategy between virtual and concrete rule bases. The algorithm has been tested on two real-world regression problems showing very promising results.     

Transforming algebraic Riccati equations into unilateral quadratic matrix equations

The problem of reducing an algebraic Riccati equation XCX − AX − XD + B = 0 to a unilateral quadratic matrix equation (UQME) of the kind PX ² + QX + R = 0 is analyzed. New transformations are introduced which enable one to prove some theoretical and computational properties. In particular we show that the structure preserving doubling algorithm (SDA) of Anderson (Int J Control 28(2):295–306, 1978) is in fact the cyclic reduction algorithm of Hockney (J Assoc Comput Mach 12:95–113, 1965) and Buzbee et al. (SIAM J Numer Anal 7:627–656, 1970), applied to a suitable UQME. A new algorithm obtained by complementing our transformations with the shrink-and-shift technique of Ramaswami is presented. The new algorithm is accurate and much faster than SDA when applied to some examples concerning fluid queue models.     

Synthesis and Pharmacological Screening of Pyridopyrimidines as Effective Anti-Diarrheal Agents through the Suppression of Cyclic Nucleotide Accumulation

The increased levels of cyclic nucleotides (cGMP and cAMP) in enterocytes trigger intracellular mechanisms of ion and fluid secretion into the lumen, causing secretory diarrhea. Twelve novel pyridopyrimidines derived from 5-(3,5-bistrifluoromethylphenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno[2,1 : 5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (FPIPP) were synthesized and evaluated on intracellular cyclic nucleotide accumulation. All compounds had no effect on either cyclic nucleotide basal levels or on pre-contracted aortic rings. The metabolic activity and viability in T84 cells, assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and the LDH (lactate dehydrogenase) assays, respectively, were not affected by incubation with the compounds (50 μM). Compound VI almost abolished cGMP accumulation (94 % inhibition) induced by STa toxin in T834 cells and significantly reduced (69 %) forskolin-induced cAMP accumulation in Jurkat cells. Compound VI was active in an in vivo model for diarrhea in rabbits. These results prompted us to perform a microscopic histopathological analysis of intestinal tissues, showing that only compound VI preserves the intestine without significant pathological changes and with a decreased inflammatory pattern in comparison to FPIPP. In vitro stability test revealed that compound VI is resistant to oxidation promoted by atmospheric oxygen.     

Gitterkonstanten und Strukturen der Verbindungen DyHg,HoHg, ErHg; DyHg2, HoHg2, ErHg2; DyHg3, HoHg3 und ErHg3

Zusammenfassung Durch direkte Reaktion der metallischen Komponenten Dy, Ho oder Er mit Hg werden die PhasenSEHg,SEHg₂ undSEHg₃ (SE-Dy, Ho, Er) hergestellt. Ihre Gitterkonstanten und Kristallstrukturen [SEHg: CsCl(B 2)-Typ;SEHg₂: AlB₂(C 32)-Typ;SEHg₃: Mg₃Cd(DO₁₉)-Typ] werden bestimmt.

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A direct reaction between the metallic components Dy, Ho or Er with Hg yields the phasesREHg,REHg₂ andREHg₃ (RE=Dy, Ho, Er). The lattice spacings and crystal structures [REHg: CsCl(B 2)-type;REHg₂: AlB₂(C 32)-type;REHg₃: Mg₃Cd(DO₁₉)-type] have been established.

     

On the computation of l- groups and natural maps

In this paper we compute surgery (resp. splitting) obstruction groups, here calledL-groups, and natural maps for many diagrams of oriented finite (not necessary abelian) 2-groups and homomorphisms which preserve orientations.     

Identification of a small molecule that inhibits herpes simplex virus DNA Polymerase subunit interactions and viral replication

The interaction between the catalytic subunit Pol and the processivity subunit UL42 of herpes simplex virus DNA polymerase has been characterized structurally and mutationally and is a potential target for novel antiviral drugs. We developed and validated an assay for small molecules that could disrupt the interaction of UL42 and a Pol-derived peptide and used it to screen approximately 16,000 compounds. Of 37 "hits" identified, four inhibited UL42-stimulated long-chain DNA synthesis by Pol in vitro, of which two exhibited little inhibition of polymerase activity by Pol alone. One of these specifically inhibited the physical interaction of Pol and UL42 and also inhibited viral replication at concentrations below those that caused cytotoxic effects. Thus, a small molecule can inhibit this protein-protein interaction, which provides a starting point for the discovery of new antiviral drugs.