Flexible antibodies with nonprotein hinges

There is a significant need for antibodies that can bind targets with greater affinity. Here we describe a novel strategy employing chemical semisynthesis to produce symmetroadhesins: antibody-like molecules having nonprotein hinge regions that are more flexible and extendible and are capable of two-handed binding. Native chemical ligation was carried out under mild, non-denaturing conditions to join a ligand binding domain (Aβ peptide) to an IgG1 Fc dimer via discrete oxyethylene oligomers of various lengths. Two-handed Aβ-Fc fusion proteins were obtained in quantitative yield and shown by surface plasmon resonance to bind an anti-Aβ antibody with a K(D) at least two orders of magnitude greater than the cognate Aβ peptide. MALDI-TOF MS analysis confirmed the protein/nonprotein/protein structure of the two-handed molecules, demonstrating its power to characterize complex protein-nonprotein hybrids by virtue of desorption/ionization mediated by peptide sequences contained therein. We anticipate many applications for symmetroadhesins that combine the target specificity of antibodies with the novel physical, chemical and biological properties of nonprotein hinges.     

Calculation of Stresses and Consistent Tangent Moduli from Automatic Differentiation of Hyerelastic Strain Energy Functions Through the Use of Hyper Dual Numbers

Many materials as e.g. engineering rubbers, polymers and soft biological tissues are often described by hyperelastic strain energy functions. For their finite element implementation the stresses and consistent tangent moduli are required and obtained mainly in terms of the first and second derivative of the strain energy function. Depending on its mathematical complexity in particular for anisotropic media the analytic derivatives may be expensive to be calculated or implemented. Then numerical approaches may be a useful alternative reducing the development time. Often-used classical finite difference schemes are however quite sensitive with respect to perturbation values and they result in a poor accuracy. The complex-step derivative approximation does never suffer from round-off errors, cf. [1], [2], but it can only provide first derivatives. A method which also provides higher order derivatives is based on hyper dual numbers [3]. This method is independent on the choice of perturbation values and does thus neither suffer from round-off errors nor from approximation errors. Therefore, here we make use of hyper dual numbers and propose a numerical scheme for the calculation of stresses and tangent moduli which are almost identical to the analytic ones. Its uncomplicated implementation and accuracy is illustrated by some representative numerical examples. (© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Rhodium-catalyzed Reformatsky-type reaction for asymmetric synthesis of difluoro-β-lactams using menthyl group as a chiral auxiliary

We developed a new methodology for the asymmetric Reformatsky-type reaction of (−)-menthyl bromodifluoroacetate (2) with imine in the presence of RhCl(PPh₃)₃. Ester 2 with the cost-effective chiral auxiliary gave (S)-difluoro-β-lactams in moderate to good yields and high diastereoselectivities through spontaneous removal of the auxiliary.     

Study on line tension of air/hexadecane/aqueous surfactant system

We measured the line tension of the air/hexadecane/aqueous solution of the dodecyltrimethylammonium bromide (DTAB) system as a function of the molality of DTAB aqueous solution at 298.15 K. The experimental values of the line tension were 10^?10 to 10^?12 N, and they coincided with the theoretical estimates. Furthermore, it was found that the line tension changes in sign from positive to negative at around 0.750 mmol kg^?1. This concentration is close to the point of transition from partial to frustrated-complete wetting. Taking into account the profiles of the free energy of the air/water surface, previously developed by Indekeu to understand the interrelationship between the wetting transition and line tension, it is suggested that the sign reversal of the line tension can be attributed to the transition from partial to frustrated-complete wetting.     

6,6'-Substituent effect of BINOL in bis-titanium chiral Lewis acid catalyzed 1,3-dipolar cycloaddition of nitrones

By the accommodation of modified BINOLs as chiral ligands, enantioselectivities in the bis-titanium chiral Lewis acid catalyzed 1,3-dipolar cycloaddition of N-diphenylmethyl nitrones and methacrolein could be improved.     

Autophagy and bacterial infectious diseases

Autophagy is a housekeeping process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic constituents. Over the past several years, accumulating evidence has suggested that autophagy can function as an intracellular innate defense pathway in response to infection with a variety of bacteria and viruses. Autophagy plays a role as a specialized immunologic effector and regulates innate immunity to exert antimicrobial defense mechanisms. Numerous bacterial pathogens have developed the ability to invade host cells or to subvert host autophagy to establish a persistent infection. In this review, we have summarized the recent advances in our understanding of the interaction between antibacterial autophagy (xenophagy) and different bacterial pathogens.     

Application of axially dissymmetric ligand recoverable with fluorous solvent as a chiral auxiliary

(Ra)-(R)₂-2,2′-Bis(1-hydroxy-1H-perfluorooctyl)biphenyl ((Ra)-(R)₂-1c), which is an axially dissymmetric ligand with two chiral centers, works as a good chiral auxiliary for asymmetric aldol reaction. Thus, the reaction of monopropanoyl ester of 1c (2) with benzaldehyde in the presence of triethylamine and titanium(IV) chloride gave (2R),(3S)- and (2R),(3R)-3-hydroxy-2-methyl-3-phenylpropanoic acid esters (3a) in an approximate ratio of 4:1 in a total high yield. This result shows that stereoselectivity at 2-position is quite high, while that at 3-position is moderate. Both isomers were easily separated by column chromatography. Methanolysis of the separated isomers gave nearly quantitative recovery of 1c by extraction with a fluorous solvent without any loss of ee, while methyl (2R),(3S)- or (2R),(3R)-3-hydroxy-2-methyl-3-phenylpropanoates were obtained by CH₂Cl₂ extraction quantitatively in >99% ee. Aldol reaction of 2 with various aldehydes gave similar results.