Peptide design by artificial neural networks and computer-based evolutionary search

A technique for systematic peptide variation by a combination of rational and evolutionary approaches is presented. The design scheme consists of five consecutive steps: (i) identification of a “seed peptide” with a desired activity, (ii) generation of variants selected from a physicochemical space around the seed peptide, (iii) synthesis and testing of this biased library, (iv) modeling of a quantitative sequence-activity relationship by an artificial neural network, and (v) de novo design by a computer-based evolutionary search in sequence space using the trained neural network as the fitness function. This strategy was successfully applied to the identification of novel peptides that fully prevent the positive chronotropic effect of anti-β1-adrenoreceptor autoantibodies from the serum of patients with dilated cardiomyopathy. The seed peptide, comprising 10 residues, was derived by epitope mapping from an extracellular loop of human β1-adrenoreceptor. A set of 90 peptides was synthesized and tested to provide training data for neural network development. De novo design revealed peptides with desired activities that do not match the seed peptide sequence. These results demonstrate that computer-based evolutionary searches can generate novel peptides with substantial biological activity.

Recent insights into the mucosal reactions associated with Giardia lamblia infections.

Giardia lamblia is an intestinal protozoan parasite infecting humans and various other mammalian hosts. The most important clinical signs of giardiasis are diarrhoea and malabsorption. Giardia lamblia is able to undergo continuous antigenic variation of its major surface antigen, named VSP (variant surface protein). While intestinal antibodies, and more specifically anti-VSP IgA antibodies, were proven to be involved in modulating antigenic variation of the parasite the participation of the local antibody response in control of the parasite infection is still controversial. Conversely, previous studies based on experimental infections in mice showed that cellular immune mechanisms are essential for elimination of the parasite from its intestinal habitat. Furthermore, recent data indicated that inflammatory mast cells have a potential to directly, or indirectly, interfere in duodenal growth of G. lamblia trophozoites. However, this finding was challenged by other reports, which did not find a correlation between intestinal inflammation and resistance to infection. Since intestinal infiltration of inflammatory cells and/or CD8+T-cells were demonstrated to coincide with villus-shortening and crypt hyperplasia immunological reactions were considered to be a potential factor of pathogenesis in giardiasis. The contribution of physiological factors to pathogenesis was essentially assessed in vitro by co-cultivation of G. lamblia trophozoites with epithelial cell lines. By using this in vitro model, molecular (through surface lectins) and mechanical (through ventral disk) adhesion of trophozoites to the epithelium was shown to be crucial for increased epithelial permeability. This phenomenon as well as other Giardia-induced intestinal abnormalities such as loss of intestinal brush border surface area, villus flattening, inhibition of disaccharidase activities, and eventually also overgrowth of the enteric bacterial flora seem to be involved in the pathophysiology of giardiasis. However, it remains to be elucidated whether at least part of these pathological effects are causatively linked to the clinical manifestation of the disease.

Traité élémentaire et pratique du dessin et de la peinture à l'usage des jeunes artistes : contenant des observations sur les différentes manières de dessiner, les règles de la composition, du clair obscur et du coloris, l'apprêt et le mélange des couleurs, la connaissance des vernis, secrets et procédés pour les paysages à l'encre de la Chine, à l'aquarelle et à la gouache, les régles pour la figure ou pour la peinture à l'huile en général, et quatre gravures raisonnées /

The folded plate is table with watercolor samples and tipped in at front.

Records relating to the early history of Boston ...

Editors: 1876-1890, W. H. Whitmore and W. S. Appleton, record commissioners; 1893-1896, W. H. Whitmore, city registrar; 1894, W. S. Appleton; 1898, E. W. McGlenen; 1900-1909, E. W. McGlenen, city registrar; 1903 (v. 32) W. H. Whitmore, W. K. Watkins, and E. W. McGlenen.

Handbuch der Altertumswissenschaft,

Includes various editions of some vols.

Theorie der statistik. Nebst ideen ueber das studium der politik ueberhaupt. 1.heft. Einleitung.

Half title: Stats gelartheit nach ihren haupt theilen, im auszug und zusammenhang. 2 th.

Verschiedenes zum Unterricht und zur Unterhaltung für Liebhaber der Gaukeltasche, des Magnetismus, und anderer Seltenheiten /

Mode of access: Internet.

Alltägliche Auftritte im Menschenleben in Erzählungen gesammelt als Beiträge zur Menschenkenntniss /

Mode of access: Internet.

Tratado de fisiologia /

Contiene: t. III (Encuadernado con el t. IV) - t. IV - t. V (Encuadernado con el t. VI y VII) - t. VI - t. VII.

Antichità ascolane /

Reprint. Originally published: 1792.

Sitzungsberichte und abhandlungen der Naturforschenden Gesellschaft zu Rostock.

Editor: 1909- Johannes Müller.

Tratado de fisiología /

Mode of access: Internet.

Nachgelassene Werke.

Viñeta en port.