A NOVEL APPROACH TO SOLID PHASE CHEMICAL SYNTHESIS OF OLIGONUCLEOTIDE mRNA CAP ANALOGS

A novel approach for the synthesis of 5′-capped 2′-O-methyloligoribonucleotides on a disulfide-tethered solid support is described. The key step of the synthesis is ZnCl₂ promoted coupling of m⁷GDP imidazolide to a fully deprotected oligonucleotide 5′-phosphate on-support. By this methodology m⁷G⁵′pppm²′Apm²′Upm^2′Ap has been prepared.     

Mechanisms of madness: evolutionary psychiatry without evolutionary psychology

Delusions are currently characterised as false beliefs produced by incorrect inference about external reality (DSM IV). This inferential conception has proved hard to link to explanations pitched at the level of neurobiology and neuroanatomy. This paper provides that link via a neurocomputational theory, based on evolutionary considerations, of the role of the prefrontal cortex in regulating offline cognition. When pathologically neuromodulated the prefrontal cortex produces hypersalient experiences which monopolise offline cognition. The result is characteristic psychotic experiences and patterns of thought. This bottom-up account uses neural network theory to integrate recent theories of the role of dopamine in delusion with the insights of inferential accounts. It also provides a general model for evolutionary psychiatry which avoids theoretical problems imported from evolutionary psychology.     

Evolution as a cognition process: Towards an evolutionary epistemology

Recently, biologist and philosophers have been much attracted by an evolutionary view of knowledge, so-called evolutionary epistemology. Developing this insight, the present paper argues that our cognitive abilities are the outcome of organic evolution, and that, conversely, evolution itself may be described as a cognition process. Furthermore, it is argued that the key to an adequate evolutionary epistemology lies in a system-theoretical approach to evolution which grows from, but goes beyond, Darwin's theory of natural selection.     

Synthesis of N-glycan units for assessment of substrate structural requirements of N-acetylglucosaminyltransferase III

N-Acetylglucosaminyltransferase (GnT) III is a glycosyltransferase which produces bisected N-glycans by transferring GlcNAc to the 4-position of core mannose. Bisected N-glycans are involved in physiological and pathological processes through the functional regulation of their carrier proteins. An understanding of the biological functions of bisected glycans will be greatly accelerated by use of specific inhibitors of GnT-III. Thus far, however, such inhibitors have not been developed and even the substrate-binding mode of GnT-III is not fully understood. To gain insight into structural features required of the substrate, we systematically synthesized four N-glycan units, the branching parts of the bisected and non-bisected N-glycans. The series of syntheses were achieved from a common core trimannose, giving bisected tetra- and hexasaccharides as well as non-bisected tri- and pentasaccharides. A competitive GnT-III inhibition assay using the synthetic substrates revealed a vital role for the Manβ(1–4)GlcNAc moiety. In keeping with previous reports, GlcNAc at the α1,3-branch is also involved in the interaction. The structural requirements of GnT-III elucidated in this study will provide a basis for rational inhibitor design.     

Synthesis,molecular docking,acetylcholinesterase and butyrylcholinesterase inhibitory potential of thiazole analogs as new inhibitors for Alzheimer disease

A series of thirty (30) thiazole analogs were prepared, characterized by ¹H NMR, ¹³C NMR and EI-MS and evaluated for Acetylcholinesterase and butyrylcholinesterase inhibitory potential. All analogs exhibited varied butyrylcholinesterase inhibitory activity with IC₅₀ value ranging between 1.59 ± 0.01 and 389.25 ± 1.75 μM when compared with the standard eserine (IC₅₀, 0.85 ± 0.0001 μM). Analogs 15, 7, 12, 9, 14, 1, 30 with IC₅₀ values 1.59 ± 0.01, 1.77 ± 0.01, 6.21 ± 0.01, 7.56 ± 0.01, 8.46 ± 0.01, 14.81 ± 0.32 and 16.54 ± 0.21 μM respectively showed excellent inhibitory potential. Seven analogs 15, 20, 19, 24, 28, 30 and 25 exhibited good acetylcholinesterase inhibitory potential with IC50 values 21.3 ± 0.50, 35.3 ± 0.64, 36.6 ± 0.70, 44.81 ± 0.81, 46.36 ± 0.84, 48.2 ± 0.06 and 48.72 ± 0.91 μM respectively. All other analogs also exhibited well to moderate enzyme inhibition. The binding mode of these compounds was confirmed through molecular docking.     

Morphology and diversity of the forcipules in Strigamia centipedes (Chilopoda,Geophilomorpha)

The morphology of the venomous limbs (forcipules) of 13 species of Strigamia and of six other geophilomorphs was studied with light microscopy, scanning electron microscopy, and, for a subsample, with confocal laser scanning microscopy. In all Strigamia species a well-distinct denticle is present invariantly on the inner side of the terminal article (tarsungulum), in sub-basal position, just proximal to a faint transverse sulcus and a cuticular introflexion that corresponds to the insertion point of a tendon. Strigamia species differ mainly in size and shape of the denticle and thickness of the distal part of the tarsungulum, suggesting some functional diversity in piercing and handling prey. Anatomical evidence supports the hypothesis that the tarsungulum corresponds to two ancestral articles and a denticle at the basis of the tarsungulum originated multiple times within geophilomorphs, however in different positions corresponding to either the ancestral sub-terminal article (in Strigamia, other Geophiloidea and some Schendylidae) or the ancestral terminal article (in the himantariid Thracophilus).     

An efficient, practical synthesis of 2-methoxyestradiol

An efficient and practical scheme to synthesize 2-methoxyestradiol has been developed. The key step was the copper-mediated methoxylation using ethyl acetate as a co-catalyst to introduce a methoxyl group. These synthetic procedures of four steps from 17β-estradiol as starting material gave 2-methoxyestradiol with a 61% overall yield.     

Evolutionary steps of ecophysiological adaptation and diversification of ruminants: a comparative view of their digestive system

Summary A review is made of the ruminant digestive system in its morphophysiological variations and adaptations relating to foraging behaviour, digestive physiology, to interactions between plants and ruminants and to geographic and climatic diversity of ruminants' ecological niches. Evidence is provided for evolutionary trends from an extreme selectivity mainly for plant cell contents and dependence upon a fractionated fore- and hindgut fermentation, to an unselective intake of bulk roughage subjected to an efficient plant cell wall fermentation, mainly in the forestomachs. The review is based on detailed comparative morphological studies of all portions of the digestive system of 65 ruminant species from four continents. Their results are related to physiological evidence and to the classification of all extant ruminants into a flexible system of three overlapping morphophysiological feeding types: concentrate selectors (40%), grass and roughage eaters (25%) and intermediate, opportunistic, mixed feeders (35%). Several examples are discussed how ruminants of different feeding types are gaining ecological advantage and it is concluded that ruminants have achieved high levels of digestive efficiency at each evolutionary stage, (including well-documented seasonal adaptations of the digestive system) and that ruminant evolution is still going on. Deductions made from the few domesticated ruminant species may have, in the past, biased scientific evaluation of the free-ranging species' ecology. The main threat to a continuous ruminant evolution and diversity appears to be man's neglect for essential ecological interactions between wild ruminants and their specific habitats, which he alters or destroys.Abbreviations bw body weight - CS concentrate selector - DFC distal fermentation chamber (distended caecocolon) - GR grass and roughage eater - IM intermediate (mixed) feeder - PFC proximal fermentation chamber (ruminoreticulum/forestomachs) - RR Ruminoreticulum - SCFA Short-chain fatty acis (acetic, butyric, propionic acid set free by rumen bacteriae) - SE Surface enlargement (of absorptive mucosa) Supported by German Research Community grant DFG Ho 273/6Dedicated to Professor Dr. Dr. h.c. Dietrich Starck on the occasion of his 80th birthday     

Evolutionary trends of the hairy-faceSaguinus in terms of the dental and cranial morphology

Shape variations in the dentition and the cranium were analyzed for sevenSaguinus forms of the hairy-face tamarin by applying the factor analysis method. The results obtained for the dental and cranial measurements were almost consistent with each other. The magnitude of the difference in shape factors between theS. nigricollis group and theS. midas group is appreciably larger than that between the former group and theS. mystax group. If the ancestral geographic centre of origin is postulated as being within the region which is inhabited by the livingS. nigricollis group, the morphological distances between any pairs of groups correlate well with the geographic distances between them. Concerning the dental and cranial morphologies, the physical changes in the three species group probably took place in two directions; that is, from theS. nigricollis group to theS. mystax group, and from theS. nigricollis group to theS. midas group. The forms belonging to each species group are more closely related to each other, with the exception ofS. imperator in theS. mystax group. The uniqueness ofS. imperator was clearly demonstrated by factor analysis and distance analysis. In theS. mystax group, although still hypothetical,S. imperator may have been related only through the basic ancestral stock toS. labiatus andS. mystax.