‘Click’ assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

Osmolytes have been proposed as treatments for neurodegenerative proteinopathies including Alzheimer’s disease. However, for osmolytes to reach the clinic their efficacy must be improved. In this work, copper(I)-catalyzed azide–alkyne cycloaddition chemistry was used to synthesize glycoclusters bearing six copies of trehalose, lactose, galactose or glucose, with the aim of improving the potency of these osmolytes via multivalency. A trehalose glycocluster was found to be superior to monomeric trehalose in its ability to retard the formation of amyloid-beta peptide 40 (Aβ40) fibrils and protect neurons from Aβ40-induced cell death.     

Impact of plant density and microbial composition on water quality from a free water surface constructed wetland

AIMS: To correlate microbial community composition and water quality changes within wetland cells containing varying plant densities and composition in a free water surface (FWS) constructed wetland. METHODS AND RESULTS: Water chemistry was monitored weekly for nitrate, orthophosphate, and suspended solids, at various sites throughout the wetland for 6 months. Treatment ponds with 50% plant cover had about a 96.3% nitrate removal. The average change between the influent and effluent was 50-60% nitrate removal and 40-50% orthophosphate removal. Community profile of total DNA, generated by using denaturing gradient gel electrophoresis (DGGE), was used to determine the major microbial composition associated with the wetland sediment, rhizosphere, and surface water. Bacterial cloned libraries were constructed, and 300 clones were analysed by amplified ribosomal DNA restriction analysis (ARDRA) and grouped into operational taxonomic units (OTUs). A total of 35, 31, and 36 different OTU were obtained from sediment, rhizosphere, and surface water, respectively. The bacterial members within the dominant group of our clone library belonged to unclassified taxa, while the second predominant group consisted of members of the phylum Proteobacteria. The dominant organisms within the class were in the gamma, beta, and delta classes. CONCLUSION: Microbial diversity as determined by Shannon-Weaver index (H) was higher in the wetland cells with 50% plant density than the 100%. This was in agreement with the most efficient wetland contaminant removal units. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides evidence that wetlands with 50% plant cover may promote the growth of diverse microbial communities that facilitate decomposition of chemical pollutants in surface water, and improve water quality.     

Synthesis and cytotoxic activity of novel acyclic nucleoside analogues with functionality in click chemistry

We describe synthesis of novel acyclic nucleoside analogues which are building blocks for CuAAC reaction and their activity against two types of human cancer cell lines (HeLa, KB). Three of chosen compounds show promising cytotoxic activity. Synthesis pathway starting from simple and easily accessible substrates employing DMT or TBDPS protective groups is described. Adenosine and thymidine analogues containing alkyne moiety and adenosine analogue containing azido group were synthesized. The obtained units showed ability of forming triazole motif under the CuAAC reaction conditions.     

The denitrification potential and density of denitrifying bacteria in the bottom sediments of Matupi Harbor (Papua New Guinea)

The denitrification potential and density of denitrifying bacteria were determined in suboxidized sediments of Matupi Harbor (Papua New Guinea). The sediments were characterized by low denitrification potentials, not exceeding 0.8 nM/(g h). The maximum density of denitrifying bacteria was recorded in the upper sediment horizons and was 10⁴ cells/g of wet ground.     

Synthesis,anticancer activity,and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system

Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N⁶-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N⁶-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N⁶-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N⁶ and no attachment at N-1, or a combined C-10 at N⁶ and a CH₂Ph at N-1. Any alkyl chain shorter or longer than C-10 at N⁶ with a CH₂Ph attached at N-1, would result in decrease of biological activity.     

Analogs of iso-azepinomycin as potential transition-state analog inhibitors of guanase: Synthesis,biochemical screening,and structure–activity correlations of various selectively substituted imidazo[4,5-e][1,4]diazepines

Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as does iso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming that iso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs of iso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O⁵ oxygen atom of iso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O⁵ results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O⁵ considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has a K_i value of 8.0 ± 1.5 μM against rabbit liver guanase.     

The Chemical Basis of Membrane Bioenergetics

All organisms rely on chemiosmotic membrane systems for energy transduction; the great variety of participating proteins and pathways can be reduced to a few universal principles of operation. This chemical basis of bioenergetics is reviewed with respect to the origin and early evolution of life. For several of the cofactors which play important roles in bioenergetic reactions, plausible prebiotic sources have been proposed, and it seems likely that these cofactors were present before elaborate protein structures. In particular, the hydrophobic quinones require only a membrane-enclosed compartment to yield a minimum chemiosmotic system, since they can couple electron transport and proton translocation in a simple way. It is argued that the central features of modern bioenergetics, such as the coupling of redox reactions and ion translocation at the cytoplasmic membrane, probably are ancient features which arose early during the process of biogenesis. The notion of a thermophile root of the universal phylogenetic tree has been discussed controversially, nevertheless, thermophiles are interesting model organisms for reconstructing the origin of chemiosmotic systems, since they are often acidophiles and anaerobic respirers exploiting iron–sulfur chemistry. This perspective can help to explain the prominent role of iron–sulfur proteins in extant biochemistry as well as the origin of both respiration and proton extrusion within the context of a possible origin of life in the vicinity of hot vents. Received: 6 June 2001 / Accepted: 16 October 2001     

Canopy throughfall links canopy epiphytes to terrestrial vegetation in pristine conifer forests

To what extent does epiphytic community composition in boreal forests reflect soil nutrient status? To answer this question, we investigated potential links between terrestrial plants and lichen-dominated communities in Picea glauca x engelmannii canopies in south-central British Columbia. We combined original data on vegetational composition in the ground and tree layers with published data on elemental uptake in standardized transplants of the lichen Lobaria pumonaria affixed to the lower branches of studied trees. Procrustean association metrics revealed a significant concordance between community composition among the epiphytic and terrestrial vegetation, which was stronger in Mn-enriched conifer canopy settings, and weaker within the cation-enriched dripzones of adjacent Populus trees. We also found that the NMDS1-gradient for each vegetation layer was strongly correlated with base cations (and inversely with Mn) in canopy throughfall, as well as with soil and bark pH. We conclude that elemental composition in canopy throughfall forms a functional link between terrestrial and epiphytic vegetation.     

Τesting models for the beginnings of the Aurignacian and the advent of figurative art and music: the radiocarbon chronology of Geißenklösterle

The German site of Geißenklösterle is crucial to debates concerning the European Middle to Upper Palaeolithic transition and the origins of the Aurignacian in Europe. Previous dates from the site are central to an important hypothesis, the Kulturpumpe model, which posits that the Swabian Jura was an area where crucial behavioural developments took place and then spread to other parts of Europe. The previous chronology (critical to the model), is based mainly on radiocarbon dating, but remains poorly constrained due to the dating resolution and the variability of dates. The cause of these problems is disputed, but two principal explanations have been proposed: a) larger than expected variations in the production of atmospheric radiocarbon, and b) taphonomic influences in the site mixing the bones that were dated into different parts of the site. We reinvestigate the chronology using a new series of radiocarbon determinations obtained from the Mousterian, Aurignacian and Gravettian levels. The results strongly imply that the previous dates were affected by insufficient decontamination of the bone collagen prior to dating. Using an ultrafiltration protocol the chronometric picture becomes much clearer. Comparison of the results against other recently dated sites in other parts of Europe suggests the Early Aurignacian levels are earlier than other sites in the south of France and Italy, but not as early as recently dated sites which suggest a pre-Aurignacian dispersal of modern humans to Italy by ∼45000 cal BP. They are consistent with the importance of the Danube Corridor as a key route for the movement of people and ideas. The new dates fail to refute the Kulturpumpe model and suggest that Swabian Jura is a region that contributed significantly to the evolution of symbolic behaviour as indicated by early evidence for figurative art, music and mythical imagery.