Reduced neuronal expression of synaptic transmission modulator HNK-1/neural cell adhesion molecule as a potential consequence of amyloid beta-mediated oxidative stress: a proteomic approach

Abstract Oxidative stress imparted by reactive oxygen species (ROS) is implicated in the pathogenesis of Alzheimer's disease (AD). Given that amyloid beta (Abeta) itself generates ROS that can directly damage proteins, elucidating the functional consequences of protein oxidation can enhance our understanding of the process of Abeta-mediated neurodegeneration. In this study, we employed a biocytin hydrazide/streptavidin affinity purification methodology followed by two-dimensional liquid chromatography tandem mass spectrometry coupled with SEQUEST bioinformatics technology, to identify the targets of Abeta-induced oxidative stress in cultured primary cortical mouse neurons. The Golgi-resident enzyme glucuronyltransferase (GlcAT-P) was a carbonylated target that we investigated further owing to its involvement in the biosynthesis of HNK-1, a carbohydrate epitope expressed on cell adhesion molecules and implicated in modulating the effectiveness of synaptic transmission in the brain. We found that increasing amounts of Abeta, added exogenously to the culture media of primary cortical neurons, significantly decreased HNK-1 expression. Moreover, in vivo, HNK-1 immunoreactivity was decreased in brain tissue of a transgenic mouse model of AD. We conclude that a potential consequence of Abeta-mediated oxidation of GlcAT-P is impairment of its enzymatic function, thereby disrupting HNK-1 biosynthesis and possibly adversely affecting synaptic plasticity. Considering that AD is partly characterized by progressive memory impairment and disordered cognitive function, the data from our in vitro studies can be reconciled with results from in vivo studies that have demonstrated that HNK-1 modulates synaptic plasticity and is critically involved in memory consolidation.     

A Stochastic Model for the Synthesis and Degradation of Natural Organic Matter. Part I. Data Structures and Reaction Kinetics

Here we present a stochastic biogeochemical model for the formation, transformation and mineralization of natural organic matter (NOM). The model is agent-based, with each software agent representing a single molecule of defined composition. Molecular properties and reactivities are estimated from composition and environmental parameters. Environmental parameters including temperature, pH, light intensity, dissolved O₂, moisture and enzyme activities are user controlled. Time is treated in discrete steps, and during each step potential reaction probabilities are evaluated for each molecule based on its structure and the environmental parameters. When reactions occur, the molecular composition is modified accordingly. The model uses small natural products and biopolymers for inputs, and the composition of the molecules produced is constrained only by the inputs and reaction stoichiometries, not by pre-defined structures. Example simulations using the program AlphaStep are presented, in which the breakdown of biopolymers and the condensation of small molecules both lead to molecular assemblages with elemental composition and average properties similar to those of aquatic NOM. This batch-reactor model can be expanded to include spatial information and environmental feedback.     

Synthesis, growth inhibition, and cell cycle evaluations of novel flavonoid derivatives

As a continuation of our search for potential new anticancer agents, a series of ten flavonoid derivatives has been synthesized by cyclization of substituted chalcones. Target compounds were evaluated for their biological activity. Among them, compounds 1–4 and 9 displayed a significant growth inhibitory action against a panel of tumor cell lines including Jurkat, PC-3, and Colon 205. On treatment with an equitoxic (IC₅₀) concentration, compounds 1–5 and 7–9 blocked cells in the G2/M phase of the Jurkat cell cycle, whereas compound 6 blocked the same in the G0/G1 phase.     

Spatiotemporal variation in benthic polychaetes (Annelida) and relationships with environmental variables in a tropical estuary

Annelida constitute a dominant functional component in soft-bottom macrobenthic communities and reveal a wide range of adaptability to different marine and coastal habitats. Analyses in different polychaete assemblages and their responses to habitat conditions reflect the biological effects of marine pollution and habitat disturbance. The present study is designed to study colonization and community structure of polychaetes in two ecologically distinct locations of the Sundarban Biosphere Reserve on the northeast coast of India. Polychaete assemblages are characteristically different at the two sites in the extreme northern (Ghusighata) and southern (Gangasagar) portions of the Biosphere Reserve. Levels of heavy metals in polychaete body tissues also reveal interspecific and regional variations. The predominant polychaete fauna exhibited a distinct and unique assemblage of two types: (i) Mastobranchus indicus – Dendronereides heteropoda in the sewage-fed substratum at Ghusighata and (ii) Lumbrinereis notocirrata – Ganganereis sootai – Glycera tesselata at Gangasagar at the mouth of the Hugli estuary where chronic anthropogenic stress and contamination with agricultural and industrial effluents occur. The faunistic composition of polychaetes and their potential for the accumulation of heavy metals from the ambient medium are distinctly different. The study demonstrates that textural composition of the sediments, together with hydrodynamic and geotechnical properties, seem to have the greatest control to quantify the differences of the polychaete community in the two study stations. An in-depth comparative study of polychaete community structure at multiple spatial scales is strongly recommended for future environmental impact assessment in this fragile environment.     

Community-based Monitoring of Natural Resource Use and Forest Quality in Montane Forests and Miombo Woodlands of Tanzania

A community-based monitoring system that focuses on natural resource use and forest quality in montane evergreen forest and miombo woodland areas was developed and implemented in 23 villages in 2002 as part of a participatory forest management regime in Iringa District, Tanzania. The scheme was developed to suit the needs and capacities of locally-elected natural resource committees managing and monitoring natural forests. Rather than measuring biodiversity, the monitoring is focused on resource extraction and disturbance. High levels of commitment to the monitoring were displayed by village level managers, and the preliminary feed-back indicates that the monitoring scheme provides them with the relevant information needed to suggest appropriate management interventions. While external support has been essential to cover development costs, natural resource revenue generated at village level can provide most of the running costs. Once developed, the scheme can, however, be transferred to similar areas at significantly lower costs that can be met by Tanzanian District budgets. Natural resource revenue generated from montane forests is generally much lower than in woodland areas due to restrictions on resource extraction imposed as a consequence of national and international interests. Opportunities to provide economic incentives for montane forest managers through direct utilisation of the resource are limited and it remains to be seen whether other non-economic incentives can sustain long term commitment in these biodiversity rich areas. Findings indicate that the key elements of this local resource utilisation monitoring scheme are simplicity, incentive mechanisms, transparency and accountability, and autonomy for local managers. However, the methods may not provide sufficient data on changes in biodiversity values in the high value forests and may need to be augmented by conventional monitoring by scientists funded by national or international institutions. Elements of the scheme are now being institutionalised within the forestry sector in Tanzania.     

Drazepinone, a trisubstituted tetrahydronaphthofuroazepinone with herbicidal activity produced by Drechslera siccans

When grown in a minimal-defined medium, a strain of Drechslera siccans, a pathogenic fungus isolated from seeds of Lolium perenne, produced phytotoxic metabolites. This strain is one of the best toxin producers among several grass pathogenic fungal strains collected and tested to find phytotoxins to be used as natural herbicides of monocot weeds. From the culture filtrates of D. siccans, we isolated a new phytotoxic trisubstituted naphthofuroazepinone, named drazepinone, and characterised it as a 3,5,12a-trimethyl-2,5,5a,12a-tetrahydro-1H-naphtho[2',3':4,5]furo[2,3-b]azepin-2-one. Assayed at 2 microg microl(-1) solution the novel metabolite proved to have broad-spectrum herbicidal properties, without antibacterial and antifungal activities, and low zootoxic activity. Its original chemical structure and the interesting biological properties make drazepinone a potential natural herbicide.     

Tyrosine kinase inhibitors from the rainforest tree Polyscias murrayi

A series of 3-(4-hydroxyphenyl) propanoic acid derivatives, which inhibit Itk (interleukin-2 inducible T-cell kinase), a Th2-cell target, were isolated from the Australian rainforest tree Polyscias murrayi. The new compound 3-(4-hydroxyphenyl) propionyl choline and a 2:1 mixture of the new compounds 3,4-di-O-3-(4-hydroxyphenyl) propionyl-1,5-dihydroxycyclohexanecarboxylic acid and 3,5-di-O-3-(4-hydroxyphenyl) propionyl-1,4-dihydroxycyclohexanecarboxylic acid were isolated along with two known compounds 3-(4-hydroxyphenyl) propanoic acid and 3-(3,4-hydroxyphenyl) propanoic acid. Their structures were determined by 1D and 2D NMR spectroscopy. The assay results suggest that both the 3-(4-hydroxyphenyl) propanoate and carboxyl moieties contribute to Itk activity of the compounds.     

Spatial and temporal distribution of carbon isotopes in soil organic matter at the Dinghushan Biosphere Reserve, South China

The spatial and temporal distribution of carbon isotopes (¹³C, ¹⁴C) in soil organic matter (SOM) were studied based on SOM content, SOM ¹⁴C and SOM ¹³C of thinly layered soil samples for six soil profiles with different elevations at the Dinghushan Biosphere Reserve (DHSBR), South China. The results indicate that variations of SOM ¹³C with depth of the soil profiles at different elevations are controlled by soil development, and correlate well with SOM composition in terms of SOM compartments with different turnover rates, and SOM turnover processes at the DHSBR. The effect of carbon isotope fractionation was obvious during transformation of organic matter (OM) from plant debris to SOM in topsoil and SOM turnover processes after the topsoil was buried, which resulted in great increments of OM ¹³C, respectively. Increments of SOM ¹³C of topsoil from ¹³C of plant debris were controlled by SOM turnover rates. Both topsoil SOM ¹³C and plant debris ¹³C increase with elevation, indicating regular changes in vegetation species and composition with elevation, which is consistent with the vertical distribution of vegetation at the DHSBR. The six soil profiles at different elevations had similar characteristics in variations of SOM ¹³C with depth, alterations of SOM contents with depth and that SOM ¹⁴C apparent ages increasing with depth, respectively. These are presumably attributed to the regular distribution of different SOM compartments with depth because of their regular turnover during soil development. Depth with the maximal SOM ¹³C value is different in mechanism and magnitude with penetrating depth of ¹⁴C produced by nuclear explosion into atmosphere from 1952 to 1962, and both indicate controls of topography and vegetation on the distribution of SOM carbon isotopes with depth. Elevation exerts indirect controls on the spatial and temporal distribution of SOM carbon isotopes of the studied mountainous soil profiles at the DHSBR. This study shows that mountainous soil profiles at different elevations and with distinctive aboveground vegetation are presumably ideal sites for studies on soil carbon dynamics in different climatic-vegetation zones.     

Investigating the morphology, function and genetics of cytotoxic cells in bony fish

Bony fish (teleosts) possess multiple cytotoxic cell lineages that recognize and destroy virally infected and transformed cells. In general, these lineages parallel their functional equivalents in mammals and include neutrophilic granulocytes, macrophages, cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. These four cell types have been morphologically identified in multiple fish species but only limited information is available about their function. In contrast, much work has gone into examining the function of a fifth cytotoxic cell lineage, termed nonspecific cytotoxic cells (NCC), that has been referred to as the bony fish equivalent of NK cells. However, evidence suggesting that NCC do not represent the NK lineage has come through the development of multiple cytotoxic catfish cell lines that are morphologically and functionally similar to human NK cells and are distinct from NCC. In addition to characterizing cytotoxic cells from fish, recent work has identified the novel immune-type receptors (NITR) and cichlid killer leukocyte receptors (cKLR) that are structurally related to mammalian NK receptors and likely play a role in cytotoxic function in fish. This review summarizes the morphological and functional evidence for cytotoxic cells within bony fish and discusses future directions for examining cytotoxicity through genomics and transgenics.