A further study of the cytotoxic constituents of a milnamide-producing sponge

A reinvestigation of Auletta sp. yielded the novel compound milnamide C (3) plus the known compounds milnamide A (1), milnamide B (hemiasterlin) (2), jasplakinolide (5), and geodiamolides A (6), D (7), E (8), and G (9). The isolation work was guided by cytoskeletal bioactivity data. Compounds 2 and 3 were shown to cause microtubule depolymerization, and 6-9 were shown to cause microfilament disruption. This biological activity and the structural elucidation of 3, including X-ray analysis, are reported here. [structure: see text]     

Selective, controllable, and reversible aggregation of polystyrene latex microspheres via DNA hybridization

The directed three-dimensional self-assembly of microstructures and nanostructures through the selective hybridization of DNA is the focus of great interest toward the fabrication of new materials. Single-stranded DNA is covalently attached to polystyrene latex microspheres. Single-stranded DNA can function as a sequence-selective Velcro by only bonding to another strand of DNA that has a complementary sequence. The attachment of the DNA increases the charge stabilization of the microspheres and allows controllable aggregation of microspheres by hybridization of complementary DNA sequences. In a mixture of microspheres derivatized with different sequences of DNA, microspheres with complementary DNA form aggregates, while microspheres with noncomplementary sequences remain suspended. The process is reversible by heating, with a characteristic "aggregate dissociation temperature" that is predictably dependent on salt concentration, and the evolution of aggregate dissociation with temperature is observed with optical microscopy.     

Psymberin, a potent sponge-derived cytotoxin from Psammocinia distantly related to the pederin family

[structure: see text] Bioassay-guided fractionation of the sponge Psammocinia sp. afforded psymberin (1) possessing 5S,8S,9S,11R,13R,15S,16R,17R stereochemistry. Psymberin exhibits structural similarities to the pederin family metabolites. The potent cytotoxicty and unique structural features of 1 make it a promising lead for therapeutic development.     

Structures and cytotoxicities of fascaplysin and related alkaloids from two marine phyla—Fascaplysinopsis sponges and Didemnum tunicates

The structural variations and bioactivity properties of the alkaloids in the fascaplysin (1) and the reticulatine (3) families were examined. Four organisms were analyzed consisting of two collections of the sponge Fascaplysinopsis reticulata and two collections of the tunicate Didemnum sp. Reported are the isolation of three new compounds: 3-bromofascaplysin (2), 14-bromoreticulatine (4), and 14-bromoreticulatate (6) along with reticulatate (5) previously known as a semi-synthetic product of 1. Compounds 1 and 5 showed selectivity in a cell based cytotoxicity assay.     

Structures and cytotoxic properties of sponge-derived bisannulated acridines

A reinvestigation of sponge natural products from additional Indo-Pacific collections of Xestospongiacf. carbonaria and X. cf. exigua has provided further insights on the structures, biological activities, and biosynthetic origin of bisannulated acridines. These alkaloids include one known pyridoacridine, neoamphimedine (2), and three new analogues, 5-methoxyneoamphimedine (4), neoamphimedine Y (5), and neoamphimedine Z (6). A completely new acridine, alpkinidine (7), was also isolated. A disk diffusion soft agar assay, using a panel of five cancer cell lines (solid tumors and leukemias) and two normal cells, was used to evaluate the differential cytotoxicity (solid tumor selectivity) of the sponge semipure extracts and selected compounds including amphimedine (1), 2, 4, and 7. While all four compounds were solid tumor selective, 1 and 2 were the most potent and 4 was the most selective. The rationale used to characterize the new structures is outlined along with the related biosynthetic pathways envisioned to generate 2 and 7.     

Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice

Background  

Proteolytic degradation has emerged as a key pathway involved in controlling levels of the Alzheimer's disease (AD)-associated amyloid-β (Aβ) peptide in the brain. The endopeptidase, neprilysin, has been implicated as a major Aβ degrading enzyme in mice and humans. Previous short and intermediate term studies have shown the potential therapeutic application of neprilysin by delivering this enzyme into the brain of APP transgenic mice using gene transfer with viral vectors. However the effects of long-term neprilysin gene transfer on other aspects of Aβ associated pathology have not been explored yet in APP transgenic mice.     

Multi-objective control optimization for semi-active vehicle suspensions

In this paper we demonstrate a method for determining the optimality of control algorithms based on multiple performance objectives. While the approach is applicable to a broad range of dynamic systems, this paper focuses on the control of semi-active vehicle suspensions. The two performance objectives considered are ride quality, as measured by absorbed power, and thermal performance, as measured by power dissipated in the suspension damper. A multi-objective genetic algorithm (MOGA) is used to establish the limits of controller performance. To facilitate convergence, the MOGA is initialized with popular algorithms such as skyhook control, feedback linearization, and sliding mode control. The MOGA creates a Pareto frontier of solutions, providing a benchmark for assessing the performance of other controllers in terms of both objectives. Furthermore, the MOGA provides insight into the remaining achievable gains in performance.     

Trends in certified reference materials for the speciation of trace elements

The measurement of the chemical species of elements (instead of the total element concentration) has become an irreversible trend in analytical chemistry. The motivation lies in the fact that the biochemical and geochemical behaviour of an element is governed by its species. Quality assurance of the analytical procedures used for speciation analysis requires the analysis of representative reference materials, certified for the relevant species. Up to now the number of existing certified reference materials for trace element species is very limited. The most important ones are environmental CRMs certified for trialkyltin compounds, methylmercury, Cr(III)/Cr(VI) and food CRMs certified for arsenic species and methylmercury. Major developments are to be expected in CRMs focussed on environmental problems, including waste treatment, on bioavailability of trace elements in food and on bio-monitoring in occupational health and hygiene. It is, however, unlikely that the producers of CRMs will ever be able to cover all needs. Add to this that many, very active species are notoriously unstable and/or short living and require in-situ analysis. This will lead to different analytical developments, such as analyses in-situ, where the classical concept of CRMs may not stand firm anymore.     

Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37

Identification of methionine aminopeptidase-2 (MetAP-2) as the molecular target of the antiangiogenic compound TNP-470 has sparked interest in N-terminal Met excision's (NME) role in endothelial cell biology. In this regard, we recently demonstrated that MetAP-2 inhibition suppresses Wnt planar cell polarity (PCP) signaling and that endothelial cells depend on this pathway for normal function. Despite this advance, the substrate(s) whose activity is altered upon MetAP-2 inhibition, resulting in loss of Wnt PCP signaling, is not known. Here we identify the small G protein Rab37 as a MetAP-2-specific substrate that accumulates in the presence of TNP-470. A functional role for aberrant Rab37 accumulation in TNP-470's mode of action is demonstrated using a Rab37 point mutant that is resistant to NME, because expression of this mutant phenocopies the effects of MetAP-2 inhibition on Wnt PCP signaling-dependent processes.