Solution structure of Atg8 reveals conformational polymorphism of the N-terminal domain

During autophagy a crescent shaped like membrane is formed, which engulfs the material that is to be degraded. This membrane grows further until its edges fuse to form the double membrane covered autophagosome. Atg8 is a protein, which is required for this initial step of autophagy. Therefore, a multistage conjugation process of newly synthesized Atg8 to phosphatidylethanolamine is of critical importance. Here we present the high resolution structure of unprocessed Atg8 determined by nuclear magnetic resonance spectroscopy. Its C-terminal subdomain shows a well-defined ubiquitin-like fold with slightly elevated mobility in the pico- to nanosecond timescale as determined by heteronuclear NOE data. In comparison to unprocessed Atg8, cleaved Atg8^G116 shows a decreased mobility behaviour. The N-terminal domain adopts different conformations within the micro- to millisecond timescale. The possible biological relevance of the differences in dynamic behaviours between both subdomains as well as between the cleaved and uncleaved forms is discussed.     

Effectiveness of liposomal paclitaxel against MCF-7 breast cancer cells

Paclitaxel is an effective chemotherapeutic agent that is widely used for the treatment of several cancers, including breast, ovarian, and non-small-cell lung cancer. Due to its high lipophilicity, paclitaxel is difficult to administer and requires solubilization with Cremophor EL (polyethoxylated castor oil) and ethanol, which often lead to adverse side effects, including life-threatening anaphylaxis. Incorporation of paclitaxel in dimyristoylphosphatidylcholine:dimyristoylphosphatidylglycerol (DPPC:DMPG) liposomes can facilitate its delivery to cancer cells and eliminate the adverse reactions associated with the Cremophor EL vehicle. Accordingly, the effectiveness of liposomal paclitaxel on MCF-7 breast cancer cells was examined. The results from this study showed that (i) the lipid components of the liposomal formulation were nontoxic, (ii) the cytotoxic effects of liposomal paclitaxel were improved when compared with those seen with conventional paclitaxel, and (iii) the intracellular paclitaxel levels were higher in MCF-7 cells treated with the liposomal paclitaxel formulation. The results of these studies showed that delivery of paclitaxel as a liposomal formulation could be a promising strategy for enhancing its chemotherapeutic effects.     

Cross-habitat impacts of species decline: response of estuarine sediment communities to changing detrital resources

Food webs of many ecosystems are sustained by organic matter from other habitats. Human activities and climatic change are increasingly modifying the quality and supply of these resources, yet for most ecosystems it is unknown how the taxonomic composition of organic matter influences community composition. Along the coastline of Sydney, Australia, the once abundant habitat-forming macroalga, Phyllospora comosa, is now locally extinct. Shallow reefs are now primarily occupied by Sargassum sp. and, to a lesser extent, the kelp Ecklonia radiata. We experimentally manipulated the supply of P. comosa, Sargassum sp. and E. radiata to estuarine sediments to assess responses by macroinvertebrate communities to: (1) changing the identity of the dominant detrital resource; and (2) varying the ratio of input of different macrophytes. Estuarine sediments dosed with P. comosa supported greater abundances of macroinvertebrates than sediments receiving Sargassum sp. or the kelp E. radiata. Whereas plots receiving Sargassum sp. or E. radiata had fewer macroinvertebrates than controls, plots receiving a moderate (120 g dry weight per m²) loading of P. comosa had more. Mixtures of detritus dominated by P. comosa supported similar macroinvertebrate communities to monocultures of the alga. Communities in sediments receiving detritus comprised of less than one-third P. comosa were, however, distinctly different. Our study provides evidence that the ecological ramifications of species decline can extend to spatially removed ecosystems, subsidised by allochthonous materials. Even prior to extinction of detrital sources, small changes in their provision of organic matter may alter the structure of subsidised communities.     

A putative transporter is essential for integrating nutrient and hormone signaling with lateral root growth and nodule development in Medicago truncatula

Legume root architecture involves not only elaboration of the root system by the formation of lateral roots but also the formation of symbiotic root nodules in association with nitrogen‐fixing soil rhizobia. The Medicago truncatula LATD/NIP gene plays an essential role in the development of both primary and lateral roots as well as nodule development. We have cloned the LATD/NIP gene and show that it encodes a member of the NRT1(PTR) transporter family. LATD/NIP is expressed throughout the plant. pLATD/NIP‐GFP promoter–reporter fusions in transgenic roots establish the spatial expression of LATD/NIP in primary root, lateral root and nodule meristems and the surrounding cells. Expression of LATD/NIP is regulated by hormones, in particular by abscisic acid which has been previously shown to rescue the primary and lateral root meristem arrest of latd mutants. latd mutants respond normally to ammonium but have defects in responses of the root architecture to nitrate. Taken together, these results suggest that LATD/NIP may encode a nitrate transporter or transporter of another compound.     

Design of a novel class of biphenyl CETP inhibitors

A new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic mouse PD model.