Clusterin facilitates in vivo clearance of extracellular misfolded proteins

The extracellular deposition of misfolded proteins is a characteristic of many debilitating age-related disorders. However, little is known about the specific mechanisms that act to suppress this process in vivo. Clusterin (CLU) is an extracellular chaperone that forms stable and soluble complexes with misfolded client proteins. Here we explore the fate of complexes formed between CLU and misfolded proteins both in vitro and in a living organism. We show that proteins injected into rats are cleared more rapidly from circulation when complexed with CLU as a result of their more efficient localization to the liver and that this clearance is delayed by pre-injection with the scavenger receptor inhibitor fucoidan. The CLU–client complexes were found to bind preferentially, in a fucoidan-inhibitable manner, to human peripheral blood monocytes and isolated rat hepatocytes and in the latter cell type were internalized and targeted to lysosomes for degradation. The data suggest, therefore, that CLU plays a key role in an extracellular proteostasis system that recognizes, keeps soluble, and then rapidly mediates the disposal of misfolded proteins.     

Philosophical Differences: The Case of Architects' Reluctance to Use Strategic Planning Software

A briefing workshop was run in an effort to involve its participants in choosing a strategic direction, and eventual form, for a proposed facility. The workshop was an action research, participative process that sought to improve final design by preconsultation with some relevant stakeholders. This paper will specifically focus on our attempt to use strategic planning software at an early stage of such a workshop. It discusses and illustrates the difficulties of importing a new technique into an established, professional setting where activities and roles may be expressed, or assumed, on the basis of previous experience. More exactly, although we hoped to use our software to analyze and explore participants' design styles, and so predict their likely choice of design option, the architects present undermined such analyzes by playing a role rather than telling the software what they really thought about the various strategic choices. Hence it was, in some ways, a waste of time using our software. We speculate below whether such undermining might be symptomatic of deep philosophical differences between the workshop organizers, planners, and architects. We also examine whether such differences bode ill for the future of architecture.     

Spectral evidence for weathered basalt as an alternative to andesite in the northern lowlands of Mars

Mineral abundances derived from the analysis of remotely sensed thermal emission data from Mars have been interpreted to indicate that the surface is composed of basalt (Surface Type 1) and andesite (Surface Type 2). The global distribution of these rock types is divided roughly along the planetary dichotomy which separates ancient, heavily cratered crust in the southern hemisphere (basalt) from younger lowland plains in the north (andesite). But the existence of such a large volume of andesite is difficult to reconcile with our present understanding of the geological evolution of Mars. Here we reinterpret martian surface rock lithologies using mineral abundances from previous work and new mineralogies derived from a spectral end-member set representing minerals common in unaltered and low-temperature aqueously altered basalts. Our results continue to indicate the dominance of unaltered basalt in the southern highlands, but reveal that the northern lowlands can be interpreted as weathered basalt as an alternative to andesite. The coincidence between locations of such altered basalt and a suggested northern ocean basin implies that lowland plains material may be composed of basalts weathered under submarine conditions or weathered basaltic sediments transported into this depocentre.     

Evolution of genes and genomes on the Drosophila phylogeny

Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.     

The sub-energetic gamma-ray burst GRB 031203 as a cosmic analogue to the nearby GRB 980425

Over the six years since the discovery of the gamma-ray burst GRB 980425, which was associated with the nearby (distance approximately 40 Mpc) supernova 1998bw, astronomers have debated fiercely the nature of this event. Relative to bursts located at cosmological distance (redshift z approximately 1), GRB 980425 was under-luminous in gamma-rays by three orders of magnitude. Radio calorimetry showed that the explosion was sub-energetic by a factor of 10. Here we report observations of the radio and X-ray afterglow of the recent GRB 031203 (refs 5-7), which has a redshift of z = 0.105. We demonstrate that it too is sub-energetic which, when taken together with the low gamma-ray luminosity, suggests that GRB 031203 is the first cosmic analogue to GRB 980425. We find no evidence that this event was a highly collimated explosion viewed off-axis. Like GRB 980425, GRB 031203 appears to be an intrinsically sub-energetic gamma-ray burst. Such sub-energetic events have faint afterglows. We expect intensive follow-up of faint bursts with smooth gamma-ray light curves (common to both GRB 031203 and 980425) to reveal a large population of such events.     

Evidence for magmatic evolution and diversity on Mars from infrared observations

Compositional mapping of Mars at the 100-metre scale with the Mars Odyssey Thermal Emission Imaging System (THEMIS) has revealed a wide diversity of igneous materials. Volcanic evolution produced compositions from low-silica basalts to high-silica dacite in the Syrtis Major caldera. The existence of dacite demonstrates that highly evolved lavas have been produced, at least locally, by magma evolution through fractional crystallization. Olivine basalts are observed on crater floors and in layers exposed in canyon walls up to 4.5 km beneath the surface. This vertical distribution suggests that olivine-rich lavas were emplaced at various times throughout the formation of the upper crust, with their growing inventory suggesting that such ultramafic (picritic) basalts may be relatively common. Quartz-bearing granitoid rocks have also been discovered, demonstrating that extreme differentiation has occurred. These observations show that the martian crust, while dominated by basalt, contains a diversity of igneous materials whose range in composition from picritic basalts to granitoids rivals that found on the Earth.     

A preliminary survey of the insect fauna of the Hajar Mountain Range,Oman

The Hajar Mountain Range of Northern Oman is an important centre of species endemism, and of biogeographical interest as a crossroads between the Afrotropical and Palaearctic regions. Despite this, the invertebrate fauna of the region is largely unknown, with very little dedicated research or surveys having been undertaken until now. Here we present the invertebrate species collected and identified from five different survey locations within the Hajar Mountains. This preliminary checklist contains 296 records, of which 36 are new records for Oman. Our surveys also discovered two new species of ant: Lepisiota omanensis collected from Jebel Qahwan Reserve and at the base of Jebel Akhdar, and Anochetus annetteae from Hibra Village in the Nakhl Region.     

普通化学实验教学改革探索与实践

针对多年来农业院校传统的普通化学实验课教学,进行了教学模式、教学内容、考核方式和实验管理体系等全方位的改革探索和实践.结果表明,经过实验教学改革与实践使学生的实验基本技能、综合素质能力和实验水平有了很大的提高,取得了满意的教学效果.     

HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.     

Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9

Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.