Molecular modeling study of the opioid receptor interactions with series of cyclic deltorphin analogues

In this study, ten tetra‐ and heptapeptide analogues of deltorphin containing the urea bridges between residues 2 and 4 have been docked into the δ‐ and µ‐opioid receptors to explain their different biological activities. The important factors explaining particular ligand activity such as free energy of binding, conformation of the ligand, its location inside the binding pocket as well as the number and strength of the receptor–ligand interactions have been discussed. Several different binding modes for investigated ligands have been proposed. It appears that the binding site is not identical even for very similar ligands. Results of this study help to explain the differences in biological activity of the deltorphin analogues, their interaction with the opioid receptors at the molecular level and support designing a new generation of potent opioid drugs with improved selectivity. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Analysis of the interacting surface of maurotoxin with the voltage‐gated Shaker B K+ channel

Maurotoxin (MTX) is a 34‐residue toxin that was isolated initially from the venom of the scorpion Scorpio maurus palmatus. Unlike the other toxins of the α‐KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C₁? C₅, C₂? C₆, C₃? C₄, and C₇? C₈ (instead of the conventional C₁? C₅, C₂? C₆, C₃? C₇, and C₄? C₈, herein referred to as Pi1‐like) that does not prevent its folding along the classic α/β scaffold of scorpion toxins. MTX_Pi1 is an MTX variant with a conventional pattern of disulfide bridging without any primary structure alteration of the toxin. Here, using MTX and/or MTX_Pi1 as models, we investigated how the type of folding influences toxin recognition of the Shaker B potassium channel. Amino acid residues of MTX that were studied for Shaker B recognition were selected on the basis of their homologous position in charybdotoxin, a three disulfide‐bridged scorpion toxin also active on this channel type. These residues favored either an MTX‐ or MTX_Pi1‐like folding. Our data indicate clearly that Lys²³ and Tyr³² (two out of ten amino acid residues studied) are the most important residues for Shaker B channel blockage by MTX. For activity on SKCa channels, the same amino acid residues also affect, directly or indirectly, the recognition of SK channels. The molecular modeling technique and computed docking indicate the existence of a correlation between the half cystine pairings of the mutated analogs and their activity on the Shaker B K⁺ channel. Overall, mutations in MTX could, or could not, change the reorganization of disulfide bridges of this molecule without affecting its α/β scaffold. However, changing of the peptide backbone (cross linking disulfide bridges from MTX‐like type vs MTX_Pi1‐like type) appears to have less impact on the molecule activity than mutation of certain key amino acids such as Lys²³ and Tyr³² in this toxin. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Using Sculptor and Situs for simultaneous assembly of atomic components into low-resolution shapes

We describe an integrated software system called Sculptor that combines visualization capabilities with molecular modeling algorithms for the analysis of multi-scale data sets. Sculptor features extensive special purpose visualization techniques that are based on modern GPU programming and are capable of representing complex molecular assemblies in real-time. The integration of graphics and modeling offers several advantages. The user interface not only eases the usually steep learning curve of pure algorithmic techniques, but it also permits instant analysis and post-processing of results, as well as the integration of results from external software. Here, we implemented an interactive peak-selection strategy that enables the user to explore a preliminary score landscape generated by the colors tool of Situs. The interactive placement of components, one at a time, is advantageous for low-resolution or ambiguously shaped maps, which are sometimes difficult to interpret by the fully automatic peak selection of colors. For the subsequent refinement of the preliminary models resulting from both interactive and automatic peak selection, we have implemented a novel simultaneous multi-body docking in Sculptor and Situs that softly enforces shape complementarities between components using the normalization of the cross-correlation coefficient. The proposed techniques are freely available in Situs version 2.6 and Sculptor version 2.0.     

Fire,landscape change and models of small mammal habitat suitability at multiple spatial scales

Fire is an important process in many ecosystems, but inappropriate fire regimes can adversely affect biodiversity. We identified a naturally flammable heathy woodland ecosystem where the use of planned fire had increased the extent of older vegetation, and quantified the abundance of two small native mammals in this landscape (silky mouse Pseudomys apodemoides and heath rat P. shortridgei). We defined four time‐since‐fire (TSF) categories representing a 2‐ to 55‐year post‐fire sequence and, on the basis of a habitat accommodation model, predicted that both species would select younger age‐classes over older ones. We also predicted that (i) much of the variance in vegetation structure would remain unexplained by TSF and (ii) statistical models of mammal abundance and occupancy including structural variables as predictors would be better than models including TSF. Pseudomys apodemoides selected 17‐ to 23‐year‐old sites, while there was no evidence that P. shortridgei selected a particular TSF category, findings that were inconsistent with our predictions. In line with our predictions, relatively large portions of the variance in vegetation structure remained unexplained by TSF (adjustedr² for four structural variables: 0.24, 0.29, 0.35 and 0.57), and in three of four cases there was strong evidence that statistical models of mammal abundance and occupancy including structural variables were better than those including TSF. At the site scale (hectares), P. shortridgei abundance was positively related to the cover of dead material at the base of Xanthorrhoea plants and at the trap scale (metres), the trapability of both species was significantly related to vegetation volume at 0–20 cm. Our findings suggest that TSF may not be a good proxy for either vegetation structure or species abundance/occupancy.     

Planted saltbush (Atriplex nummularia) and its value for birds in farming landscapes of the South Australian Murray Mallee

Summary In the fragmented agricultural landscapes of temperate southern Australia, broad‐scale revegetation is underway to address multiple natural resource management issues. In particular, commercially‐driven fodder shrub plantings are increasingly being established on non‐saline land to fill the summer‐autumn feed gap in grazing systems. Little is known of the contribution that these and other planted woody perennial systems make to biodiversity conservation in multifunctional landscapes. In order to address this knowledge gap, a study was conducted in the southern Murray Mallee region of South Australia. Selected ecological indicators, including plant and bird communities, were sampled in spring 2008 and autumn 2009 in five planted saltbush sites and nearby areas of remnant vegetation and improved pasture. In general, remnant vegetation sites had higher biodiversity values than saltbush and pasture sites. Saltbush sites contained a diverse range of plants and birds, including a number of threatened bird species not found in adjacent pasture sites. Plant and bird communities showed significant variation across saltbush, pasture and remnant treatments and significant differences between seasons. This study demonstrates that saltbush plantings can provide at least partial habitat for some native biota within a highly modified agricultural landscape. Further research is being conducted on the way in which biota, such as birds, use available resources in these dynamic ecosystems. An examination of the effects of grazing on biodiversity in saltbush would improve the ability of landholders and regional natural resource management agencies in making informed land management decisions.     

Rapid recovery of mammal fauna in the central Kimberley,northern Australia,following the removal of introduced herbivores

Australia has lost more native mammal species than any other country in the past two centuries, and this record of loss looks likely to worsen over the next few decades. Small‐ to medium‐sized mammals are declining in both distribution and density across large tracts of northern Australia's tropical savannas, including within protected areas. The most likely causes are a combination of changed fire patterns, the impacts of introduced herbivores and predation by feral cats. Here, in contrast to the prevailing trend across northern Australia, we report the recovery of native mammals in response to a large‐scale (>40 000 ha) destocking experiment carried out at Mornington Wildlife Sanctuary in the central Kimberley, north‐west Australia. Following the removal of introduced herbivores from 2004, the species richness and abundance of small native rodents and dasyurids increased significantly across all sampled habitats over the next 3 years. We discuss the implications of these results for guiding land management and applied research to help to reduce the impending risk of mammalian extinctions in northern Australia.     

Distance-limited dispersal promotes coexistence at habitat boundaries: reconsidering the competitive exclusion principle

Understanding the conditions for the stable coexistence of different alleles or species is a central topic in theoretical evolution and ecology. Different causes for stable polymorphism or species coexistence have already been identified but they can be grouped into a limited number of general processes. This article is devoted to the presentation and illustration of a new process, which we call 'habitat boundary polymorphism', and which relies on two key ingredients: habitat heterogeneity and distance-limited dispersal. Under direct competition and with fixed population densities, we show that this process allows for the equilibrium coexistence of more than n types in a n-habitat environment. Distance-limited dispersal indeed creates local maladaptation at habitat edges, which leaves room for the invasion of more generalist alleles or species. This mechanism provides a generic yet neglected process for the maintenance of polymorphism or species coexistence.     

Systematic error is of minor importance to feedback structure estimates derived from time series of nonlinear population indices

Most modern population dynamics analyses of time series use simple population indices for ecological inference. These indices, collected for many years for various agricultural pests or game animals, are generally believed not to distort systematically feedback estimates because the assumption of linearity to population size roughly holds. To assess the relative importance of this assumption, we examined the effect of nonlinearity in a burrow index for voles on feedback estimates obtained through autoregressive modeling. We show that the issue of linearity is of less importance to ecological inference because the feedback estimates are routinely obtained on a logarithmic scale. Transforming data to logs has a strong linearization effect, removing most of the nonlinearity observed on the original scale. We conclude that the statistical tools for ecological inference, such as autoregressive log-linear models, are sufficiently robust to the systematic error imposed by index nonlinearity and that indices are valuable sources of ecological information even in situations when the assumed linear functional forms to population size were not exactly validated. We suggest that for time series modelers, the issue of a large sampling variation in small “noisy” populations is by far a more burning one than the systematic error due to index nonlinearity.     

上海地区医院图书馆的现状与发展探讨

目的：为了解上海医院图书馆的现状,为医院图书馆的标准化,规范花建设提供依据。方法：采用中国图书馆学会医院图书馆委员会统一编制的＂中国图书馆情况调查表＂,对上海医院图书馆进行问卷调查。结果：对医院图书馆人员的学历职称构成,年度经费、设备、馆舍面积、学科馆员设置、馆藏、数字资源的建设等方面的数据,按三级、二级医院分别进行统计分析,归纳总结。结论：通过本次调查,了解到上海地区45家三、二级医院在人员结构、经费、设备、数字资源的利用等方面差距较大,有待与各方面共同探索,改进工作,缩小差距。     

Caspase-8 activity has an essential role in CD95/Fas-mediated MAPK activation

Stimulation of CD95/Fas/APO-1 results in the induction of both apoptotic and non-apoptotic signaling pathways. The processes regulating these two opposing pathways have not been thoroughly elucidated to date. In this study, using quantitative immunoblots, imaging, and mathematical modeling, we addressed the dynamics of the DED proteins of the death-inducing signaling complex (DISC), procaspase-8, and cellular FLICE inhibitory proteins (c-FLIPs) to the onset of CD95-mediated ERK1/2 and p38 mitogen-activated protein kinase (MAPK) activation. We found that CD95 DISC-induced caspase-8 activity is important for the initiation of ERK1/2 and p38 MAPK activation. The long c-FLIP isoform, c-FLIP_L, and the short c-FLIP isoform, c-FLIP_R, inhibited MAPK induction by blocking caspase-8 processing at the DISC. Furthermore, we built a mathematical model describing CD95 DISC-mediated MAPK activation and apoptosis. The model quantitatively defined the dynamics of DED proteins, procaspase-8, and c-FLIP, which lead to caspase-8 activation and induction of apoptotic and non-apoptotic signaling pathways. In conclusion, the combination of biochemical analysis with mathematical modeling provides evidence for an important role of caspase-8 in CD95-mediated activation of MAPKs, while c-FLIP exerts a regulatory function in this process.