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101.
Blanchard B Nurisso A Hollville E Tétaud C Wiels J Pokorná M Wimmerová M Varrot A Imberty A 《Journal of molecular biology》2008,383(4):837-853
The opportunistic pathogen Pseudomonas aeruginosa contains several carbohydrate-binding proteins, among which is the P. aeruginosa lectin I (PA-IL), which displays affinity for alpha-galactosylated glycans. Glycan arrays were screened and demonstrated stronger binding of PA-IL toward alphaGal1-4betaGal-terminating structures and weaker binding to alphaGal1-3betaGal ones in order to determine which human glycoconjugates could play a role in the carbohydrate-mediated adhesion of the bacteria. This was confirmed in vivo by testing the binding of the lectin to Burkitt lymphoma cells that present large amounts of globotriaosylceramide antigen Gb3/CD77/P(k). Trisaccharide moieties of Gb3 (alphaGal1-4betaGal1-4Glc) and isoglobotriaosylceramide (alphaGal1-3betaGal1-4Glc) were tested by titration microcalorimetry, and both displayed similar affinity to PA-IL in solution. The crystal structure of PA-IL complexed to alphaGal1-3betaGal1-4Glc trisaccharide has been solved at 1.9-A resolution and revealed how the second galactose residue makes specific contacts with the protein surface. Molecular modeling studies were performed in order to compare the binding mode of PA-IL toward alphaGal1-3Gal with that toward alphaGal1-4Gal. Docking studies demonstrated that alphaGal1-4Gal creates another network of contacts for achieving a very similar affinity, and 10-ns molecular dynamics in explicit water allowed for analyzing the flexibility of each disaccharide ligand in the protein binding site. The higher affinity observed for binding to Gb3 epitope, both in vivo and on glycan array, is likely related to the presentation effect of the oligosaccharide on a surface, since only the Gb3 glycosphingolipid geometry is fully compatible with parallel insertion of neighboring trisaccharide heads in two binding sites of the same tetramer of PA-IL. 相似文献
102.
Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. These diseases can be hereditary in humans and four of the many disease-associated missense mutants of PrP are in the hydrophobic core: V180I, F198S, V203I and V210I. The T183A mutation is related to the hydrophobic core mutants as it is close to the hydrophobic core and known to cause instability. We used extensive molecular dynamics simulations of these five PrP mutants to compare their dynamics and conformations to those of the wild type PrP. The simulations highlight the changes that occur upon introduction of mutations and help to rationalize experimental findings. Changes can occur around the mutation site, but they can also be propagated over long distances. In particular, the F198S and T183A mutations lead to increased flexibility in parts of the structure that are normally stable, and the short β-sheet moves away from the rest of the protein. Mutations V180I, V210I and, to a lesser extent, V203I cause changes similar to those observed upon lowering the pH, which has been linked to misfolding. Early misfolding is observed in one V180I simulation. Overall, mutations in the hydrophobic core have a significant effect on the dynamics and stability of PrP, including the propensity to misfold, which helps to explain their role in the development of familial prion diseases. 相似文献
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104.
Policing occurs in insect, animal and human societies, where it evolved as a mechanism maintaining cooperation. Recently, it has been suggested that policing might even be relevant in enforcing cooperation in much simpler organisms such as bacteria. Here, we used individual‐based modelling to develop an evolutionary concept for policing in bacteria and identify the conditions under which it can be adaptive. We modelled interactions between cooperators, producing a beneficial public good, cheaters, exploiting the public good without contributing to it, and public good‐producing policers that secrete a toxin to selectively target cheaters. We found that toxin‐mediated policing is favoured when (a) toxins are potent and durable, (b) toxins are cheap to produce, (c) cell and public good diffusion is intermediate, and (d) toxins diffuse farther than the public good. Although our simulations identify the parameter space where toxin‐mediated policing can evolve, we further found that policing decays when the genetic linkage between public good and toxin production breaks. This is because policing is itself a public good, offering protection to toxin‐resistant mutants that still produce public goods, yet no longer invest in toxins. Our work thus highlights that not only specific environmental conditions are required for toxin‐mediated policing to evolve, but also strong genetic linkage between the expression of public goods, toxins and toxin resistance is essential for this mechanism to remain evolutionarily stable in the long run. 相似文献
105.
Objective: To conduct a clinical and economic evaluation of outpatient weight loss strategies in overweight and obese adult U.S. women. Research Methods and Procedures: This study was a lifetime cost‐use analysis from a societal perspective, using a first‐order Monte Carlo simulation. Strategies included routine primary care and varying combinations of diet, exercise, behavior modification, and/or pharmacotherapy. Primary data were collected to assess program costs and obesity‐related quality of life. Other data were obtained from clinical trials, population‐based surveys, and other published literature. This was a simulated cohort of healthy 35‐year‐old overweight and obese women in the United States. Results: For overweight and obese women, a three‐component intervention of diet, exercise, and behavior modification cost $12,600 per quality‐adjusted life year gained compared with routine care. All other strategies were either less effective and more costly or less effective and less cost‐effective compared with the next best alternative. Results were most influenced by obesity‐related effects on quality of life and the probabilities of weight loss maintenance. Discussion: A multidisciplinary weight loss program consisting of diet, exercise, and behavior modification provides good value for money, but more research is required to confirm the impacts of such programs on quality of life and the likelihood of long‐term weight loss maintenance. 相似文献
106.
Immunotherapy with Bacillus Calmette–Guérin (BCG)—an attenuated strain of Mycobacterium bovis (M. bovis) used for anti tuberculosis immunization—is a clinically established procedure for the treatment of superficial bladder cancer.
However, the mode of action has not yet been fully elucidated, despite much extensive biological experience. The purpose of
this paper is to develop a first mathematical model that describes tumor-immune interactions in the bladder as a result of
BCG therapy. A mathematical analysis of the ODE model identifies multiple equilibrium points, their stability properties,
and bifurcation points. Intriguing regimes of bistability are identified in which treatment has potential to result in a tumor-free
equilibrium or a full-blown tumor depending only on initial conditions. Attention is given to estimating parameters and validating
the model using published data taken from in vitro, mouse and human studies. The model makes clear that intensity of immunotherapy
must be kept in limited bounds. While small treatment levels may fail to clear the tumor, a treatment that is too large can
lead to an over-stimulated immune system having dangerous side effects for the patient. 相似文献
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109.
阔叶红松(Pinus koraiensis)林是中国东北地区的地带性植被,长白山区是阔叶红松林的核心分布区。参照巴拿马Barro Colorado Island (BCI) 50 hm2 热带雨林样地的技术规范,于2004年在长白山自然保护区的阔叶红松林内建立了一块25 hm2的固定样地(简称CBS),这是目前中国科学院生物多样性委员会中国森林多样性动态研究网络中最北端的一块,也是全球温带地区最大的一块森林样地。2004年夏的第一次调查结果表明,样地内胸径≥1 cm的木本植物有52种,隶属于18科32属。总的独立个体数为38 902,包括分枝的总个体数为59 121。植物组成上属典型的长白山植物区系,同时混有一些亚热带和亚寒带成分。群落优势种明显,个体数最多的前3个种的个体数占到总个体数的60%,前14个种占到95%,而其余38个种只占到5 %。从物种多度、 胸高断面积、平均胸径和重要值来看,群落成层现象显著,具有比较明显的优势种。主要树种的径级结构近似于正态分布或双峰分布,而次林层和林下层树种则表现出倒 “J\" 形或 “L\"形。红松、紫椴(Tilia amurensis)、蒙古栎(Quercus mongolica)、 水曲柳(Fraxinus mandshurica)、色木槭(Acer mono)和春榆(Ulmus japonica )几个主要树种的空间分布随物种、径级的变化表现出不同的分布格局,其它一些树种的分布格局也表现出一定的空间异质性。 相似文献
110.