The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.     

SUS441不锈钢/Al金属间化合物微叠层复合板的界面结构与力学性能

采用“表面预处理—交替层叠—热轧复合—热处理”的工艺流程制备了SUS441不锈钢/Al金属间化合物微叠层复合板。利用光学显微镜、X射线衍射仪、扫描电子显微镜等检测与表征方法研究了热处理温度对复合板界面形貌、微观组织、物相组成、维氏硬度、拉伸性能的影响。结果表明：复合板界面结合良好;热处理后,固–液反应界面氧化严重,易导致界面分层而开裂;固–固、固–半固、固–液热处理后,金属间化合物层由均匀层和两相层组成,均匀层的物相组成为Fe₂A1₅,两相层的物相组成为Fe₄Al₁₃和Al₁₃Cr₂,且两相层具有韧性特征,固–半固反应所得到的复合板的综合力学性能最佳。     

Asymptotic limits and stabilization for the 1D nonlinear Mindlin-Timoshenko system

<正> This paper shows how the so called von Karman model can be obtained as a singular limitof a modified Mindlin-Timoshenko system when the modulus of elasticity in shear k tends to infinity,provided a regularizing term through a fourth order dispersive operator is added.Introducing dampingmechanisms,the authors also show that the energy of solutions for this modified Mindlin-Timoshenkosystem decays exponentially,uniformly with respect to the parameter k.As k→∞,the authors obtainthe damped von Karman model with associated energy exponentially decaying to zero as well.     

A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles

Poly(MePEG₂₀₀₀cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1. The high values of transendothelial electrical resistance and low permeability coefficients of marker molecules demonstrated the functionality of this model. The comparative passage of polyhexadecylcyanoacrylate and PEG-PHDCA nanoparticles through this model was investigated, showing a higher passage of PEGylated nanoparticles, presumably by endocytosis. This result was confirmed by confocal microscopy. Thanks to a good in vitro/in vivo correlation, this rat BBB model will help in understanding the mechanisms of nanoparticle translocation and in designing new types of colloidal carriers as brain delivery systems.Received 4 March 2005; accepted 14 April 2005     

Decision-making at the surface of the intact or barrier disrupted skin: potential applications for vaccination or therapy

The skin is a highly accessible organ and constitutes an active immunological site. Both these properties make this surface an attractive route for what promises to be a cost-effective, simple, practical and needle-free delivery of vaccines and immunomodulators. Less obvious is the fact that the state of the skin barrier can influence quantitative and qualitative aspects of antigen-specific immune responses. The everyday decision-making at the skin epithelium concerns the choice between the induction of an immune response and the establishment of a state of non-responsiveness (tolerance). This decision is influenced by various factors such as the dose, the route (intact vs barrier-disrupted skin), the cytokine microenvironment and the nature of the antigenic stimulus. By increasing our understanding of how immune responses are regulated in the epidermis we can envisage the development of immunisation protocols aimed at eliciting a protective immune response or inducing tolerance, with direct applications to preventive or therapeutic vaccination, respectively.Received 29 November 2004; received after revision 2 February 2005; accepted 22 February 2005