Two classes of metabolites fromTheonella swinhoei are localized in distinct populations of bacterial symbionts

The marine spongeTheonella swinhoei (lithistid Family Theonellidae, Order Astrophorida) has yielded many important, bioactive natural products, most of which share structural features with bacterial natural products. The presence of microbial symbionts inT. swinhoei has been reported, and it was originally suggested that the cytotoxic macrolide swinholide A and many of the bioactive cyclic peptides fromT. swinhoei were all produced by symbiotic cyanobacteria. By transmission electron microscopy, we found four distinct cell populations to be consistently present inT. swinhoei: eukaryotic sponge cells, unicellular heterotrophic bacteria, unicellular cyanobacteria and filamentous heterotrophic bacteria. Purification and chemical analyses of each cell type showed the macrolide swinholide A to be limited to the mixed population of unicellular heterotrophic bacteria, and an anti-fungal cyclic peptide occurred only in the filamentous heterotrophic bacteria. Contrary to prior speculation, no major metabolites were located in the cyanobacteria or sponge cells.     

Germline gain-of-function mutations in SOS1 cause Noonan syndrome

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.     

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

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。     

Managing Complexity Through Methodic Participation: The Case of Air Quality in Santiago,Chile

Three concrete results have been achieved over a 5-year period in Santiago, Chile, in a process addressed to managing through participation the difficult air quality situation of this 5-million-person metropolis: (1) a highly complex problem has become manageable, (2) a legitimate and effective Prevention and Decontamination Plan is in operation, and (3) citizens and the government are mutually committed to this process. This paper describes how these results have been achieved by applying Innovative Development, a social systems methodology developed by the author and co-workers and applied in many fields over the last 20 years. Following a review of the problem and results that have been achieved, an explanation is offered for why a participative methodology is necessary for dealing with a highly complex problem like the current one. The fourth section provides a brief outline of the Innovative Development methodology. The last section presents the case itself, describing three stages. In the short space available we have tried to balance the practical, methodological, and conceptual issues of this case and this approach.     

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.