Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease. Although a major cause of AD is the accumulation of amyloid-β (Aβ) peptide that induces neuronal loss and cognitive impairments, our understanding of its neurotoxic mechanisms is limited. Recent studies have identified putative Aβ-binding receptors that mediate Aβ neurotoxicity in cells and models of AD. Once Aβ interacts with a receptor, a toxic signal is transduced into neurons, resulting in cellular defects including endoplasmic reticulum stress and mitochondrial dysfunction. In addition, Aβ can also be internalized into neurons through unidentified Aβ receptors and induces malfunction of subcellular organelles, which explains some part of Aβ neurotoxicity. Understanding the neurotoxic signaling initiated by Aβ-receptor binding and cellular defects provide insight into new therapeutic windows for AD. In the present review, we summarize the findings on Aβ-binding receptors and the neurotoxicity of oligomeric Aβ.     

Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.     

Homoclinic and heteroclinic solutions of cubic strongly nonlinear autonomous oscillators by hyperbolic Lindstedt-Poincaré method

The hyperbolic Lindstedt-Poincaré method is applied to determine the homoclinic and heteroclinic solutions of cubic strongly nonlinear oscillators of the form  + c_1 x + c_3 x~3 =ε f ( μ, x, ).In the method, the hyperbolic functions are employed instead of the periodic functions in the Lindstedt-Poincaré procedure. Critical value of parameter μ under which there exists homoclinic or heteroclinic orbit can be determined by the perturbation procedure. Typical applications are studied in detail. To illustrat...     

Carboxyhemoglobin levels between jogging and non-jogging smokers

Summary The hypothesis that regular jogging diminishes blood carboxyhemoglobin levels was tested. 63 smokers were chosen, with 30 of them regular joggers for 3 years and 33 of them sedentary non-joggers. Blood samples were taken and carbon monoxide levels measured by a gas chromatograph. Results showed that smoking joggers had significantly lower carbon monoxide levels than smoking non-joggers, with values of the former comparable to non-smokers.Acknowledgments. The author is deeply indebted to Mrs Katy Seifert and Ms Susan Reichmann for their encouragement throughout the study.     

Germline KRAS mutations cause Noonan syndrome

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.     

Restructuring Versus Destructuring? the Hong Kong Textile and Clothing Industry

The purpose of the study was to examine the "push" factors, which are the factors explaining the phenomena of the moving out of the textile and clothing industry in Hong Kong. The focus was put on its relationship to the time and the decision preference level. Data were collected by a questionnaire survey with 85 successful replies. A three dimensional contingency table was formulated to analyse the situation.     

金、银、铜等典型高反射率材料的激光增材制造

激光增材制造金银材料可用于艺术品、首饰、手表等的定制化制造.铜是传统工业的重要材料,具有良好的导电性和导热性;铜的激光增材制造材料被广泛用于电子设备、热管理系统、交通运输、工业制造等领域.金、银、铜的激光增材制造具有广阔的应用前景,但也面临着重要问题:金、银、铜材料对激光的吸收率很低.理论分析表明,光吸收率受材料的电导率和激光波长的直接影响.用合金化粉末或表面改性的粉末替代原始粉末打印,或用短波长蓝光或绿光激光打印,可以提高粉体对激光的吸收率,得到更好的打印态样品.本文总结了铜、金等高反射率材料的激光增材制造的激光成型现状和原料端现状,亦对铜、金等高反射率材料的激光增材制造的未来发展趋势做出了展望.     

OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin

The gamma (γ)-secretase holoenzyme is composed of four core proteins and cleaves APP to generate amyloid beta (Aβ), a key molecule that causes major neurotoxicity during the early stage of Alzheimer’s disease (AD). However, despite its important role in Aβ production, little is known about the regulation of γ-secretase. OCIAD2, a novel modulator of γ-secretase that stimulates Aβ production, and which was isolated from a genome-wide functional screen using cell-based assays and a cDNA library comprising 6,178 genes. Ectopic expression of OCIAD2 enhanced Aβ production, while reduction of OCIAD2 expression suppressed it. OCIAD2 expression facilitated the formation of an active γ-secretase complex and enhanced subcellular localization of the enzyme components to lipid rafts. OCIAD2 interacted with nicastrin to stimulate γ-secretase activity. OCIAD2 also increased the interaction of nicastrin with C99 and stimulated APP processing via γ-secretase activation, but did not affect Notch processing. In addition, a cell-permeable Tat-OCIAD2 peptide that interfered with the interaction of OCIAD2 with nicastrin interrupted the γ-secretase-mediated AICD production. Finally, OCIAD2 expression was significantly elevated in the brain of AD patients and PDAPP mice. This study identifies OCIAD2 as a selective activator of γ-secretase to increase Aβ generation.