SUMMARY Recent events have made public health officials acutely aware of the importance of rapidly and accurately detecting acts of bioterrorism. Because bioterrorism is difficult to predict or prevent, reliable platforms to rapidly detect and identify biothreat agents are important to minimize the spread of these agents and to protect the public health. These platforms must not only be sensitive and specific, but must also be able to accurately detect a variety of pathogens, including modified or previously uncharacterized agents, directly from complex sample matrices. Various commercial tests utilizing biochemical, immunological, nucleic acid, and bioluminescence procedures are currently available to identify biological threat agents. Newer tests have also been developed to identify such agents using aptamers, biochips, evanescent wave biosensors, cantilevers, living cells, and other innovative technologies. This review describes these current and developing technologies and considers challenges to rapid, accurate detection of biothreat agents. Although there is no ideal platform, many of these technologies have proved invaluable for the detection and identification of biothreat agents.
Oxidized low density lipoprotein (oxLDL) induces apoptosis in macrophages, smooth muscle cells, and endothelial cells. To elucidate the molecular mechanism of oxLDLinduced cytotoxicity and determine its tissue specificity, we have used Chinese hamster ovary (CHO)-K1 cells expressing human CD36 (CHO/CD36). Expression of CD36 rendered these cells susceptible to killing by oxLDL. This cytotoxicity was due to the induction of apoptosis. Therefore, CD36 expression is the only requirement for oxLDLinduced apoptosis. Oxysterols apparently mediate the cytotoxicity of oxLDL in macrophage foam cells and endothelial cells. 25-Hydroxycholesterol, at concentrations higher than 1 g/ml, killed CHO-K1 cells, by apoptosis, in medium supplemented with serum as a source of cholesterol. These effects were not seen in a 25-hydroxycholesterol-resistant CHO/CD36 mutant (OX R ), which was otherwise capable of undergoing apoptosis in response to staurosporine. This mutant was also resistant to killing by oxLDL, suggesting that oxysterols are at least partially responsible for the toxic effects of oxLDL. Oxysterol-induced apoptosis did not involve regulation of sterol regulatory element-binding protein proteolysis or the cholesterol biosynthetic pathway. 25-Hydroxycholesterol stimulated calcium uptake by CHO-K1 cells within 2 min after addition. Treatment of CHO or THP-1 (macrophage) cells with the calcium channel blocker nifedipine prevented 25-hydroxycholesterol induction of apoptosis. OX R showed no enhanced calcium uptake in response to 25-hydroxycholesterol. Oxidized low density lipoprotein (oxLDL)1 plays an important role in atherogenesis (1, 2). oxLDL can be generated in vivo by at least three classes of mechanisms: 1) autoxidation in the presence of transition metals (3, 4); 2) cell-mediated oxidation (5-7); and 3) plasma enzyme-mediated oxidation (8 -11). oxLDL plays a role in many early events of atherosclerosis; it induces the expression of adhesion molecules on endothelial cells (12), the transformation of macrophages and smooth muscle cells to foam cells (13), the production of various proinflammatory cytokines and growth factors by almost all vascular cells (14, 15), the proliferation and migration of vascular cells (16 -18), and the retardation of endothelial regeneration (19), and it increases the procoagulant activity on the vascular cells (20). These changes eventually result in the formation of atheromatous lesions. Local oxidative degradation of trapped LDL may generate lipid-derived inflammatory mediators, such as oxysterols, lysophospholipids, and fatty acid peroxides.oxLDL and its lipid components have also been shown to be cytotoxic for cultured vascular smooth muscle cells, endothelial cells, macrophages, fibroblasts, and central nervous system cells (5, 21-23). Recently, this cytotoxicity has been partly attributed to induction of apoptosis. oxLDL induces both the morphological changes and DNA fragmentation characteristic of apoptosis in cultured smooth muscle cells (24), macrophages (24, 25), endothelial cells ...
The erythroid-specific isoform of 5-aminolevulinate synthase (ALAS2) catalyzes the rate-limiting step in heme biosynthesis. The hypoxia-inducible factor-1 (HIF-1) transcriptionally up-regulates erythropoietin, transferrin, and transferrin receptor, leading to increased erythropoiesis and hematopoietic iron supply. To test the hypothesis that ALAS2 expression might be regulated by a similar mechanism, we exposed murine erythroleukemia cells to hypoxia (1% O 2 ) and found an up to 3-fold up-regulation of ALAS2 mRNA levels and an increase in cellular heme content. A fragment of the ALAS2 promoter ranging from ؊716 to ؉1 conveyed hypoxia responsiveness to a heterologous luciferase reporter gene construct in tran
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