The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo

Carbazole based anion receptors

Anions are of great importance in the environment and health, thus it is no wonder that a great deal of research has been conducted to create synthetic receptors that can bind to various anions. In the past few decades, research and synthesis of novel receptors containing pyrrole, such as “expanded” porphyrins, has increased tremendously. These new synthetic molecules have been used as means for various applications including anion binding, sensing, transport and delivery. Previous work has shown some success in trying to use carbazole as a key component in combination with pyrrole for receptor synthesis. Carbazole has a large size, flourescent properties and a more acidic NH donor than the pyrrolic NH normally found in these analogues to bind ions. The synthesis and analysis of new carbazole-based receptors, “expanded” porphyrin macrocycles and amidopyrroles, is discussed with special attention paid to the modification of carbazole in an attempt to enhance binding and solubility of the receptors. Binding with various anions (chloride, benzoate, and dihydrogen phosphate) was studied and all molecules were shown to have an increased affinity for phosphate. However, there were notable differences in anion selectivity between the various receptors.Biochemistr

Information hiding in printed documents

In today\u27s digital world securing different forms of content is very important in terms of protecting copyright and verifying authenticity. One example is watermarking of digital audio and images. We believe that a marking scheme analogous to digital watermarking but for documents is very important. There currently exist techniques to secure documents such as bank notes using paper watermarks, security fibers, holograms, or special inks. There are a number of applications in which it is desirable to be able to identify the technology, manufacturer, model, or specific unit that was used to print a given document even if the printer in question does not make use of these existing security devices to explicitly identify itself. It would be useful to achieve the same or a better level of protection without the use of any additional devices or technologies. Two strategies are proposed for printer identification based upon examination of a printed document. The first strategy is passive. It involves characterization of the printer by finding features in the printed document that are intrinsic to that particular printer, model, or manufacturer\u27s products. The second strategy is active. It involves the embedding of an extrinsic signature into a printed page. This signature can be generated by modulating the process parameters of the printer mechanism to encode identifying information such as the printer serial number and date of printing. It is shown that good separation between printers is achievable using gray-level co-occurrence based texture features obtained from text documents. Experiments using ten printers and a support vector machine classifier show very low classification error even between printers with the same electromechanical structure. The technique is also shown to work for various font sizes, font types, paper types, and printer age. The features are observed to migrate with the age of the consumables indicating that it may be possible to estimate the age of the consumables at the time of printing. In addition, the intrinsic nature of the features makes it difficult to obscure or remove them without physically modifying the printer itself. Combining both texture features and banding features it is possible to identify a printer under several attack scenarios. A coding technique for embedding extrinsic signatures in text documents is presented. Both time and frequency domain signaling and detection schemes are investigated. It is shown that better performance is achieved using a time domain signaling scheme with a correlation detector due to the limited length of text character edges. It is also shown that by treating the document as a communication channel, a coding technique allowing approximately 3600 bits in a full page of 12 point text is achievable with a 7.74% bit error rate. By using the data hiding technique described above, a counterfeit and tamper detection method based on combinatorial group testing is developed and investigated. The low error rate achievable by the data hiding system allows reliable determination of document authenticity and the location of tampered data within a document. From results of previous work a printer dot model is proposed to simulate the printing of cluster-dot halftone patterns. It has been shown that the original parameters chosen for that model do not adequately represent vertical edges in saturated regions such as text. Estimating the parameters by minimizing the error between the simulated and experimental edge profiles and edge sharpness for both the left and right edges provides values that more accurately represent the actual edge with and without embedded signals

Effects of Coating Solvent and Thermal Treatment on Transport and Morphological Characteristics of PDMS/Torlon Composite Hollow Fiber Membrane

A new approach for formation of the polydimethylsiloxane (PDMS) layer on Torlon polyamide-imide hollow fiber (PAI-HF) support has been developed by directly after fiber spinning without the need to undergo the final conventional solvent exchange and drying step, thereby saving postspinning processing steps. The produced PDMS/PAI-HF composite membranes were found to have high CO2 permeance (i.e., 1100 GPU) and exhibited good CO2/N2 selectivities of 8—10 which is close to 90% of that of a PDMS dense film. The effects of coating solution, rewetting and crosslinking temperature on the PAI-HF morphological features, that is, gas transport, skin thickness, skin integrity, and substructure resistance are investigated. The rewetting and thermal treatment of the PAI-HF caused the densification of the skin layer and reduced the pore sizes on the top layer. In addition, the potential use of the PAI-HF support with polymers that are insoluble in hexane is also considered. Effects of water, methanol, and hexane exposure of PAI-HF to these solvents are considered. This evaluation calls attention to issues that must be addressed in any eventual use of the PAI-HF with water-soluble or methanol-soluble selective layer polymers, rather than simple hexane-soluble polymers such as PDMS