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DEC Alpha
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Alpha-based systems
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Digital also produced single-board computers based on the VMEbus for embedded and industrial use. The first generation includes the 21068-based AXPvme 64 and AXPvme 64LC, and the 21066-based AXPvme 160. These were introduced on March 1, 1994. Later models such as the AXPvme 100, AXPvme 166 and AXPvme 230 are based on the 21066A processor, while the Alpha VME 4/224 and Alpha VME 4/288 are based on the 21064A processor. The last models, the Alpha VME 5/352 and Alpha VME 5/480, are based on the 21164 processor.
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DEC Alpha
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Alpha-based systems
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The 21066 chip is used in the DEC Multia VX40/41/42 compact workstation and the ALPHAbook 1 laptop from Tadpole Technology.
In 1994, DEC launched a new range of AlphaStation and AlphaServer systems. These use 21064 or 21164 processors and introduced the PCI bus, VGA-compatible frame buffers and PS/2-style keyboards and mice. The AlphaServer 8000 series supersedes the DEC 7000/10000 AXP and also employs XMI and FutureBus+ buses.
The AlphaStation XP1000 is the first workstation based on the 21264 processor. Later AlphaServer/Station models based on the 21264 are categorised into DS (departmental server), ES (enterprise server) or GS (global server) families.
The final 21364 chip is used in the AlphaServer ES47, ES80 and GS1280 models and the AlphaStation ES47.
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DEC Alpha
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Alpha-based systems
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A number of OEM motherboards were produced by DEC, such as the 21066 and 21068-based AXPpci 33 "NoName", which was part of a major push into the OEM market by the company, the 21164-based AlphaPC 164 and AlphaPC 164LX, the 21164PC-based AlphaPC 164SX and AlphaPC 164RX and the 21264-based AlphaPC 264DP. Several third parties such as Samsung and API also produced OEM motherboards such as the API UP1000 and UP2000.
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DEC Alpha
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Alpha-based systems
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To assist third parties in developing hardware and software for the platform, DEC produced Evaluation Boards, such as the EB64+ and EB164 for the Alpha 21064A and 21164 microprocessors respectively.
The 21164 and 21264 processors were used by NetApp in various network-attached storage systems, while the 21064 and 21164 processors were used by Cray in their T3D and T3E massively parallel supercomputers.
Supercomputers The fastest supercomputer based on Alpha processors was the ASCI Q at Los Alamos National Laboratory. The machine was built as an HP AlphaServer SC45/GS Cluster. It had 4096 Alpha (21264 EV-68, 1.25 GHz) CPUs, and reached an Rmax of 7.727 TFLOPS.
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Milk equivalent
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Milk equivalent
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Milk equivalent is a measure of the quantity of fluid milk used in a processed dairy product. Measured on a milkfat basis, it takes about 21.8 pounds of farm milk to make a pound of butter, and about 9.2 pounds to make a pound of American cheese. Measured on a skim solids basis, it takes about 11.6 pounds of farm milk to make a pound of nonfat dry milk. Farm milk weighs about 8.6 pounds per gallon.
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SimRefinery
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SimRefinery
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SimRefinery is a computer management simulation game designed to simulate Chevron's Richmond refinery operation. It was developed by the Maxis Business Simulations division of Maxis in 1993. John Hiles, who was the head of the Maxis division, was a lead designer on the project.
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SimRefinery
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Development
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After the success of SimCity, Maxis received numerous requests from various companies to develop simulations for their industries. After rejecting many requests from other companies, the team eventually agreed to make a prototype of SimRefinery for Chevron: [SimRefinery was] a simulation of their refinery operation, for orienting people in the company as to how a refinery works. It wasn't so much for the engineers as it was for the accountants and managers who walked through this refinery every day and didn't know what these pipes were carrying.
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SimRefinery
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Release and rediscovery
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As a commissioned business aid, it was not made available to the public. Until 2020, little information about the game had existed, though Maxis had discussed its creation and some screenshots existed. Most of the assets stayed with Maxis Business Simulations, which Maxis eventually divested in 1996. The division rebranded itself as Thinking Tools Inc. and continued to develop similar corporate simulations, but eventually had to shutter itself, and most of its assets were destroyed.In May 2020, librarian Phil Salvador published a long form investigative article about Maxis Business Simulations and SimRefinery featuring interviews with Hiles and other members of the division. Ars Technica reported on the article, which led to a commentor on the website uncovering a floppy disc that contains an in-development build of the game. The anonymous commenter then uploaded a digital copy to the Internet Archive to work within its DOSBox emulator.This emulated version reveals more details about the "gameplay" of SimRefinery. The game resembles SimCity with different graphics, disasters, and rules, the former to represent oil tanker ports, petroleum storage and piping systems. The user's role in the simulation was the plant manager of a refinery. One of the things the user learned was about supply and demand and how it affects the financial situation. The game was not defined to be an accurate representation of the chemical processes of a plant, as this would have been considered extremely dangerous. Instead, it was intended to show how disparate systems of a chemical plant may end up interacting at the larger scale, incorporating the financial, production, and logistics related to operating a plant. The game allowed some "disasters" to be created by creating explosive mixtures of components that set off fires, as well as external events that may disrupt the plant. The game was not considered to be a fully finished product based on the version received by the Internet Archive.
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Anti-neutrophil cytoplasmic antibody
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Anti-neutrophil cytoplasmic antibody
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Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of autoantibodies, mainly of the IgG type, against antigens in the cytoplasm of neutrophils (the most common type of white blood cell) and monocytes. They are detected as a blood test in a number of autoimmune disorders, but are particularly associated with systemic vasculitis, so called ANCA-associated vasculitides (AAV).
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Anti-neutrophil cytoplasmic antibody
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ANCA IF patterns
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Immunofluorescence (IF) on ethanol-fixed neutrophils is used to detect ANCA, although formalin-fixed neutrophils may be used to help differentiate ANCA patterns. ANCA can be divided into four patterns when visualised by IF; cytoplasmic ANCA (c-ANCA), C-ANCA (atypical), perinuclear ANCA (p-ANCA) and atypical ANCA (a-ANCA), also known as x-ANCA. c-ANCA shows cytoplasmic granular fluorescence with central interlobular accentuation. C-ANCA (atypical) shows cytoplasmic staining that is usually uniform and has no interlobular accentuation. p-ANCA has three subtypes, classical p-ANCA, p-ANCA without nuclear extension and granulocyte specific-antinuclear antibody (GS-ANA). Classical p-ANCA shows perinuclear staining with nuclear extension, p-ANCA without nuclear extension has perinuclear staining without nuclear extension and GS-ANA shows nuclear staining on granulocytes only. a-ANCA often shows combinations of both cytoplasmic and perinuclear staining.
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Anti-neutrophil cytoplasmic antibody
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ANCA antigens
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The c-ANCA antigen is specifically proteinase 3 (PR3). p-ANCA antigens include myeloperoxidase (MPO) and bacterial permeability increasing factor Bactericidal/permeability-increasing protein (BPI). Other antigens exist for c-ANCA (atypical), however many are as yet unknown. Classical p-ANCA occurs with antibodies directed to MPO. p-ANCA without nuclear extension occurs with antibodies to BPI, cathepsin G, elastase, lactoferrin and lysozyme. GS-ANA are antibodies directed to granulocyte specific nuclear antigens. Atypical ANCA are thought to be antigens similar to that of the p-ANCAs, however may occur due to differences in neutrophil processing.Other less common antigens include HMG1 (p-ANCA pattern), HMG2 (p-ANCA pattern), alpha enolase (p and c-ANCA pattern), catalase (p and c-ANCA pattern), beta glucuronidase (p-ANCA pattern), azurocidin (p and c-ANCA pattern), actin (p and a-ANCA) and h-lamp-2 (c-ANCA).
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Anti-neutrophil cytoplasmic antibody
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ELISA
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Enzyme-linked immunosorbent assay (ELISA) is used in diagnostic laboratories to detect ANCAs. Although IF can be used to screen for many ANCAs, ELISA is used to detect antibodies to individual antigens. The most common antigens used on an ELISA microtitre plate are MPO and PR3, which are usually tested for after a positive IF test.
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Anti-neutrophil cytoplasmic antibody
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Development
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It is poorly understood how ANCA are developed, although several hypotheses have been suggested. There is probably a genetic contribution, particularly in genes controlling the level of immune response – although genetic susceptibility is likely to be linked to an environmental factor, some possible factors including vaccination or exposure to silicates. Two possible mechanisms of ANCA development are postulated, although neither of these theories answers the question of how the different ANCA specificities are developed, and there is much research still being undertaken on the development of ANCA.
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Anti-neutrophil cytoplasmic antibody
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Development
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Theory of molecular mimicry Microbial superantigens are molecules expressed by bacteria and other microorganisms that have the power to stimulate a strong immune response by activation of T-cells. These molecules generally have regions that resemble self-antigens that promote a residual autoimmune response – this is the theory of molecular mimicry. Staphylococcal and streptococcal superantigens have been characterized in autoimmune diseases – the classical example in post group A streptococcal rheumatic heart disease, where there is similarity between M proteins of Streptococcus pyogenes to cardiac myosin and laminin. It has also been shown that up to 70% of patients with granulomatosis with polyangiitis are chronic nasal carriers of Staphylococcus aureus, with carriers having an eight times increased risk of relapse. This would therefore be considered a type II hypersensitivity reaction.
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Anti-neutrophil cytoplasmic antibody
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Development
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Theory of defective apoptosis Neutrophil apoptosis, or programmed cell death, is vital in controlling the duration of the early inflammatory response, thus restricting damage to tissues by the neutrophils. ANCA may be developed either via ineffective apoptosis or ineffective removal of apoptotic cell fragments, leading to the exposure of the immune system to molecules normally sequestered inside the cells. This theory solves the paradox of how it could be possible for antibodies to be raised against the intracellular antigenic targets of ANCA.
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Anti-neutrophil cytoplasmic antibody
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Role in disease
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Disease associations ANCAs are associated with small vessel vasculitides including granulomatosis with polyangiitis, microscopic polyangiitis, primary pauci-immune necrotizing crescentic glomerulonephritis (a type of renal-limited microscopic polyangiitis), eosinophilic granulomatosis with polyangiitis and drug induced vasculitides. PR3 directed c-ANCA is present in 80-90% of granulomatosis with polyangiitis, 20-40% of microscopic polyangiitis, 20-40% of pauci-immune crescentic glomerulonephritis and 35% of eosinophilic granulomatosis with polyangiitis. c-ANCA (atypical) is present in 80% of cystic fibrosis (with BPI as the target antigen) and also in inflammatory bowel disease, primary sclerosing cholangitis and rheumatoid arthritis (with antibodies to multiple antigenic targets). p-ANCA with MPO specificity is found in 50% of microscopic polyangiitis, 50% of primary pauci-immune necrotizing crescentic glomerulonephritis and 35% of eosinophilic granulomatosis with polyangiitis. p-ANCA with specificity to other antigens are associated with inflammatory bowel disease, rheumatoid arthritis, drug-induced vasculitis, autoimmune liver disease, drug induced syndromes and parasitic infections. Atypical ANCA is associated with drug-induced systemic vasculitis, inflammatory bowel disease and rheumatoid arthritis. The ANCA‐positive rate is much higher in patients with type 1 diabetes mellitus than in healthy individuals.Levamisole, which is a common adulterant of cocaine, can cause an ANCA positive vasculitis.The presence or absence of ANCA cannot indicate presence or absence of disease and results are correlated with clinical features. The association of ANCA and disease activity remains controversial; however, the reappearance of ANCA after treatment can indicate a relapse.
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Anti-neutrophil cytoplasmic antibody
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Role in disease
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Pathogenesis Although the pathogenic role of ANCA is still controversial, in vitro and animal models support the idea that the antibodies have a direct pathological role in the formation of small vessel vasculitides. MPO and PR3 specific ANCA can activate neutrophils and monocytes through their Fc and Fab'2 receptors, which can be enhanced by cytokines which cause neutrophils to display MPO and PR3 on their surface. Aberrant glycosylation of the MPO and PR3 specific ANCA enhances their ability to interact with activating Fc receptors on neutrophils. The activated neutrophils can then adhere to endothelial cells where degranulation occurs. This releases free oxygen radicals and lytic enzymes, resulting in damage to the endothelium via the induction of necrosis and apoptosis. Furthermore, neutrophils release chemoattractive signalling molecules that recruit more neutrophils to the endothelium, acting as a positive feedback loop. Animal models have shown that MPO antibodies can induce necrotizing crescentic glomerulonephritis and systemic small vessel vasculitis. In these animal models the formation of glomerulonephritis and vasculitis can occur in the absence of T-cells, however neutrophils must be present. Although ANCA titres have been noted to have limited correlation with disease activity, except for kidney disease, and with risk of relapse, this is explained by differences in the epitopes and affinity of ANCAs. ANCAs induce excess activation of neutrophils, resulting in the production of neutrophil extracellular traps (NETs), which cause damage to small blood vessels. In addition, in patients with active disease, treated with Rituximab, an anti-CD20 antibody which remove circulating B-cells, clinical remission correlates more to the decreasing number of circulating B-cells than decrease in ANCA titre, which in some patient does not change during treatment. The same study found that clinical relapse in some patients were in association with the return of circulating B-cells. Based on the above observations and that ANCA reactive B-cells can be found in circulation in patients with AAV, an alternative hypothesis have been proposed assigning a direct pathogenic role of these cells, whereby activated neutrophils and ANCA-reactive B-cells engage in intercellular cross-talk, which leads not only to neutrophil degranulation and inflammation but also to the proliferation and differentiation of ANCA-reactive B-cells. However, this hypothesis remains to be tested.
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Anti-neutrophil cytoplasmic antibody
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Role in disease
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Treatment Avacopan was approved for medical use in the United States to treat anti-neutrophil cytoplasmic autoantibody-associated vasculitis in October 2021.
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Anti-neutrophil cytoplasmic antibody
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History
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ANCAs were originally described in Davies et al. in 1982 in segmental necrotising glomerulonephritis. The Second International ANCA Workshop, held in The Netherlands in May 1989, fixed the nomenclature on perinuclear vs. cytoplasmic patterns, and the antigens MPO and PR3 were discovered in 1988 and 1989, respectively. International ANCA Workshops have been carried out every two years.
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Developer Certificate of Origin
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Developer Certificate of Origin
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The Developer Certificate of Origin (DCO) is a statement that a software developer agrees to, saying that "the contributor is allowed to make the contribution and that the project has the right to distribute it under its license." It was introduced in 2004 by the Linux Foundation, to enhance the submission process for software used in the Linux kernel, shortly after the SCO–Linux disputes.DCOs are often used as an alternative to a Contributor License Agreement (CLA). Instead of a signed legal contract, a DCO is an affirmation that the source code being submitted originated from the developer, or that the developer has permission to submit the code. Proponents of the DCO contend that it reduces the barriers of entry introduced by a CLA.
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Developer Certificate of Origin
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Developer Certificate of Origin
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Developer Certificate of Origin Version 1.1 Copyright (C) 2004, 2006 The Linux Foundation and its contributors.
1 Letterman Drive Suite D4700 San Francisco, CA, 94129 Everyone is permitted to copy and distribute verbatim copies of this license document, but changing it is not allowed.
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Developer Certificate of Origin
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Developer Certificate of Origin
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Developer's Certificate of Origin 1.1 By making a contribution to this project, I certify that: (a) The contribution was created in whole or in part by me and I have the right to submit it under the open source license indicated in the file; or (b) The contribution is based upon previous work that, to the best of my knowledge, is covered under an appropriate open source license and I have the right under that license to submit that work with modifications, whether created in whole or in part by me, under the same open source license (unless I am permitted to submit under a different license), as indicated in the file; or (c) The contribution was provided directly to me by some other person who certified (a), (b) or (c) and I have not modified it.
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Developer Certificate of Origin
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Developer Certificate of Origin
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(d) I understand and agree that this project and the contribution are public and that a record of the contribution (including all personal information I submit with it, including my sign-off) is maintained indefinitely and may be redistributed consistent with this project or the open source license(s) involved.
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GO64
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GO64
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GO-64! was an early software emulation of the Commodore 64 computer, with a copyright date of 1988 for version 2.0.
The name most likely comes from the ability for the Commodore 128 computer to switch to a hardware emulation of the Commodore 64 by typing GO64 at the BASIC prompt and pressing the return key.
This software was created by Christopher P. Zura and Cliff Dugan of Software Insight Systems Inc.
It allowed the use of some software and hardware designed for Commodore 64 computers on Amiga computers.
It required a minimum of 512kb of RAM to operate, but 1024kb of RAM was required to make use of all features. If a 68020 CPU was installed, it could operate at speeds exceeding the speed of a real Commodore 64, according to the developers.
This software does not operate on versions later than 1.3 of the Amiga Kickstart, and so does not operate on the Amiga 3000, Amiga 500 plus, Amiga 600, Amiga 4000 or Amiga 1200.
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McASP
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McASP
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McASP is an acronym for Multichannel Audio Serial Port, a communication peripheral found in Texas Instruments family of digital signal processors (DSPs) and Microcontroller Units (MCUs).
The McASP functions as a general-purpose audio serial port optimized for the needs of multichannel audio applications.
Depending on the implementation, the McASP may be useful for time-division multiplexed (TDM) stream, Inter-Integrated Sound (I2S) protocols, and intercomponent digital audio interface transmission (DIT). However, some implementations are limited to supporting just the Inter-Integrated Sound (I2S) protocol.
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McASP
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McASP
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The McASP consists of transmit and receive sections that may operate synchronized, or completely independently with separate master clocks, bit clocks, and frame syncs, and using different transmit modes with different bit-stream formats. The McASP module also includes up to 16 serializers that can be individually enabled to either transmit or receive. In addition, all of the McASP pins can be configured as general-purpose input/output (GPIO) pins.
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McASP
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Features
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Features of the McASP include: Two independent clock generator modules for transmit and receive Clocking flexibility allows the McASP to receive and transmit at different rates. For example, the McASP can receive data at 48 kHz but output up-sampled data at 96 kHz or 192 kHz.
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McASP
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Features
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Independent transmit and receive modules, each includes: Programmable clock and frame sync generator TDM streams from 2 to 32, and 384 time slots Support for time slot sizes of 8, 12, 16, 20, 24, 28, and 32 bits Data formatter for bit manipulation Individually assignable serial data pins (up to 16 pins) Glueless connection to audio analog-to-digital converters (ADC), digital-to-analog converters (DAC), Codec, digital audio interface receiver (DIR), and S/PDIF transmit physical layer components.
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McASP
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Features
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Wide variety of I2S and similar bit-stream format Integrated digital audio interface transmitter (DIT) supports: S/PDIF, IEC60958-1, AES-3 formats Up to 16 transmit pins Enhanced channel status/user data RAM 384-slot TDM with external digital audio interface receiver (DIR) device For DIR reception, an external DIR receiver integrated circuit should be used with I2S output format and connected to the McASP receive section.
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McASP
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Features
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Extensive error checking and recovery Transmit underruns and receiver overruns due to the system not meeting real-time requirements Early or late frame sync in TDM mode Out-of-range high-frequency master clock for both transmit and receive External error signal coming into the AMUTEIN input DMA error due to incorrect programming
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McASP
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Protocols
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The McASP supports a wide variety of protocols.
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McASP
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Protocols
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Transmit section supports Wide variety of I2S and similar bit-stream formats TDM streams from 2 to 32 time slots S/PDIF, IEC60958-1, AES-3 formats Receive section supports Wide variety of I2S and similar bit-stream formats TDM streams from 2 to 32 time slots TDM stream of 384 time slots specifically designed for easy interface to external digital interface receiver (DIR) device transmitting DIR frames to McASP using the I2S protocol (one time slot for each DIR subframe)The transmit and receive sections may each be individually programmed to support the following options on the basic serial protocol: Programmable clock and frame sync polarity (rising or falling edge): ACLKR/X, AHCLKR/X and AFSR/X Slot length (number of bits per time slot): 8, 12, 16, 20, 24, 28, 32 bits supported Word length (bits per word): 8, 12, 16, 20, 24, 28, 32 bits; always less than or equal to the time slot length First-bit data delay: 0, 1, 2 bit clocks Left/right alignment of word inside slot Bit order: MSB first or LSB first Bit mask/pad/rotate function Automatically aligns data for DSP internally in either Q31 or integer formats Automatically masks nonsignificant bits (sets to 0, 1, or extends value of another bit)In DIT mode, additional features of the transmitter are: Transmit-only mode- 384 time slots (subframe) per frame Bi-phase encoded 3.3 V output Support for consumer and professional applications Channel status RAM (384 bits) User data RAM (384 bits) Separate valid bit (V) for subframe A, B
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Triple-negative breast cancer
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Triple-negative breast cancer
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Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e. the tumor is negative on all three tests giving the name triple-negative). Triple-negative is sometimes used as a surrogate term for basal-like.Triple-negative breast cancer comprises 15–20% of all breast cancer cases and affects more young women or women with a mutation in the BRCA1 gene than other breast cancers. Triple-negative breast cancers comprise a very heterogeneous group of cancers. TNBC is the most challenging breast cancer type to treat. Hormone therapy that is used for other breast cancers does not work for TNBC. In its early stages, the cancer is typically treated through surgery, radiation and chemotherapy. In later stages where surgery is not possible or the cancer has spread from the initial localised area, treatment is limited to chemotherapy and in some cases further targeted therapy.Triple-negative breast cancers have a relapse pattern that is very different from hormone-positive breast cancers where the risk of relapse is much higher for the first 3–5 years, but drops sharply and substantially below that of hormone-positive breast cancers afterwards.
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Triple-negative breast cancer
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Risk factors
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The overall proportion of TNBC is very similar in all age groups. Younger women have a higher rate of basal or BRCA related TNBC, while older women have a higher proportion of apocrine, normal-like and rare subtypes including neuroendocrine TNBC.A study in the US has shown that, among younger women, African American and Hispanic women have a higher risk of TNBC, with African Americans facing worse prognosis than other ethnic groups.One known risk factor for triple-negative breast cancer is germline mutations. These are alterations within the heritable lineage that is being passed down to the offspring. Due to their high disposition for cancers of the breast, ovaries, pancreas, and prostate, the BRCA1 and BRCA2 genes were identified as high risk for triple-negative. Changes or mutations in 19p13.1 and MDM4 loci have also been associated with triple-negative breast cancer, but not other forms of breast cancer. Thus, triple-negative tumors may be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline alterations.In 2009, a case-control study of 187 triple-negative breast cancer patients described a 2.5 increased risk for triple-negative breast cancer in women who used oral contraceptives (OCs) for more than one year, compared to women who used OCs for less than one year or never. The increased risk for triple-negative breast cancer was 4.2 among women 40 years of age or younger who used OCs for more than one year, while there was no increased risk for women between the ages of 41 and 45. Also, as duration of OC use increased, triple-negative breast cancer risk increased.
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Triple-negative breast cancer
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Classification
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Breast cancer classification is used to assess the tumor to decide on treatment and prognosis. Classification can be performed using molecular, immunohistochemical, and clinical characteristics. One of the important classification types is receptor status, because it identifies those cancers that have specific targeted treatments available. Breast cancer tumors have traditionally been classed using immunohistochemistry as one of four types: estrogen receptor positive progesterone receptor positive HER2 overexpression positive triple-negativeThere are targeted therapies for estrogen and progesterone receptor cancers and more recently HER2 receptor cancers but there are no targeted therapies for TNBC as a whole.The threshold level for hormone receptor positivity was changed in 2010 and now requires more than 1% positive tumor nuclei are found in the tumor sample.Newer techniques for categorising breast cancer are based on gene expression in the tumor which classifies breast cancer into: luminal A (HR+/HER2-) 68% luminal B (HR+/HER2+) 10% HER2 overexpressing (HR-/HER2+) 4% basal-like (HR-/HER2-) 10%with 7% of unknown subtype. HR indicates hormone receptor and +/- indicates status whether positive or negative.
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Triple-negative breast cancer
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Classification
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The basal-like subtype has many overlapping features to TNBC and in addition to being receptor negative, has increased expression of basal cytokeratins. 85% of basal-like tumors are TNBC.Subtypes are used to try to define better treatments or a more accurate prognosis. However, there is no standard classification for TNBC subtypes. Although TNBC has a variety of different subtypes that may vary depending on how they are determined, to date the disease is still uniformly treated with chemotherapy although they may have additional targeted treatments. One of the popular subtype classification for TNBC is: basal-like 1 (BL1) 35% basal-like 2 (BL2) 22% mesenchymal (M) 25% luminal androgen receptor (LAR) 16%Most of TNBC is invasive carcinoma of no special type. The following rarer breast tumors have a higher proportion of being TNBC: adenoid cystic carcinoma 78.2% are TNBC metaplastic 76.2% are TNBC medullary carcinoma 60.5% are TNBC apocrine adenocarcinoma 56.7% are TNBC inflammatory 25.9% are TNBC
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Triple-negative breast cancer
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Prognosis
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TNBC is more likely to recur within the first five years after treatment than other breast cancers. However, after five years the chance of recurrence is much less than for other breast cancers. The risk of recurrence peaks at three years from diagnosis and reduces after that.Cancer survival is typically based on 5-year survival rates which is the survival rate compared to women without breast cancer and is based on the stage when the cancer is first diagnosed. These statistics do not apply if the cancer returns after treatment.
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Triple-negative breast cancer
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Prognosis
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Approximately 25% of those with localised disease will relapse with distant metastasis also known as stage IV. Median survival from diagnosis of metastasis is around 12 months. Metastasis in TNBC is different from other breast cancers with a tendency to spread to the brain and other organs such as lungs and liver and there is less of a tendency to spread to bones.
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Triple-negative breast cancer
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Treatment
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Early stage disease Standard treatment is surgery with adjuvant chemotherapy and radiotherapy.
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Triple-negative breast cancer
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Treatment
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Surgery is primarily used for early stage disease and may be either a lumpectomy or a mastectomy. Studies have found that the overall survival for lumpectomy and radiotherapy was the same or higher than for a mastectomy for TNBC patients.Neoadjuvant chemotherapy (before surgery) is very frequently used for triple-negative breast cancers as they are more susceptible to platinum-based regimen, allowing for a higher rate of breast-conserving surgeries. Important details on the individual responsiveness of particular cancers can be gained from evaluating the response to this form of chemotherapy. However, the improvement in breast conservation is only 10–15% and the clues to individual responsiveness have conclusively proven to make an improvement in outcomes.
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Triple-negative breast cancer
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Treatment
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Early stage TNBC is generally very susceptible to chemotherapy and can lead to a pathological complete response (pCR) i.e. no detectable cancer cells in the breast or lymph nodes. Although this does not always translate into overall survival.
Chemotherapy used to treat early stage cancers are: anthracyclines alkalating agents such as cisplatin and carboplatin. These are particularly effective with BRCA positive cases. These agents cause DNA damage which is unable to be repaired when there are BRCA defects leading to cell death.
taxanes Late stage disease Late stage disease is known as metastatic TNBC (mTNBC).
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Triple-negative breast cancer
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Treatment
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Treatment depends on whether the tumour tests positive for the programmed death cell ligand 1 (PD-L1) protein or BRCA gene mutation. Also known as immunotherapy the presence of PD-L1 on cancer cells mates with an associate PD-1 receptor on the bodies own immune killer T cells which prevents the T cell from further attacking the cancer cell. By blocking these receptors the T-cells can attack both cancer cells and healthy cells.
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Triple-negative breast cancer
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Treatment
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The following treatment is recommended by the American Society of Clinical Oncology (ASCO) for metastatic TNBC: mTNBC +PD-L1: 1st line: offered chemo + immune checkpoint inhibitor mTNBC -PD-L1: 1st line: single-agent chemo; 3rd line: sacituzumab govitecan mTNBC +BRCA: patients previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease should be offered PARP inhibitor rather than chemotherapy.Sacituzumab govitecan (Trodelvy ) is an anti-Trop-2 antibody linked to SN-38, developed by Immunomedics Inc. (now Gilead Sciences). It was approved by the FDA on 22 April 2020 for the treatment of metastatic TNBC. Sacituzumab govitecan had previously received FDA priority review, breakthrough therapy, and fast track designations.
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Triple-negative breast cancer
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Clinical trials
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Angiogenesis and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy. Treatment modalities are not sufficiently established for normal use, and it is unclear in which stage they are best used and which patients would profit.
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Triple-negative breast cancer
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Clinical trials
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By 2009 A number of new strategies for TNBC were being tested in clinical trials, including the PARP inhibitor BSI 201, NK012.A novel antibody-drug conjugate known as glembatumumab vedotin (CDX-011), which targets the protein GPNMB, has also shown encouraging clinical trial results in 2009.PARP inhibitors had shown some promise in early trials but failed in some later trials.An accelerated approval Phase II clinical trial (METRIC) investigating glembatumumab vedotin versus capecitabine began in November 2013, expected to enroll 300 patients with GPNMB-expressing metastatic TNBC.Three early stage trials reported TNBC results in June 2016, for IMMU-132, Vantictumab, and atezolizumab in combination with the chemotherapy nab-paclitaxel.In 2019, CytoDyn initiated a Phase 1b/2 trial with its humanized monoclonal antibody, leronlimab (PRO 140), in combination with chemotherapy following strong results in animal murine models. Among other mechanisms of action, leronlimab is believed to inhibit metastasis by inhibiting the CCR5 receptor on cell surfaces, which is commonly expressed in triple-negative breast cancer. On November 11, 2019, CytoDyn reported that the first TNBC patient injected under its naïve protocol (not previously treated for triple-negative breast cancer) demonstrated significantly reduced levels of circulating tumor cells (CTCs) and decreased tumor size at two-week and five-week observation intervals compared to baseline observations. CTCs are a potential surrogate endpoint in oncology trials, with reduced levels suggesting long-term clinical benefit.
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Triple-negative breast cancer
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Research
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Triple-negative breast cancers (TNBC) have, on average, significantly higher fluorine-18 fluorodeoxyglucose (FDG) uptake (measured by the SUVmax values) compared with uptake in ER+/PR+/HER2- tumors using fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET).
It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology.
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Triple-negative breast cancer
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Research
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The widely used diabetes drug, metformin, holds promise for the treatment of triple-negative breast cancer. In addition metformin may influence cancer cells through indirect (insulin-mediated) effects, or it may directly affect cell proliferation and apoptosis of cancer cells. Epidemiologic and preclinical lab studies indicate that metformin has anti-tumor effects, via at least two mechanisms, both involving activation of the AMP-activated protein kinase (AMPK). A large-scale phase III trial of metformin in the adjuvant breast cancer setting is being planned in 2009.Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.
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Adenylosuccinate synthase
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Adenylosuccinate synthase
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In molecular biology, adenylosuccinate synthase (or adenylosuccinate synthetase) (EC 6.3.4.4) is an enzyme that plays an important role in purine biosynthesis, by catalysing the guanosine triphosphate (GTP)-dependent conversion of inosine monophosphate (IMP) and aspartic acid to guanosine diphosphate (GDP), phosphate and N(6)-(1,2-dicarboxyethyl)-AMP. Adenylosuccinate synthetase has been characterised from various sources ranging from Escherichia coli (gene purA) to vertebrate tissues. In vertebrates, two isozymes are present: one involved in purine biosynthesis and the other in the purine nucleotide cycle.
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Adenylosuccinate synthase
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Structure
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The crystal structure of adenylosuccinate synthetase from E. coli reveals that the dominant structural element of each monomer of the homodimer is a central beta-sheet of 10 strands. The first nine strands of the sheet are mutually parallel with right-handed crossover connections between the strands. The 10th strand is antiparallel with respect to the first nine strands. In addition, the enzyme has two antiparallel beta-sheets, composed of two strands and three strands each, 11 alpha-helices and two short 310-helices. Further, it has been suggested that the similarities in the GTP-binding domains of the synthetase and the p21ras protein are an example of convergent evolution of two distinct families of GTP-binding proteins. Structures of adenylosuccinate synthetase from Triticum aestivum and Arabidopsis thaliana when compared with the known structures from E. coli reveals that the overall fold is very similar to that of the E. coli protein.
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Adenylosuccinate synthase
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Isozymes
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Humans express two adenylosuccinate synthase isozymes:
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Zero ionic layer
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Zero ionic layer
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Zero ionic layer is the main site of interaction in the core SNARE complex. Dipole-dipole interactions take place between 3 glutamine (Q) residues and 1 arginine (R) residue exposed in this layer. Despite that, the majority of the SNARE complex is hydrophobic because of the leucine zipper. Extensively studied layers within the SNARE alpha-helical bundle are designated from "-7" to "+8". Zero ionic layer is at the center of the bundle, and thus designated as "0" layer.
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Zero ionic layer
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Structure
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SNARE complex is a bundle formed by 4 alpha-helical proteins, including vesicle-associated Synaptobrevin and cell-membrane-associated Syntaxin and SNAP. When the bundle is viewed on the side, for every alpha-helical turn, the alpha-carbons from each helix form a plane, which is thus designated as a "layer". Along the helical bundle from N-terminus to C-terminus, layers are designated from "-7" to "+8" respectively. "0" layer (i.e. zero ionic layer) is at the center of the helical bundle.The zero ionic layer is an ionic domain within the otherwise largely hydrophobic alpha-helical complex (SNARE complex) . It is stabilized by attractive forces(dipole-dipole interactions) between three partially negatively charged carbonyl groups of glutamine residues and a positively charged arginine. Specifically, these interacting groups include Q226 on Syntaxin, Q53 on SNAP-25 (Sn1), Q174 on SNAP-25 (Sn2) and R56 on Synaptobrevin (v-SNARE).The 4 amino acids are asymmetrically arranged in the layer, as shown in the picture. However, their intensive interactions ensure the layer's stability: the arginine side chain end lies in the center of the asymmetry and amino groups form hydrogen bonds with the three glutamine residues. Thus, steric and electrostatic fit is well established.
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Zero ionic layer
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Function and research interest
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SNARE proteins are a family of a proteins that are located in cell membranes to mediate any secretory pathways. The complex is formed during exocytosis, a process where the vesicles inside the cell fuse with the cell membrane to secrete molecules into the extracellular space.The zero ionic layer of the SNARE complex is at special interest to scientists studying SNARE because of its three characteristics. Firstly, it is the only hydrophilic region in the entire hydrophobic SNARE complex; secondly, unlike most of the other layers, it displays asymmetry; thirdly, the 3Q:1R arrangement is found in almost all of the SNARE superfamily among eukaryotic cells. These unique aspects imply its importance to eukaryotic organisms in general. However, the exact and functions of zero ionic layer is still under investigation.Previous studies have focused on how mutations in this layer would affect the functionality of SNARE complex in secretory pathways. Even though the exact mechanism still awaits further investigation, these studies have revealed that the integrity of zero ionic layer is not essential to the proper alignment during complex formation, but it is essential to the disassociation of SNARE complex and the recycling of its 4 constituent alpha-helical proteins after exocytosis.An ATPase (NSF) together with a cofactor (α-SNAP) facilitates the breakdown of the SNARE complex after the completion of exocytosis. Studies have suggested that, during the disassociation process, the NSF/α-SNAP complex acts specifically on the zero ionic layer, particularly, the glutamine residue (Q226) in Syntaxin. The glutamine residue transmits the conformational change of NSF/α-SNAP complex to the SNARE complex in order to disrupt and thus disassociate the SNARE complex at the zero ionic layer. More specifically, even though the ionic layer is buried within the hydrophobic complex for the most part, during disassociation, NSF/α-SNAP complex may disturb the hydrophobic shielding and thus let water molecules into the core. This exposure of other hydrophilic molecules disturb the original hydrogen bonding equilibrium and thus facilitate disassembly of the alpha-helical bundle.
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Zero ionic layer
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Mutation and alternation
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In studies that use exocytotic SNAREs of yeast as models, a mutation from glutamine to arginine in the zero ionic layer leads to yeast cells that have deficient growth and protein secretion ability. However, a mutation from arginine to glutamine in this layer leads to yeast cells that are functionally wild-type. In the mutation where all four amino acids in the zero ionic layer are glutamine residues, the cells still exhibit normal secretory ability, but defects may become pronounced when there are other mutations.Complementary mutations, where a glutamine to arginine mutation is paired with an arginine to glutamine mutation in the zero ionic layer, have resulted in functionally wild-type yeast cells too, according to their secretory ability.These mutation studies have been done to study the role of the four amino acids in zero ionic layer. Underlying mechanisms of why these mutations would lead to certain results are not well discussed. In general, the glutamine residues in this layer are of critical importance to the functionality of mutated strains. As long as the glutamine is intact or compensated in someway during mutation, functionality of SNARE complex will be retained.
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Congenital distal spinal muscular atrophy
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Congenital distal spinal muscular atrophy
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Congenital distal spinal muscular atrophy is a hereditary condition characterized by muscle wasting (atrophy), particularly of distal muscles in legs and hands, and by early-onset contractures (permanent shortening of a muscle or joint) of the hip, knee, and ankle. Affected individuals often have shorter lower limbs relative to the trunk and upper limbs. The condition is a result of a loss of anterior horn cells localized to lumbar and cervical regions of the spinal cord early in infancy, which in turn is caused by a mutation of the TRPV4 gene. The disorder is inherited in an autosomal dominant manner. Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved.
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Congenital distal spinal muscular atrophy
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Signs and symptoms
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The presentation is as follows: Neurogenic muscle weakness Atrophy (of lower and upper limbs) Club foot Arthrogryposis Scoliosis Platyspondyly Pes cavus Vocal cord paralysis
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Congenital distal spinal muscular atrophy
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Causes
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Congenital distal spinal muscular atrophy is caused by a mutation of the TRPV4 gene found on the 12q23-12q24.1. The mutation causes an affected individual to have lower levels of TRPV4 expression. This deficiency can lead to abnormal osmotic regulation. Congenital dSMA is genetically heterogeneous, meaning a mutation on this gene can cause a plethora of other phenotypically related or phenotypically unrelated diseases depending on the region that is mutated.
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Congenital distal spinal muscular atrophy
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Pathophysiology
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The TRPV4 (transient receptor potential vanilloid 4) gene, located on chromosome 12, encodes for a protein that serves as an ion channel, typically found in the plasma membrane and is permeable to Ca2+. Abnormal regulation of Ca2+ can lead to inefficient muscle contraction. TRPV4 plays a major role in mechanosensation, as well as osmosensory functions in nerve endings, endothelia, and alveoli. The TRPV4 protein consists of 871 amino acids with its N- and C- terminals facing intracellularly. The protein also contains six alpha helices that pass through the plasma membrane. Mutations in TRPV4 can result in the loss of its normal function, or a toxic gain of function. In the latter case, intracellular Ca2+ levels are increased, which results in abnormal regulation.
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Congenital distal spinal muscular atrophy
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Pathophysiology
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Mechanism The ankyrin repeat domain (ARD) is a region located near the intracellular N-terminal of the TRPV4 protein and consists of six ankyrin repeats. Four missense mutations have been identified at three specific positions all located within the ARD. All of these mutations are due to the swapping out of arginine with a different amino acid. Arginine is highly polar and positively charged, while its replacements are less polar or nonpolar. Some of these identified amino acid substitutions are: R296H, arginine to histidine substitution R315W, arginine to tryptophan substitution R316C, arginine to cysteine substitution R594H, arginine to histidine substitution
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Congenital distal spinal muscular atrophy
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Diagnosis
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Electrophysiological evidence of denervation with intact motor and sensory nerve conduction findings must be made by using nerve conduction studies, usually in conjunction with EMG. The presence of polyphasic potentials and fibrillation at rest are characteristic of congenital dSMA.
The following are useful in diagnosis: Nerve conduction studies (NCS), to test for denervation Electromyography (EMG), also to detect denervation X-ray, to look for bone abnormalities Magnetic resonance imaging (MRI) Skeletal muscle biopsy examination Serum creatine kinase (CK) level in blood, usually elevated in affected individuals Pulmonary function test
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Congenital distal spinal muscular atrophy
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Management
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Congenital dSMA has a relatively stable disease course, with disability mainly attributed to increased contractures rather than loss of muscle strength. Individuals frequently use crutches, knee, ankle, and/or foot orthoses, or wheelchairs. Orthopaedic surgery can be an option for some patients with severely impaired movement. Physical therapy and occupational therapy can help prevent further contractures from occurring, though they do not reverse the effects of preexisting ones. Some literature suggests the use of electrical stimulation or botulinum toxin to halt the progression of contractures.
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DT Carnage
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DT Carnage
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DT Carnage is a racing game developed by South Korean studio Axis Entertainment. The Nintendo Wii release was cancelled.
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DT Carnage
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Plot
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The game revolves around a fictional tournament called the DT Tournament where people race using modified cars and are allowed the use of weapons. The player's father is injured in one of the tournaments, and the player swears revenge against the one who injured him.
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DT Carnage
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Features
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Allows the player to use items to slow down opponents Crush other drivers against the side of the track RPG mode - use various items and techniques to excel on the track.
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Congenital epulis
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Congenital epulis
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Congenital epulis is a proliferation of cells most frequently occurring on the alveolar ridge of the upper jaw at birth. Less frequently, the mass may arise from the mandibular alveolus. Rare cases can arise from the tongue. This lesion is more commonly found in female babies, suggesting hormonal involvement during embryonic development. The cause of this type of epulis is unknown. Also known as congenital granular cell tumor or Neumann's tumor; historically referred to as granular cell myoblastoma.
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Congenital epulis
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Congenital epulis
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Multiple lesions occur in 10% of affected neonates. The tumor is typically pedunculated and varies in maximum size from 0.5 cm to 9 cm. The lesion is typically painless and does not increase in size after discovery. Some small lesions may regress over time. Treatment is surgical excision. Recurrence is extremely rare even after incomplete excision.
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DYNLT1
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DYNLT1
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Dynein light chain Tctex-type 1 is a protein that in humans is encoded by the DYNLT1 gene.Cytoplasmic dynein is the major motor protein complex responsible for minus-end, microtubule-based motile processes. Each dynein complex consists of 2 heavy chains that have ATPase and motor activities, plus a group of accessory polypeptides. TCTEX1 is a dynein light chain involved in cargo binding (Chuang et al., 2005).[supplied by OMIM]
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Radio propaganda
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Radio propaganda
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Radio propaganda is propaganda aimed at influencing attitudes towards a certain cause or position, delivered through radio broadcast. The power of radio propaganda came from its revolutionary nature. The radio, like later technological advances in the media, allowed information to be transmitted quickly and uniformly to vast populations. Internationally, the radio was an early and powerful recruiting tool for propaganda campaigns.
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Radio propaganda
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Radio propaganda
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Before television, radio was by far the most effective way to prevent or promote social change. In many areas, it still is. Radio propaganda can be broadcast over great distances to a large audience at a relatively low cost. Through radio, a propagandist can bring his voice and all the persuasive power of his emotions to millions of people. A similar approach is used in every war employing radio propaganda: aside from convincing those on the home front of the necessity of war, a different kind of propaganda must be directed towards the enemy. Radio became a powerful propaganda tool because it ignored national borders and made enemy lines more accessible. One of the most common ways hosts got the civilian and enemy populations to listen to their broadcasts was by dropping leaflets from hot air balloons or airplanes. Most programs were broadcast on selected stations at certain times of the day; the dropped leaflets explained exactly when and where the broadcasts could be heard.
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Radio propaganda
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World War II
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The use of radio as a wartime propaganda tool was made famous during World War II by broadcasting organizations such as Voice of America and by shows such as Tokyo Rose, Axis Sally, and Lord Haw Haw.
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Radio propaganda
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World War II
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Nazi Germany The radio was an important tool of the Nazi propaganda efforts and it has been argued that it was the Nazis who pioneered the use of what was still a relatively new technology. A few months after the break out of World War II, German propagandists were transmitting no less than eleven hours a day of programs, offering most of them in English as well. In the first year of Nazi propaganda programming, broadcasters attempted to destroy pro-British feeling rather than arouse pro-German sentiment. These propagandists targeted certain groups, including capitalists, Jews, and selected newspapers/politicians. By the summer of 1940, the Nazis had abandoned all attempts to win American sympathy and the tone of German radio broadcasts towards the United States had become critical.
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Radio propaganda
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World War II
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German propaganda minister, Joseph Goebbels, claimed the radio was the "eighth great power" and he, along with the Nazi party, recognized the power of the radio in the propaganda machine of Nazi Germany. Recognizing the importance of radio in disseminating the Nazi message, Goebbels approved a mandate whereby millions of cheap radio sets were subsidized by the government and distributed to German citizens. It was Goebbels' job to propagate the anti-Bolshevik statements of Hitler and aim them directly at neighboring countries with German-speaking minorities. In Goebbels' "Radio as the Eighth Great Power" speech, he proclaimed: “It would not have been possible for us to take power or to use it in the ways we have without the radio...It is no exaggeration to say that the German revolution, at least in the form it took, would have been impossible without the airplane and the radio…[Radio] reached the entire nation, regardless of class, standing, or religion. That was primarily the result of the tight centralization, the strong reporting, and the up-to-date nature of the German radio.”As well as domestic broadcasts, the Nazi regime used the radio to deliver its message to both occupied territories and enemy states. One of the main targets was the United Kingdom to which William Joyce broadcast regularly, gaining him the nickname "Lord Haw-Haw" in the process. Broadcasts were also made to the United States, notably through Robert Henry Best and 'Axis Sally', Mildred Gillars.
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Radio propaganda
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World War II
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United Kingdom British propaganda during the First World War set a new benchmark that inspired the fascist and socialist regimes during the Second World War and the Cold War; Marshal Paul von Hindenburg stated, "This English propaganda was a new weapon, or rather a weapon which had never been employed on such a scale and so ruthlessly in the past." It was clear that large numbers of civilians could be mobilized for a massive war effort through persuasive techniques derived from the emerging disciplines of behavioral psychology and social sciences.An example of effective radio propaganda by the United States for the United Kingdom is the news reports of Edward R. Murrow. When the United Kingdom was at the time the only remaining nation opposing Germany in the autumn of 1940, Murrow covered the Battle of Britain and particularly the nightly bombing raids on London. His reports described the falling of the bombs, their impact, and the destruction they brought. As he described his approach to a London newspaper in 1941, "The official news is perhaps less important than the more intimate stories of life, work, and sacrifice."Murrow's objective was to focus on reaching the common man through his broadcasts, intimating to the world that the United Kingdom was fighting a "people’s war," not a war for its colonies, as the American isolationists charged. He wanted Americans to know that the UK was standing tall, united in its cause and protecting Western liberties and European civilization. He wanted Americans to see the UK as their natural ally and hurry to extend a helping hand. Many say he had far greater influence than the American ambassador to London; "He was an ambassador, in a double role, representing Britain in America as well as America in Britain.... He was a diplomat without a portfolio, a spokesman for a cause." United States Historians believe the moment when American radio made its debut as the preeminent means of foreign news was the Munich Crisis in September 1938. Early that month, Hitler began implementing his plans to dominate Europe by demanding self-determination for Germans living in a region of Czechoslovakia known as the Sudetenland. He left few doubts that he meant to annex the Sudetenland as part of an enlarged German Reich. High-level negotiations ensued, during which Britain's Prime Minister, Neville Chamberlain, journeyed to Germany three times in less than three weeks in a desperate attempt to save the peace. Fearful that a European war would once again entangle them, Americans became glued to their radios for daily and sometimes hourly updates and interpretations of the latest developments of the crisis. Within a couple of days, American listeners were bombarded with news programs, special news bulletins, and expert commentary on the crisis.America's first real venture into international broadcasting was in 1940 after Nazi victories in Europe, when the Roosevelt administration was becoming increasingly concerned about the effects of Nazi propaganda, both domestically and internationally. In August 1940, President Roosevelt issued an Executive Order establishing the Office of Coordination of Commercial and Cultural Relations to promote the use of government/private radio, and the Office of the Coordinator of Information. By 1942, the most famous radio program airing overseas became known as the "Voice of America." Even before the Japanese attack on Pearl Harbor, the U.S. government's Office of the Coordinator of Information began providing war news and commentary to commercial American shortwave radio stations for use on a voluntary basis.A popular government wartime radio show, performed by President Franklin D. Roosevelt, was known as "fireside chats". Two of the most famous programs on the radio show were entitled "On National Security" and "On the Declaration of War with Japan". "The Arsenal of Democracy" was a slogan coined by President Roosevelt during his national security radio broadcast delivered on 29 December 1940. Roosevelt promised to help the UK fight Nazi Germany by providing them with military supplies in a program known as Lend-Lease, while the United States stayed out of the actual fighting. This announcement was made a year before the attacks on Pearl Harbor, at a time when Germany had occupied much of Europe and threatened the UK. The day after the attack on Pearl Harbor, Roosevelt delivered his famous Infamy Speech to the United States, which was broadcast to the American people. The President called for a formal declaration of war on the Empire of Japan. The Infamy Speech was brief, running to just a little over seven minutes, and Roosevelt made a point of emphasizing that the United States and her interests were in grave danger. In so doing, he sought to end the isolationist stance the United States had previously been advocating concerning involvement in the war. The overall tone of the speech was one of determined realism. Roosevelt made no attempt to glaze over the extensive damage that had been caused to the American armed forces, noting the number of American lives lost in the attack. However, he emphasized his confidence in the strength of the America to face the challenge posed by Japan.
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Radio propaganda
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World War II
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"Yesterday, December 7th, 1941 – a date which will live in infamy – the United States of America was suddenly and deliberately attacked by naval and air forces of the Empire of Japan. It will be recorded that the distance of Hawaii from Japan makes it obvious that the attack was deliberately planned many days or even weeks ago. During the intervening time, the Japanese Government has deliberately sought to deceive the United States by false statements and expressions of hope for continued peace.”"As Commander-in-Chief of the Army and Navy I have directed that all measures be taken for our defense, that always will our whole nation remember the character of the onslaught against us. No matter how long it may take us to overcome this premeditated invasion, the American people, in their righteous might, will win through to absolute victory.”"Hostilities exist. There is no blinking at the fact that our people, our territory and our interests are in grave danger. With confidence in our armed forces, with the un-bounding determination of our people, we will gain the inevitable triumph. So help us God.”President Franklin D. Roosevelt – 8 December 1941With this declaration of war, radio became part of the propaganda campaign. Throughout the war, the attack on Pearl Harbor was frequently used in American propaganda. Direct wartime programming began shortly after the United States entry into the war. The first live broadcast to Germany, called Stimmen aus Amerika ("Voices from America") took place on 1 February 1942. It was introduced by "The Battle Hymn of the Republic" and included the pledge: "Today, and every day from now on, we will be with you from America to talk about the war.... The news may be good or bad for us – We will always tell you the truth."The Armed Forces Radio Service created a number of radio shows for American GIs stationed overseas. The most popular of these "mosquito networks" was GI Jive. In Agra, India, Virginia C. Claudon Allen broadcast nightly to counter Tokyo Rose.
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Radio propaganda
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World War II
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Famous radio shows During World War II, American GIs in both the Pacific and European theaters of war heard anonymous voices on the radio playing carefully selected American music and extolling the virtues of Japanese and Nazi causes. The DJs continuously encouraged GIs to stop fighting and constantly made false claims of American defeats and Japanese or Nazi victories. They frequently referred to specific American units and individuals by name, and in rare cases mentioned the names of loved ones back home. GIs dubbed the voice from Japan "Tokyo Rose"; two popular voices from Germany were "Axis Sally" and "Lord Haw-Haw".
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Radio propaganda
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World War II
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"Tokyo Rose": After being stranded in Japan while visiting her sick aunt after the United States refused to let her reenter the country after the attack on Pearl Harbor, Iva Toguri wound up at Radio Tokyo as a typist, preparing English-language scripts drafted by Japanese authorities for broadcast to the Allied troops in the Pacific. At Radio Tokyo, Toguri met captured Australian Major Charles Cousens and his associates, American Captain Wallace Ince and Filipino Lieutenant Normando Reyes. A supporter of the Allies in the war, she was delighted to meet soldiers who had been fighting for her side. Put off by her overt friendliness and pro-Americanism, the POWs initially suspected her of being a Kempeitai spy, but over the next few months they eventually came to trust her. When Radio Tokyo directed Cousens to include a woman DJ in his Zero Hour program, he asked for Toguri by name. Since their capture and conscription into Radio Tokyo, the Allied POWs had waged a covert campaign to sabotage the Japanese propaganda effort through the use of on-air innuendos, satire, and sarcastic, rushed or muffled readings. Now they had to bring a fourth party into the conspiracy, and the only person they could trust to support their efforts was Toguri. She was dubbed with the name "Tokyo Rose" and listeners came to know her by that name.
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Radio propaganda
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World War II
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After the war, the Army Counter Intelligence Corps, the Federal Bureau of Investigation, and the press continued to refer to Toguri by that name as she was taken into custody and brought to trial. Those defending Toguri stated that she was clearly "forced" to broadcast for the Japanese and was always a loyal American, shown by her many attempts to return home, which were continuously rejected. They also pointed to the lack of "tangible" evidence; American investigators never discovered any Japanese documents with the name "Tokyo Rose" because "Tokyo Rose" was a name coined by American GIs. However, under the United States Constitution, treason is the act of providing "aid and comfort" to an enemy. It does not say that force, loneliness, trickery, coercion, or fright are mitigating factors in favor of traitors. On 6 October 1949, Toguri was sentenced to 10 years in prison and fined $10,000. She served less than half that time and was pardoned by President Gerald Ford.
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Radio propaganda
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World War II
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"Axis Sally" was the pseudonym of Mildred Gillars, an American broadcaster employed by the Third Reich in Nazi Germany to proliferate propaganda during World War II. By 1941, the U.S. State Department advised American nationals to return home, but Gillars chose to stay in Germany after her fiancé, a German citizen named Paul Karlson, refused to marry her if she returned to the United States. Shortly afterwards, Karlson was sent to the Eastern Front, where he died in action. In 1940 she obtained work as an announcer with the Reichs-Rundfunk-Gesellschaft (RRG), German State Radio. On 7 December 1941, Gillars was working in the studio when the Japanese attack on Pearl Harbor was announced. She broke down in front of her colleagues and announced her allegiance to the East. However, since she decided to stay in Germany, Gillar was faced with the prospect of joblessness or prison, so she produced a written oath of allegiance to Germany and returned to work, her duties being limited to announcing records and participating in chat shows. She soon acquired several names amongst her GI listeners, including Berlin Bitch, Berlin Babe, Olga, and Sally, but the one that became most common was "Axis Sally." Her most successful show was known as Home Sweet Home. Home Sweet Home attempted to exploit the fears of American soldiers about the home front. The broadcasts were designed to make the soldiers cast doubt on their mission, their leaders, and their prospects after the war. Another show was known as Midge at the Mike, broadcast to late fall 1943. Gillar played American songs interspersed with defeatist propaganda and anti-Semitic rhetoric, as well as G.I.’s Letter box and Medical Reports in 1944, in which Gillars used information on wounded and captured U.S. airmen to cause fear and worry in their families. She was convicted of treason by the United States in 1949 following her capture in post-war Berlin. Her arrest came about after the U.S. attorney general specially dispatched prosecutor Victor C. Woerheide to Berlin to find and arrest Gillars. He only had one solid lead: Raymond Kurtz, a B-17 pilot shot down by the Germans, recalled that a woman who had visited his prison camp seeking interviews was the broadcaster. Gillars was indicted on 10 September 1948, and charged with 10 counts of treason, but only eight were presented at her trial, which began on 25 January 1949. The prosecution relied on the large number of her programs recorded by the Federal Communications Commission to demonstrate her active participation in propaganda activities against the United States. It was also shown that she had made an oath of allegiance to Adolf Hitler. She was sentenced to 10 to 30 years in prison and a $10,000 fine.
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Radio propaganda
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World War II
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"Lord Haw-Haw" was a pseudonym for William Joyce, German radio's most prominent English-language speaker. He hosted a propaganda show on a radio program called Germany Calling, broadcast by Nazi German radio to audiences in the UK on the station Reichssender Hamburg. The program started on 18 September 1939 and continued until 30 April 1945, when Hamburg was overrun by the British Army. Through his broadcasts, the Reich Ministry of Public Enlightenment and Propaganda attempted to discourage and demoralize British, Canadian, Australian, and American troops and the British population within radio range to suppress the effectiveness of the Allied war effort through propaganda and to motivate the Allies to agree to peace terms leaving the Nazi regime intact and in power. The Nazi broadcasts prominently reported on the shooting down of Allied aircraft and the sinking of Allied ships, presenting discouraging reports of high losses and casualties among Allied forces. Although listening to his broadcasts was highly discouraged, many Britons did indeed tune into them. In 1940, at the height of his influence, Joyce had an estimated 6 million regular and 18 million occasional listeners in the United Kingdom.At the end of the war, Joyce was captured by British forces at Flensburg, near the German border with Denmark. Spotting a dishevelled figure resting from gathering firewood, intelligence soldiers engaged him in conversation, asked if he was Joyce, and when he reached in his pocket for his false passport, the soldiers, believing he was armed, shot him in the buttocks, leaving four wounds. Joyce was charged on the basis that, even though he had misstated his nationality to gain possession of a British passport, until it expired this entitled him to British diplomatic protection in Germany, and therefore he owed allegiance to the King of England at the time he commenced working for the Germans. Joyce was convicted and sentenced to death on 19 September 1945.
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Radio propaganda
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Cold War
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By 1946, it became clear to the United States that the Soviet Union did not share the American vision of postwar collaboration for peace in Europe. Soviet authorities began to install Communist regimes in liberated territories of Eastern Europe, a direct violation of the provisions in the Teheran and Yalta Conferences. The radio became crucial in the propaganda war between the two blocs and was the main concern of both participants’ information agencies as the "war of ideas" began. In 1948, the Soviet Union organized the Communist Information Bureau (Cominform), which was formed to unite the Communist states in forthcoming struggle against "Anglo-American Imperialism."One of the earliest responses in Europe was known as Radio in the American Sector (RIAS). RIAS was established in 1946 to serve the American sector in West Berlin. The station's importance was magnified during the 1948 Berlin blockade, when it carried the message of Allied determination to resist Soviet intimidation. In East Germany, broadcasts included news, commentary, and cultural programs that were unavailable in the controlled media of the German Democratic Republic. The management of RIAS developed many of the techniques later used to develop Radio Free Europe/Radio Liberty. The RIAS broadcasts concentrated on the idea of democracy and the importance of the breakdown of the international communications barriers erected by the Communists. The programming was generally geared towards "special groups" within the East German population, including youth, women, farmers, etc. The broadcast became known as the "bridge" from West to East Germany over the Berlin Wall.
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Radio propaganda
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Cold War
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Aside from RIAS, Voice of America (VOA) began broadcasting in 1947 in the Soviet Union for the first time as a part of U.S. foreign policy to fight the propaganda of the Soviet Union and other countries. Initially, there was only one hour per day of news and other features broadcast on the pretext of countering "more harmful instances of Soviet propaganda directed against American leaders and policies" on the part of the internal Soviet Russian-language media. The Soviet Union responded by initiating aggressive, electronic jamming of Voice of America broadcasts on 24 April 1949. This led critics to question the broadcasts' actual impact. However, after the collapse of the Warsaw Pact and the Soviet Union, interviews with participants in anti-Soviet movements verified the effectiveness of VOA broadcasts in transmitting information to socialist societies.While many acknowledged the importance of propaganda as an instrument of foreign policy, it was primarily the Cold War that institutionalized propaganda as a permanent instrument of U.S. foreign policy. The Soviets suddenly increased the tempo of the war, by taking over Czechoslovakia and attempting to take complete control of Berlin. Realizing there was no further hope of considering the Soviet Union as an ally, the North Atlantic Treaty Organization was formed in April 1949, establishing the policy of containment of Communism as the organization's priority. The escalation of the Cold War intensified America's interest in broadcasting and information policy. The world was entering into a new era of foreign relations; therefore, the United States National Security Council produced a study in 1949 that concluded that there was a need for the United States to have a major information program to counter Soviet aggression. The council issued document 10/2, approved by President Truman in June 1948, authorizing a comprehensive program of clandestine warfare, including black propaganda, psychological warfare, subversion, assistance to underground resistance movements, paramilitary operations, and economic warfare. The most famous form of anti-Soviet propaganda was the development of Radio Free Europe (RFE) and Radio Liberty (RL), which broadcast to Eastern Europe. The stations' purpose, above all, was fighting a political mission against Communism and Sovietism, against the representatives of the terrorist regimes. Its job was to mask Communist plans and expose all of those who were propagandist of Communist ideology. While other countries established international broadcasting entities, RFE/RL's purpose was to change the form of government in foreign nations by airing news not about the country from which the broadcasts originated, but about the countries that were the targets of the broadcasts.President Harry Truman announced in 1950 that the United States would launch an information program known as the "Campaign of Truth." The name was strategically picked to avoid any connotation of propaganda. The goals of the campaign included: 1) Establish a “healthy international community” with confidence in American leadership.
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Radio propaganda
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Cold War
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2) Present America fairly and counter “all the misrepresentations.” 3) Discourage further Soviet encroachment by showing that American is desirous of peace but is prepared for war.
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Radio propaganda
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Cold War
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4) Help “to roll back Soviet influence” by all means short of force, making captive people feel that they can identify with the West, weakening the morale of the Soviet military personnel, and encouraging non-Communist forces.In late 1950, RFE/RL began to assemble a full-fledged foreign broadcast staff, becoming more than a "mouthpiece for exiles." Teams of journalists were hired for each language service and an elaborate system of intelligence gathering provided up-to-date broadcast material. Most of this material came from a network of well-connected émigrés and interviews with travelers and defectors. The Communist regimes devoted considerable resources to countering Western broadcasts. They organized radio jamming on a massive scale, spending more on jamming than the West did on broadcasting. They placed spies in Western radio stations in an attempt to disrupt information sharing and organize counterpropaganda, while also attempting to gain access to top level officials who could provide them with information controlled by Western media outlets or intelligence services. These countermeasures by foreign regimes significantly drained domestic resources, and failed to neutralize Western broadcasts.During these years, the practice of propaganda became inextricably tied to the practices of psychological warfare. During World War II, psychological warfare was largely seen as an accessory to military operations, but during the Cold War psychological warfare was used to influence public opinion and advance foreign policy interests. Psychological warfare became, in essence, a synonym for the Cold War. It reflected the belief that the Cold War was an ideological, psychological, and cultural contest for hearts and minds that would be won or lost on the plain of public opinion. When President John F. Kennedy took office, his administration had a greater interest in the U.S. information effort than any other president up until that time. With Soviet premier Nikita Khrushchev’s address to the Soviet Central Committee in 1961, U.S. leaders believed the Soviet Union would be ready to seek a more limited form of conflict, emphasizing their winning of hearts and minds. The United States saw this as a good sign to use psychological resources to their advantage. However, these components of propaganda were put on hold with the Bay of Pigs scandal, the Cuban Missile Crisis, and the abrupt end of the Kennedy Administration.
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Radio propaganda
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Vietnam
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The first Vietnamese-language radio transmission was made on 2 September 1945, when Ho Chi Minh read out the Declaration of Independence. Prior to 1945, Vietnamese people were banned from owning radio receivers, and broadcasting was under control of the French colonial government, which established the first radio station in Vietnam, Radio Saigon, in the late 1920s. Vietnam's national radio station, now called the Voice of Vietnam, started broadcasting from Hanoi the week after declaration of the Democratic Republic of Vietnam, stating, "This is the Voice of Vietnam, broadcasting from Hanoi, the capital of the Democratic Republic of Vietnam." During the Vietnam War, Radio Hanoi operated as a propaganda tool of North Vietnam. Following reunification, all radio stations were combined into the Voice of Vietnam, which became the national radio station in 1978.
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Radio propaganda
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Vietnam
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"Hanoi Hannah" or Trịnh Thị Ngọ, was a Vietnamese radio personality best known for her work during the Vietnam War, when she made English-language broadcasts for North Vietnam directed at U.S. troops. During the Vietnam War in the 1960s and 1970s, Ngo became famous among U.S. soldiers for her propaganda broadcasts on Radio Hanoi. She made three broadcasts a day, reading the list of the newly killed or imprisoned Americans, attempting to persuade U.S. GIs that the U.S. involvement in the Vietnam War was unjust and immoral and playing popular U.S. anti-war songs in an attempt to incite feelings of nostalgia and homesickness amongst U.S. troops. Although she used the alias Thu Huong, the GIs usually called her "Hanoi Hannah" or "the Dragon Lady". Few were believed to have been influenced by her propaganda work and the soldiers often mocked her tactics, but they were also impressed by her military intelligence, especially when she mentioned the location of their own unit or listed specific U.S. casualties. After the war, she returned to live in Ho Chi Minh City with her husband where her voice was better known in the U.S. than in her own country.
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Radio propaganda
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Iraq and Afghanistan
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The United States took the lead in broadcasting psychological operations due to its superior technology and its ability to use aircraft to broadcast AM, FM and shortwave radio from directly above target audiences. America had dropped battery or crank-powered radios on third-world nations like Haiti so that the populace could hear U.S. broadcasts. In the more recent struggles in Iraq and Afghanistan, the United States distributed various battery and solar-powered satellite radios so that its story could be heard. The U.S. also dropped leaflets to inform Afghans about the attacks of 11 September and the Taliban, and to infiltrate Iraq with information on anti-Saddam radio programs that would be broadcast.
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Radio propaganda
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Iraq and Afghanistan
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In the 2001 invasion of Afghanistan, psychological operations (PSYOP) tactics were employed to demoralize the Taliban and to win the sympathies of the Afghan population. At least six EC-130E Commando Solo aircraft were used to jam local radio transmissions and transmit replacement propaganda messages even before the United States invaded Afghanistan. The primary PSYOP objectives were used to counter adversarial propaganda, to discourage interference with humanitarian affairs activities, to support objectives against state and non-state supporters and sponsors of terrorism, and to disrupt support for and relationships among terrorist organizations. In Afghanistan, the U.S. military has long conducted propaganda campaigns to try to sway public opinion against insurgents. Today (2013), the U.S. is teaching Afghan army units how to counter Taliban propaganda, especially with local radio broadcasts. The idea is to counter the Taliban-sponsored stations, so called "Mullah Radios," that operate mainly in the tribal areas along the Pakistani border and broadcast propaganda that helps turn public opinion against foreign troops and the pro-Western Afghan government. Radio is key to reaching the majority of Afghans; with only limited access to television, newspapers, and the Internet, most depend on radio programs for information.During the Iraq War, the U.S. implemented "black propaganda" by creating false radio personalities who disseminated pro-American information, but were supposedly supporters of Saddam Hussein. Radio Tikrit was a radio station in Iraq that broadcast programs that reflected strong support for the Iraqi leader Saddam Hussein and his government. The station's name is also the name of the Iraqi town where Saddam and other members of his government were born. However, the tone of Radio Tikrit's programs began to change dramatically; one show reportedly described Iraqis as being so poor that they had to sell their windows and doors. Another broadcast reported to have encouraged Iraqi soldiers to refuse the "orders of the tyrant" and to "be brave before it is too late," suggesting that the United States may have infiltrated the station. The U.S. was also successful with the Voice of America efforts once the censorship of the Iraqi media was lifted with the removal of Saddam from power.
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Radio propaganda
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Voice of America
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Voice of America, The Voice, or VOA is the official external broadcast institution of the United States federal government, sponsoring programming for broadcast on the radio, television, and the Internet outside of the U.S. in 43 languages. Currently, VOA produces about 1,500 hours of news and feature programming each week to global audience in order, "to promote freedom and democracy and to enhance understanding through multimedia communication of accurate, objective, and balanced news, information and other programming about America and the world to audiences overseas." Under § 501 of the Smith–Mundt Act of 1948, the Voice of America was forbidden to broadcast directly to American citizens until July 2013 when it was repealed in the Smith-Mundt Modernization Act provision of the National Defense Authorization Act for 2013. The intent of the legislation was to protect the American public from propaganda actions by its own government.On 12 July 1976, the principles were signed into law by President Gerald Ford: "The long-range interests of the United States are served by communicating directly with the peoples of the world by radio. To be effective, the Voice of America must win the attention and respect of listeners. These principles will therefore govern Voice of America (VOA) broadcasts: 1. VOA will serve as a consistently reliable and authoritative source of news. VOA news will be accurate, objective, and comprehensive.
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Radio propaganda
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Voice of America
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2. VOA will represent America, not any single segment of American society, and will therefore present a balanced and comprehensive projection of significant American thought and institutions.
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Radio propaganda
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Voice of America
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3. VOA will present the policies of the United States clearly and effectively, and will also present responsible discussions and opinion on these policies.”Today, the VOA operates shortwave radio transmitters and antenna farms at one site in the United States close to Greenville, North Carolina. The 44 languages that Voice of America currently broadcasts in include (TV broadcasts are marked with an asterisk): From 1942 to 1945, VOA was part of the Office of War Information, from 1945 to 1953, a function of the State Department, and in 1953 it was placed under the U.S. Information Agency. When the USIA was abolished in 1999, the VOA was placed under the Broadcasting Board of Governors (BBG), where the control remains today. The BBG was established as a buffer to protect VOA and other U.S.-sponsored, non-military, international broadcasters from political interference.
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Radio propaganda
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Voice of America
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In 1994, Voice of America became the first broadcast-news organization to offer continuously updated programs on the Internet in English and 44 other languages, using more than 20,000 servers across 71 countries. Since many listeners in Africa and other areas still receive much of their information via radio and have only limited access to computers, VOA continues to maintain regular shortwave-radio broadcasts.
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Radio propaganda
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Radio Free Europe/Radio Liberty
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Radio Free Europe/Radio Liberty is a broadcaster funded by the United States Congress that provides news, information, and analysis to countries in Eastern Europe, Central Asia, and the Middle East "where the free flow of information is either banned by government authorities or not fully developed". RFE/RL is supervised by the Broadcasting Board of Governors, alongside Voice of America.
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Radio propaganda
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Radio Free Europe/Radio Liberty
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Founded as an anti-Communist propaganda source during the Cold War, RFE/RL was headquartered in Munich, Germany, from 1949 to 1995. In 1995, the headquarters were moved to Prague in the Czech Republic, where operations have been significantly reduced since the end of the Cold War. In addition to the headquarters, the service maintains 20 local bureaus in countries throughout their broadcast region, including a corporate office in Washington, D.C. RFE/RL broadcasts in 28 languages to 21 countries including Russia, Iran, Afghanistan, Pakistan, and Iraq.
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Radio propaganda
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Radio Free Europe/Radio Liberty
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RFE/RL was developed out of a belief that the Cold War would eventually be fought by political rather than military means. American policymakers such as George Kennan and John Foster Dulles acknowledged that the Cold War was essentially a "war of ideas". The United States, acting through the Central Intelligence Agency, funded a long list of projects to counter the Communist appeal in Europe and the developing world. The missions of RFE/RL were separate from Voice of America in the sense that VOA was meant to be the voice of America, reflecting American foreign policy and disseminating world news from an official American viewpoint, whereas RFE/RL has the mission of captivating people and stimulating non-cooperation in Communist countries.
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EIF4E
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EIF4E
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Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene.
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EIF4E
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Structure and function
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Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine five-prime cap structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. eIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs as well as other steps in RNA metabolism that require cap-binding. It is a 24-kD polypeptide that exists as both a free form and as part of the eIF4F pre-initiation complex. Many cellular mRNAs require eIF4E in order to be translated into protein. The eIF4E polypeptide is considered by some to be the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis.
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EIF4E
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Structure and function
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The other subunits of eIF4F are a 47-kD polypeptide, termed eIF4A, that possesses ATPase and RNA helicase activities, and a 220-kD scaffolding polypeptide, eIF4G.Some viruses cut eIF4G in such a way that the eIF4E binding site is removed and the virus is able to translate its proteins without eIF4E. Also some cellular proteins, the most notable being heat shock proteins, do not require eIF4E in order to be translated. Both viruses and cellular proteins achieve this through an internal ribosome entry site in the RNA or through other RNA translation mechanisms such as those going through eIF3deIF4E plays roles outside of translation and other cap-binding proteins can engage in cap-dependent translation in an eIF4E-independent manner including factors such as eIF3D, eIF3I, PARN, the nuclear cap-binding complex CBC. Many of these appear to be dependent on both specific features of transcripts as well as cellular context.
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EIF4E
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Structure and function
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eIF4E is found in the nucleus of many mammalian cell types as well as in other species including yeast, drosophila and humans. eIF4E is found in nuclear bodies a subset of which colocalize with PML nuclear bodies, and eIF4E is additionally found diffusely in parts of the nucleoplasm in mammalian. In the nucleus, eIF4E plays well defined roles in the export of selected RNAs which contributes to its oncogenic phenotypes. This relies on the ability of eIF4E to bind the m7G cap of RNAs and the presence of the 50 nucleotide eIF4E sensitivity element (4ESE) in the 3’UTR of sensitive transcripts; although other elements may also play a role. This form of export relies on the CRM1/XPO1 pathway. Nuclear eIF4E has been shown to play other roles in RNA processing including in m7G capping, alternative polyadenylation and splicing.Increased nuclear accumulation of eIF4E as well as increased eIF4E-dependent RNA export, m7G capping and splicing of selected transcripts is characteristic of high-eIF4E AML patient samples. RNAs are selected based on USER codes, or cis-acting elements, within their RNAs for specific levels of RNA processing; thus not all transcripts are sensitive to all levels of regulation (including translation). For its RNA export function, eIF4E directly binds to the leucine rich pentatricopeptide repeat protein (LRPPRC) which directly binds the dorsal surface of eIF4E and simultaneously to the 4ESE RNA thereby acting as a platform for assembly for the RNA export complex. The current model is then LRPPRC binds to CRM1/XPO1 to engage the nuclear pore and traffic the 4ESE RNA to the cytoplasm. In all, the nuclear functions of eIF4E can have potent impacts on the proteome allowing eIF4E to both re-write the message as well as to increase production of proteins based on increased accumulation in the cytoplasm due to increased export as well as to increased number of ribosomes per transcript in some cases. Its multiple roles in RNA processing require its association of RNAs through the m7G cap, and thus eIF4E can be considered a cap-chaperone protein.
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EIF4E
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Regulation
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Since eIF4E is an initiation factor that is relatively low in abundance, eIF4E can be controlled at multiple levels. Regulation of eIF4E may be achieved at the levels of transcription, RNA stability phosphorylation, subcellular localization and partner proteins.a. Regulation of eIF4E by Gene Expression and RNA stability The mechanisms responsible for eIF4E transcriptional regulation are not entirely understood. However, several reports suggest a correlation between myc levels and eIF4E mRNA levels during the cell cycle. The basis of this relationship was further established by the characterization of two myc-binding sites (CACGTG E box repeats) in the promoter region of the eIF4E gene. This sequence motif is shared with other in vivo targets for myc and mutations in the E box repeats of eIF4E inactivated the promoter region, thereby diminishing its expression.
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EIF4E
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Regulation
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Recent studies shown that eIF4E levels can be regulated at transcriptional level by NFkB and C/EBP. Interestingly, transduction of primary AML cells with IkB-SR resulted not only in reduction of eIF4E mRNA levels, but also re-localization of eIF4E protein. eIF4E mRNA stability are also regulated by HuR and TIAR proteins. eIF4E gene amplification has been observed in subset of head and neck and breast cancer specimens.b. Regulation of eIF4E by Phosphorylation Stimuli such as hormones, growth factors, and mitogens that promote cell proliferation also enhance translation rates by phosphorylating eIF4E. Although eIF4E phosphorylation and translation rates are not always correlated, consistent patterns of eIF4E phosphorylation are observed throughout the cell cycle; wherein low phosphorylation is seen during G0 and M phase and wherein high phosphorylation is seen during G1 and S phase. This evidence is further supported by the crystal structure of eIF4E which suggests that phosphorylation on serine residue 209 may increase the affinity of eIF4E for capped mRNA.
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