![]() Call Forwarding allows you to redirect your calls to a forwarding number so you don't miss an important phone call. Note: When Call Forwarding is activated, you will not be able to answer calls in your home, as they will only ring at the forwarding number. Activate or Deactivate Call Forwarding Online You can administer Call Forwarding using the Optimum Voice Homepage. • Log into the. If you haven't set up an account,. • From the Features menu in the top navigation, click on Call Forwarding. • By default, the Call Forwarding feature will be set to OFF. To activate Call Forwarding, click the ON dial button next to Call Forwarding. • Using Call Forwarding, you can forward your calls to: • A Phone Number where you would like your calls forwarded. • Directly to your Voicemail (if activated). • A Do Not Disturb Message from a list of pre-recorded greetings. • Using the Call Forwarding - Advanced options, you can also schedule which calls you would like to have forwarded and when. You can choose to forward: • All Calls - you can have this call forwarding feature selected as, Always On or Set Up a Schedule for when you would like to set up a schedule for this to be enabled. ![]() Call Forwarding can be scheduled by days of the week and time of day. • When your Line is Busy • Or if your Line is Not Answered. Set a Call Forwarding. Activating Call Forwarding You can activate Call Forwarding whenever you want your calls to be sent to another phone, including a. FAQs related to Call Forwarding Answers to some of your questions about Call Forwarding. How do I activate Call. If Call Forwarding is activated, the phone. If you select to forward calls when the Line Is Not Answered you can also select the number of rings the caller would hear before the call is forwarded. • Once you have made your selections above, click Submit. • To disable Call Forwarding, simply click the OFF dial button to change the current status to OFF. Back-Up Phone This feature forwards calls when there is a system interruption. You can have your calls automatically sent to an alternate number, such as a mobile phone. • To setup this feature, you would simply enter a phone number in the Back-Up Phone section (which is located at the bottom of the Call Forwarding section) and click Submit. Note: When your service is restored, calls will automatically ring to your Optimum voice home telephone number. However, if you have basic call forwarding set up, calls will continue to be forwarded to the specified number. Activate or Deactivate Call Forwarding From Your Phone Call Forwarding can also be controlled from your phone: • Dial *72. • Listen for stutter dial tone. • Dial the number to which you want calls forwarded. • Listen for ring tone: • If the phone is answered, your calls will be forwarded. • If line is busy or there is no answer, try the above steps again. To verify Call Forwarding is in effect: Dial *72 and you will hear an announcement that the feature is successfully activated. To deactivate call forwarding dial *73. You will hear 3 beeps followed by a dial tone indicating that Call Forwarding has been successfully turned off. Note: Even when Call Forwarding is active, you will hear a short, abbreviated ring on your Optimum Voice line indicating that an incoming call has been forwarded. Note: Call Forwarding is available within the United States, Alaska, Canada, Hawaii, Puerto Rico and the US Virgin Islands. Call Forwarding is one of included with Optimum Voice. ![]() You can manage Forward All Calls: •. To activate Forward All Calls from your phone: • Pick up your handset and press *72. Listen for stutter tone (a series of short beeps). • When the stutter tone begins, enter the ten-digit area code and phone number to which you want calls forwarded, and wait for the confirmation tone. After the confirmation tone, the system automatically places a courtesy call to the phone number you dialed. If the call is answered or the voice mail at that number answers the courtesy call, the feature is activated. • A confirmation tone indicates successful activation. • If the number you dialed is invalid, you will hear an error message or a busy signal. • You can attempt to forward the number again if it fails; this time add a 1 before the area code when entering the forward-to number. • If no one answers the call and voice mail does not pick up, you cannot forward your calls to that number. To cancel Forward All Calls from your phone, press *73. Listen for the confirmation tone. To activate Forward All Calls online: •. • Select Manage Phone Features. • For Call Forwarding, select (edit). • Select Forward All Calls. • Enter the number you want to forward calls to, or select a number you've used previously from the drop-down list. • Select Save Changes. To cancel Forward All Calls online, select Off.
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Developed by Rockstar Studios, and released on May 15, 2012, for PlayStation 3 and Xbox 360; Max Payne 3 is a third-person shooter video game, which became available for PC on June 1, 2012, in North America. It is one of the most expected video games of 2012 and in the following guide is revealed a megatrainer that can be used by fans of the game who wish to activate six different while playing the PC version of the game. As most trainers, the trainer for Max Payne 3, which is presented below, may not work on all versions of the game; however, those who wish to try it and use it, will get access to several useful Max Payne 3 cheat codes that will grant infinite ammo, health and painkillers, and will freeze the bullet time featured in the game. If these cheats are activated during the game, players have more time to focus on finding all without having to worry about their enemies. After its official release, Max Payne 3 received multiple positive scores from users and critics. For example, on GameSpot, the video game managed to gather 9 points out of 10, on GamesRadar, 10 out of 10, and on IGN, 9/10. Keep pressing ` until a command prompt appears at the bottom left of the screen -- that's what you use to input cheats. Guys i think i have a similar problem.have played max payne 1 and the cheats worked wonderfully but now in max payne 2 the cheat console fails to show up and u cannot type the. It is important to know that all Max Payne 3 cheats and trainers should be used only in the single-player mode, not while playing the video game online, against other players. Additionally, players must know that some antivirus programs may report trainers as infected files. In this case, the antivirus must be disabled and the trainer used at the player’s own risk. Max Payne 3 Cheats and Trainers To activate all Max Payne 3 cheat codes listed below, players need one of the trainers that can be found on various websites, including DLH.net. The mega-trainer gives access to a Max Payne 3 cheat for health, for ammo, for unlimited bullet time, for unlimited painkillers, etc To use the trainer on PC, during the game, players must follow these steps: Get the trainer from DLH.net Extract all files included in Max_Payne_3_v1.0.0.22_Plus_6_Trainer.rar. Copy or move the extracted files in the games directory Start the trainer Run the game Max Payne 3 Cheats List When the game starts, if the trainer was installed correctly, and if its compatible with the players version of the game, pressing the following keys will automatically activate the corresponding Max Payne 3 cheats: NUMPAD 1 God Mode (Infinite Health) NUMPAD 2 Infinite ammo for all weapons NUMPAD 3 No reload time NUMPAD 4 Unlimited Bullet Time NUMPAD 5 – Unlimited Painkillers NUMPAD 0 One hit kills HOME Disable all active cheats Source: rockstargames.com. Max Payne Cheats For PlayStation 2 • Pause Codes Press Start to pause, then press the following: Effect Effect L1, L2, R1, R2, Triangle, Circle, X, Square All weapons and full ammunition and pain killers L1, L2, R1, R2, TRIANGLE, X, X, TRIANGLE Get Unlimited Bullet Time L1, L1, L2, L2, R1, R1, R2, R2, Triangle, Circle, X, Square Invincibility Pass the subway level. Then return to the main menu and press the folowing Up, Down, Left, Right, Up, Left, Down, Circle. Level Select L1, L2, R1, R2, Triangle, Square, X, Circle Slow-Motion Sounds Contributed by: casper316, Dogg, WillDay, CDBavg400, Girbaud • Secret Modes and Areas Please do the following: Unlockable Unlockable Beat the game so you can unlock the Dead on Arrival and the New York Minute difficutly modes. Dead on Arrival and New York Minute Settings Complete Hard-boiled mode to unlock Dead On Arrival mode. Dead On Arrival mode Complete the game once to unlock Hard-Boiled mode and New York Minute mode. Hard-Boiled and New York Minute mode Successfully complete the Last Challenge level. The doors in the back of the room will open up to the Remedy Room. Secret programmer room Complete Dead On Arrival mode to unlock the secret stage. Secret Stage In the training level, near the police barricade look across the street and you should see a van. Jump on it, the front first and then the top. Time a jump onto the set of stairs and ascend them and jump through the window at the top. This is secret room. Secret Training Level Room Contributed by: Dogg, EDDY555, scorpion232 Walkthroughs & FAQs Type Name File Size General FAQs 189K General FAQs 136K General FAQs 211K General FAQs 159K General FAQs 67K General FAQs 113K General FAQs 229K General FAQs 195K General FAQs 164K General FAQs 129K General FAQs 55K In-Depth FAQs 115K In-Depth FAQs 42K In-Depth FAQs 38K. Max Payne Cheats For Xbox • Secret Room in Tutorial Mode In the last section of the Tutorial stage,there is a secret room.Across from the Subway Entrance,you can hop up onto a few boxes and then onto a catwalk.Go up the catwalk and jump through the window on the far left (you can easily see the room through it).Inside is a hidden room with four painkillers,an Ingram and some ammo for it. Contributed by: ZokeThe2nd • Secret Room on Docks Level On the Docks Level (Part II Chapter II) shortly after you crash the Truck into the Bridge you'll come across a room with two computers,a photo copier and a few shelves in it.In the far right corner across from the shelf,you'll find a switch.Hit it and it'll open up a hidden pannel in the wall that will reveal more shelves that hold ammo for your weapons,grenades and some painkillers. Contributed by: ZokeThe2nd • Armed Rats In Part 1 Chapter 2, at the very beginning, throw a grenade (you must cheat to have one) in the hole in the brick wall in front of you. A new objective should appear if you select show objectives: I had declared a war against rats. ![]() ![]() Now continue the level pass the sewer and then up the stairs. There you will find rats that will shoot at you. Contributed by: MonsterManiac • Secret Room on Parking Garage Level Just before you go down the first ramp (your still outside), jump on the barrels to the right of the entrance.Next hop on the small AC jutting out of the wall,then onto the roof.Shoot at the wall to your right until it falls away and go into the room,then drop down the grate into the hidden room.Inside are some supplies,and if you use the radio you can listen to some of the developers talk a bit. Contributed by: ZokeThe2nd • Secret Finale Beat the game on 'Dead on Arrival' with no codes and you will be transfered to the 'Final Battle.' ' There you will have to fight at least 20 guys in permanent bullet time. The secret is to kill as many guys in the right corner as you can, then run to the back right corner and 'Quick Save' it. Then, in that hall you are now in, you will find a little indentation. Hide there and wait for the enemies to come at you and you can kill all them and win! Once you are done, it says, 'Well Done,' the bullet time stops and then a door opens in the back of the level with a picture of the producers of Max Payne and such. There is also a laser that is forming the 'Rockstar' sign. I don't know if you can officially 'End' the level, but if you find a way, post it here please. This 'Bonus' level is actually pretty fun.try it out! Contributed by: Lancorn411 • Dopefish lives! The room with the 'Dopefish lives' poster is in part 1 chapter 7. To get to the room, do the following: Go through chapter 7 until you get to the scene where Gognitti runs down the stairs and gets stuck in from of the locked door. Once the cut scene ends, kill enough of the baddies that you can go down the stairs safely (or just do it balls out gung-ho style guns blazing all the way.) Once you get to the bottom, turn around and head beneith the stairs to the door. Open the door, and presto! Contributed by: siddacious • Secret Ending Sequence Defeat the game on the 'Dead On Arrival' setting to get a secret ending sequence. Contributed by: grandmaster2real • Hidden Room In Hotel When you are first going through the hotel level you will eventually come upon a room that is bare except for a pole in the middle that is leaning upwards and some windows on the side. Blow out a window and exit onto the ledege. Crawl along to your rigth until your come to two pieces of wood. Blow out the one that is partially broken and enter the room. There should be a body with a knife through it and Max will say something like 'I didn't even want to know what went on in here.' ' On a bookcase by the body there should be some Ammo and Painkillers. Contributed by: jeeves • All Weapons, Full Ammo, and Painkillers At the main menu after beating the game on any difficulty. Effect Effect While holding both Triggers and Joysticks down Press White, Black, Black, White, White, Black Cheats option will appear with all Weapons, Full Ammo, and Painkillers. Contributed by: DJ_BIG_GOUJI • Extra Gameplay modes Unlockable Unlockable Successfully Complete The Game On Either 'Fugitive' or 'Hard Boiled' GamePlay Modes. Unlock 'Dead On Arrival' and 'New York Minute' gameplay modes Contributed by: GameBeater Walkthroughs & FAQs Type Name File Size General FAQs 136K General FAQs 211K General FAQs 159K General FAQs 67K General FAQs 113K General FAQs 229K General FAQs 195K General FAQs 164K General FAQs 129K General FAQs 55K General FAQs 189K In-Depth FAQs 115K In-Depth FAQs 42K In-Depth FAQs 38K. Max Payne Cheats For Macintosh • Additional difficulty settings Complete the game on Fugitive to unlock the Hard-Boiled and New York Minute difficulty settings. Contributed by: Starky27 • Cheat Codes Hold [Option]+D as soon as you start the game until you hear a beep. A window w/ a picture of Max will appear, click the picture and then select 'Developer Mode' to enable cheat mode. Press F12 to display the console, then enter these codes: Effect Effect gethealth 100% Health c_addhealth Adds # to health getm79 M79 getpainkillers Painkillers getsniper Sniper rifle Contributed by: Starky27 • Cheat Codes Hold [Option]+D as soon as you start the game until you hear a beep. A window w/ a picture of Max will appear, click the picture and then select 'Developer Mode' to enable cheat mode. Max Payne Cheats For PC • Secret Area In Max Payne Tutorial In the tutorial stage, jump on the van where you got the sniper rifle. Then jump to the square thingy on the wall. From there, jump to the fire escape balcony. Go up 3 floors and destroy the glass window. A secret room with a new gun. I got the hint at the end of the tutorial where it says: 'Or you can continue exploring the rest of the environment.' ' Contributed by: devil • Extra Difficulty Settings If you successfully beat the game on Fugative mode you will unlock two new difficulty settings. 'The New York Minute' and 'Hard-Boiled'. Contributed by: AntiAppel • Vampire Easter Egg On Part I-Chapter 3, there is a door that you can break down (just before the toppling boiler). Go through the door and out a window. After following the bloodstains on the ledge, you'll come to another window to go through after bashing in. Lots of goodies here, and also a body with a stake in its back on the floor with the letters 'BUFF' drawn next to it in blood -- a little tip of the hat to a famous vampire slayer. Contributed by: Phased_5EK • Thank-You Easter Eggs There are (at least?) two parts in the game where Max will thank you for shooting something -- the first is in the bank's vault where the nosy alarms are going off. Shoot the red alarm hanging above the security area. The second is in Lupino's hotel when you enter the elevator and it's playing 'muzak'. Shoot out the speaker in the ceiling to the right after entering. Contributed by: Phased_5EK • Musical Instrument Easter Eggs There are several instances where Max will do something when you 'use' a music-related item. In the Ragna Rock club, you can play a rim-shot on the drums, walk across the guitar to get a twang noise, or use one of the mics to have him say 'Karoke was never my thing.' ' Later in the game when in the Punchinelo manor, you can have Max try a few -- unsuccessful! -- times to play the theme to the game on the piano [make sure you have NOT knocked out the lid support before doing this]. Contributed by: Phased_5EK • Developer Messages On the level where you are confronting B.B. On the parking garage, there is a hidden area where you can get a sniper rifle & ammo. Before going down the first ramp that leads deeper in to the garage, jump on the various objects by the entrance to the lower levels to get on a roof with a small metal-walled building on top. Bash on all the walls with the bat until a panel falls away and then go inside. Once inside, you'll also see a radio you can turn on to hear a rather humourous message from a couple of the game's developers. Contributed by: Phased_5EK • Secret Room Beat the game on the hardest difficulty setting, Dead On Arrival, to unlock a secret room, which loads after the final comic book sequence has finished. Contributed by: Hazden • God Mode, Unlimited Ammo, All Guns Make sure you modified your short-cut first on your desktop, or this won't work. Press F12 inside the game to bring up the console. Type in 'coder' without the quotes. It will give you God Mode, Unlimited Ammo, and All Guns without having to actually type in each of the other codes. Contributed by: Liquid Crash • Access the secret ending To view the secret ending of 'Max Payne', enter this into the devloper console, without quotes: 'maxpayne_gamemode->gm_sendendofgamemessages( );' Contributed by: mozwazherez • War of the Rats On Part I: Chapter 2, you can cause the rats to war amongst themselves. Use the developer command line cheat and give yourself a grenade ( then 'getgrenade' in the console) at the start of the level. Toss it in the gap of broken titles after the initial level_start camera panning. This will cause the mission objectives to change to 'I had declared war against the rats'. As you progress through the level, you will come across the two factions of rats -- WITH DESERT EAGLES! Shoot at one of the ceiling lamps that's off at its base to make it fall, causing the start of the war. If your group of rats wins, they will join forces and follow you through the rest of the level. If the other rats win, they'll turn their remaining forces on you. Contributed by: Phased_5EK • Turning off more klaxon sirens While in the underground portion of the Cold Steel plant (Project Valhalla labs), you can turn off the annoying klaxons -- the Max Payne way! Any time you hear a siren blaring, look around the ceiling for the loud speakers. They are usually located by a doorway, except in the main control room where they are near the middle of the room's ceiling. Pop a round or two in to them and the god-awful noise will stop in that vicinity. Contributed by: Phased_5EK • Secret Soldier of Fortune 2 Room During the chase across the rooftop, inspect the dark window at the back to find a room with ammo and Soldier of Fortune 2: Double Helix posters. Contributed by: goldenX87 • Secret room in Asgard Building In the second part of the Asgard Building, after picking up the video tape and watching the TV news report about Aesir Corp being a huge monopoly, there is a small, dark room with a table, couch etc. Shoot the small painting to make it fall off and a small white button is revealed. Press this button to make the couch behind you rise. Go down underneath it and use the control panel to open the door. Inside, switch the TV on to hear a funny version of Star Trek (called the Void) and open the cupboard behind the curtain to find, er. Something else. Contributed by: Crono667 • Bad Ending To view the 'bad ending' of Max Payne, just let the helicopter on the final level take off. Contributed by: Jeevan • Secret Room beside Basketball Court Near the end of the chase in part 1 chapter 7, when it shows Gognitti trying to get into a door (yelling punching and kicking). Go behind the satelite dish and jump down onto the ledge of the opposite building. From there you can jump down under the emergency stairway beside the basketball court. Funny poster inside 'Dopefish lives!' ', molotov cocktails, and other weapons. Contributed by: TaX • Endless Empty Clips When reloading a gun like the Double Beretta or Ingram, press jump as soon as the empty clips fall out, and Max will reload his gun again upon landing, producing more empty clips. You can do this an unlimited number of times. Contributed by: hel • Different Character Models To set up this code, you will first need to add '-developerkeys' (sans quotes) to the end of the shortcut target. It should read something like 'C: Program Files Max Payne maxpayne.exe' -developerkeys' if done correctly. Then, during gameplay, press F11, then press Page Up and Page Down to view (and control) the game's various character models. Contributed by: Mortal Quietus • 'All Your Base' easter egg. In the training level, look closely at the sign on the TAR CAFE (it's near the Police Mobile Arrest Centre on the street). It says: 'World's Best Since 1964 615 ALL YOUR BASE ARE.' ' Contributed by: Pyro Vesten • Secret area after completing game. If you manage to beat Max Payne on the hardest difficulty setting, after the game ends you will appear in a secret area in which Max is in permanent bullet time. There’s a bunch of jackhammer ammo lying around, some painkillers and a few other things. There are around 20 guards waiting for you. After defeating all of the guards the game says “Well Done” and you’ll be able to access a room with photographs of the development team, a special Remedy logo and some other things. Contributed by: Pyro Vesten • Instantly Unlock All Gameplay Modes Go to Start Menu->Run and type in 'regedit'. In the directory tree on the left, Go to HKEY_CURRENT_USER->Software->Remedy Entertainment->Max Payne. Click on the 'Game Level' folder, and some items will appear on the right side of the screen. Right-Click and select New-DWORD Value Double-Click on the entry you just made and set the value to 1. Rename the entries to the following: Effect Effect hell Dead On Arrival mode nightmare Hard-Broiled mode timedmode New York Minute mode Contributed by: hel • Console Cheats To gain access to the cheats edit the game shortcut so it reads the following: 'C:(LOCATION OF GAME) Maxpayne.exe -developer' From within the game, you are then able to bring up the console using the F12 key. With the console on the screen type in the below commands to access the cheats. Max Payne Cheats For PlayStation 4 • Trophies Trophy Complete Part III on any difficulty. A Bit Closer to Heaven Complete Part II on any difficulty. A Cold Day in Hell Complete the game in Hard-Boiled mode. Feel the Payne Kill four enemies with one thrown grenade. Four for the Price of One Snipe 10 consecutive enemies without missing a shot. Plenty to Go Around Kill 10 enemies during one use of Bullet Time. Quickest on the Draw Complete Part I on any difficulty. The American Dream Complete the End Combat. The Last Challenge Kill two enemies during one Shoot Dodge. Trick Shot Finish the game quicker than the Remedy par time in New York Minute mode. Under Par Locate the Secret Room during the Tutorial. Weapons Training Contributed by: KeyBlade999. Stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site. The, which modulates receptor function when bound to a ligand, is not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine. The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a and found in. The NMDA receptor is one of three types of, the others being the and. ![]() It is activated when and (or ) bind to it, and when activated it allows to flow through the. The NMDA receptor is very important for controlling and function. The NMDAR is a specific type of. The NMDA receptor is so named because the molecule (NMDA) binds selectively to it, and not to other glutamate receptors. Activation of NMDA receptors results in the opening of an that is nonselective to, with a combined near 0 mV. While the opening and closing of the ion channel is primarily gated by binding, the current flow through the ion channel is voltage dependent. Extracellular magnesium (Mg 2+) and zinc (Zn 2+) ions can bind to specific sites on the receptor, blocking the passage of other cations through the open ion channel. Depolarization of the cell dislodges and repels the Mg 2+ and Zn 2+ ions from the pore, thus allowing a voltage-dependent flow of sodium (Na +) and small amounts of calcium (Ca 2+) ions into the cell and potassium (K +) out of the cell. Ca 2+ flux through NMDARs is thought to be critical in, a cellular mechanism for and. The opening and closing (gating) of the NMDA receptor is complex. While it is primarily a ligand-gated channel, it does display weaker voltage-dependence modulation of the ligand-dependent gating. The ligand gating requires co-activation by two ligands: and either. The voltage-dependence of current through the channel is mainly due to binding of Mg 2+ or Zn 2+ ions to the protein as described above. The activity of the NMDA receptor is affected by many drugs such as (PCP), () and (DXM). The and effects of the drugs and are partially because of their effects on NMDA receptor activity. Contents • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • In 1972 a possible therapeutic importance of, an derivative, was discovered for treating disorders. Since 1989 memantine has been recognized to be an of the (NMDA receptor), entering the channel of the receptor after it has been activated and thereby blocking the flow of ions. The NMDA receptor is a glutamate and ion channel protein receptor that is activated when glycine and glutamate bind to it. The receptor is a heteromeric complex that. How can the answer be improved? ![]() NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor. Through the NMDA receptors and the resultant activation of Ca. Article Mechanism of NMDA Receptor Inhibition and Activation Shujia Zhu, 1Richard A. Stein,2 Craig Yoshioka,3 Chia-Hsueh Lee,1,5 April Goehring, Hassane S. The NMDA receptor channels play an important role in and synapse formation underlying memory, learning and formation of neural networks during development in the (CNS). Overactivation of the receptor, causing excessive influx of Ca 2+ can lead to which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases. The main problem with the development of for is that the physiological NMDA receptor activity is essential for normal neuronal function. To be clinically accepted the antagonists must block excessive activation without blocking the normal function. History [ ] The discovery of NMDA receptors was followed by the synthesis and study of N-Methyl-D-aspartic acid (NMDA) in the 1960s by Jeff Watkins and colleagues. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways. Receptor subunit selectivity was discovered in the early 1990s, which led to recognition of a new class of compounds that selectively inhibit the subunit. These findings led to vigorous campaign in the pharmaceutical industry. From this it was considered that NMDA receptors were associated with a variety of such as,,, and other CNS disorders. A fortuitous finding was made in 1968 when a woman was taking as flu medicine and experienced remarkable remission of her Parkinson's symptoms. This finding, reported by Scawab et al., was the beginning of of adamantane derivatives in the context of diseases affecting the CNS. Before this finding, memantine, another adamantane derivative, had been synthesized by Eli Lilly and Company in 1963. The purpose was to develop drug, but it showed no such. It was not until 1972 that a possible therapeutic importance of memantine for treating neurodegenerative disorders was discovered. From 1989 memantine has been recognized to be an uncompetitive antagonist of the NMDA receptor. NMDA receptor [ ]. Figure 2: Transmembrane region of NR1 (left) and NR2B (right) subunits of NMDA receptor. The NMDA receptor is a and protein receptor that is activated when and glutamate bind to it. The receptor is a heteromeric complex that interacts with multiple intracellular proteins by three different subunits: NR1, NR2 and NR3. NR1 has eight different subunits generated by alternative splicing from a single gene. There are four different NR2 subunits (A-D) and late in the 20 century NR3A and NR3B subunits have been reported. Six separate genes encode for NR2 and NR3. All the subunits share a common membrane topology that is dominated by a large extracellular N-terminus, a membrane region comprising three transmembrane segments, a re-entrant pore loop, an extracellular loop between the transmembrane segments that are structurally not well known, and an intracellular C-terminus, which are different in size depending on the subunit and provide multiple sites of interaction with many intracellular proteins. Figure 1 shows a basic structure of NR1/NR2 subunits that forms the for memantine, Mg 2+,, and amantadine. Mg 2+ block the NMDA receptor channels in voltage dependent manner but they are highly permeable to Ca 2+. Activation of the receptor depends on glutamate binding, or glycine binding at its NR1-linked binding site and -mediated of the postsynaptic membrane, which relieves the voltage-dependent channel block by Mg 2+. Activation and opening of the receptors channel thus allows the flow of K +, Na + and Ca 2+ ions, and the influx of Ca 2+ triggers intracellular signaling pathways. Allosteric receptor binding sites for zinc, proteins and the polyamines spermidine and spermine are also modulators for the NMDA receptor channels. The NR2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangement. The basic structure and functions associated with the NMDA receptor can be attributed to the NR2B subunit. For example, the glutamate binding site and the control of the Mg 2+ block are formed by the NR2B subunit. The high affinity sites for glycine are also exclusively displayed by the NR1/NR2B receptor. NR1/NR2B transmembrane segments are considered to be the part of the receptor that forms the binding pockets for uncompetitive NMDA receptor antagonists, but the transmembrane segments structures are not fully known as stated above. It is claimed that three binding sites within the receptor, A644 on the NR2B subunit and A645 and N616 on the NR1 subunit, are important for binding of memantine and related compounds as seen in figure 2. The NMDA receptor forms a between two GluN1 and two GluN2 subunits (the subunits were previously denoted as NR1 and NR2), two obligatory NR1 subunits and two regionally localized NR2 subunits. A related family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits. Each receptor subunit has modular design and each structural module also represents a functional unit: • The contains two globular structures: a modulatory domain and a -binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate. • The agonist-binding module links to a membrane domain, which consists of three transmembrane segments and a re-entrant loop reminiscent of the selectivity filter of. • The membrane domain contributes residues to the channel pore and is responsible for the receptor's high-unitary, high-calcium permeability, and voltage-dependent magnesium block. • Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of and, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins. The glycine-binding modules of the NR1 and NR3 subunits and the glutamate-binding module of the NR2A subunit have been expressed as soluble proteins, and their three-dimensional structure has been solved at atomic resolution. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors. Mechanism of action [ ] Overactivation of NMDA receptors, relieving the Mg 2+ block and causing excessive influx of Ca 2+ can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases. It is, however, important to preserve physiological NMDA receptor activity while trying to block its excessive, excitotoxic activity. This can possibly be achieved by uncompetitive antagonists, blocking the receptors ion channel when excessively open. Uncompetitive NMDA receptor antagonists, or channel blockers, enter the channel of the NMDA receptor after it has been activated and thereby block the flow of ions. MK-801, ketamine, amantadine and memantine are examples of such antagonists, see figure 1. The off-rate of an antagonist from the receptors channel is an important factor as too slow off-rate can interfere with normal function of the receptor and too fast off-rate may give ineffective blockade of an excessively open receptor. Memantine is an example of an uncompetitive channel blocker of the NMDA receptor, with a relatively rapid off-rate and low affinity. At physiological pH its amine group is positively charged and its block of the channel is voltage-dependent. It thereby mimics the physiological function of Mg 2+ as channel blocker. Memantine only blocks NMDA receptor associated channels during prolonged activation of the receptor, as it occurs under excitotoxic conditions, by replacing magnesium at the binding site. During normal receptor activity the channels only stay open for several milliseconds and under those circumstances memantine is unable to bind within the channels and therefore doesn't interfere with normal synaptic activity. Variants [ ] GluN1 [ ] There are eight variants of the subunit produced by alternative splicing of: • NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form. • NR1-2a, NR1-2b; • NR1-3a, NR1-3b; • NR1-4a, NR1-4b; GluN2 [ ]. NR2 subunit in vertebrates (left) and invertebrates (right). Ryan et al., 2008 While a single NR2 subunit is found in invertebrate organisms, four distinct isoforms of the NR2 subunit are expressed in vertebrates and are referred to with the nomenclature NR2A through NR2D (encoded by,,, ). Strong evidence shows that the genes encoding the NR2 subunits in vertebrates have undergone at least two rounds of gene duplication. They contain the binding-site for the. More importantly, each NR2 subunit has a different intracellular C-terminal domain that can interact with different sets of signalling molecules. Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor. NR2B to NR2A switch [ ]. The time course of NR2B-NR2A switch in human cerebellum. Bar-Shira et al., 2015 Whereas is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually subunits outnumber NR2B. This is called the NR2B-NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor. For instance, greater ratios of the NR2B subunit leads to NMDA receptors which remain open longer compared to those with more NR2A. This may in part account for greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behind genetically altered '. The detailed time course of this switch in the human cerebellum has been estimated using expression microarray and RNA seq and is shown in the figure on the right. There are three hypothetical models to describe this switch mechanism: • Increase in synaptic NR2A along with decrease in NR2B • Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A • Increase of NR2A diluting the number of NR2B without the decrease of the latter. The NR2B and NR2A subunits also have differential roles in mediating neuronal death. The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity. Disruption of the gene for NR2B in mice causes perinatal, whereas the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity. One study suggests that may play a role in the NMDA receptor maturation by increasing the subunit mobility. NR2B to NR2C switch [ ] Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division in the external granule-cell layer (EGL), migrate into the internal granule-cell layer (IGL) where they downregulate NR2B and activate NR2C, a process that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors. Role in excitotoxicity [ ] NMDA receptors have been implicated by a number of studies to be strongly involved with. Because NMDA receptors play an important role in the health and function of, there has been much discussion on how these receptors can affect both cell survival and cell death. Recent evidence supports the hypothesis that overstimulation of extrasynaptic NMDA receptors has more to do with excitotoxicity than stimulation of their counterparts. In addition, while stimulation of extrasynaptic NMDA receptors appear to contribute to cell death, there is evidence to suggest that stimulation of synaptic NMDA receptors contributes to the health and longevity of the cell. There is ample evidence to support the dual nature of NMDA receptors based on location, and the hypothesis explaining the two differing mechanisms is known as the 'localization hypothesis'. Differing cascade pathways [ ] In order to support the localization hypothesis, it would be necessary to show differing are activated by NMDA receptors based on its location within the cell membrane. Experiments have been designed to stimulate either synaptic or non-synaptic NMDA receptors exclusively. These types of experiments have shown that different pathways are being activated or regulated depending on the location of the signal origin. Many of these pathways use the same, but are regulated oppositely by NMDARs depending on its location. For example, synaptic NMDA excitation caused a decrease in the intracellular concentration of p38 mitogen-activated protein kinase (). Extrasynaptic stimulation NMDARs regulated p38MAPK in the opposite fashion, causing an increase in intracellular concentration. Experiments of this type have since been repeated with the results indicating these differences stretch across many pathways linked to cell survival and excitotoxicity. Two specific proteins have been identified as a major pathway responsible for these different cellular responses, and Jacob. ERK1/2 is responsible for phosphorylation of Jacob when excited by synaptic NMDARs. This information is then. Phosphorylation of Jacob does not take place with extrasynaptic NMDA stimulation. This allows the in the nucleus to respond differently based in the phosphorylation state of Jacob. Neural plasticity [ ] NMDA receptors are also associated with synaptic plasticity. The idea that both synaptic and extrasynaptic NMDA receptors can affect (LTP) and (LTD) differently has also been explored. Experimental data suggest that extrasynaptic NMDA receptors inhibit LTP while producing LTD. Inhibition of LTP can be prevented with the introduction of a. A that usually induces LTP with synaptic NMDARs, when applied selectively to extrasynaptic NMDARs produces a LTD. Experimentation also indicates that extrasynaptic activity is not required for the formation of LTP. In addition, both synaptic and extrasynaptic are involved in expressing a full LTD. Role of differing subunits [ ] Another factor that seems to affect NMDAR induced toxicity is the observed variation in makeup. NMDA receptors are heterotetramers with two GluN1 subunits and two variable subunits. Two of these variable subunits, GluN2A and GluN2B, have been shown to preferentially lead to cell survival and cell death cascades respectively. Although both subunits are found in synaptic and extrasynaptic NMDARs there is some evidence to suggest that the GluN2B subunit occurs more frequently in extrasynaptic receptors. This observation could help explain the dualistic role that NMDA receptors play in excitotoxicity. Despite the compelling evidence and the relative simplicity of these two theories working in tandem, there is still disagreement about the significance of these claims. Some problems in proving these theories arise with the difficulty of using pharmacological means to determine the subtypes of specific NMDARs. In addition, the theory of subunit variation does not explain how this effect might predominate, as it is widely held that the most common tetramer, made from two GluN1 subunits and one of each subunit GluN2A and GluN2B, makes up a high percentage of the NMDARs. Excitotoxicity in a clinical setting [ ] Excitotoxicity has been thought to play a role in the degenerative properties of conditions since the late 1950s. NMDA receptors seem to play an important role in many of these degenerative diseases affecting the brain. Most notably excitotoxic events involving NMDA receptors have been linked to Alzheimer's disease and Huntington's disease as well as with other medical conditions such as strokes and epilepsy. Treating these conditions with one of the many known NMDA receptor antagonists, however, lead to a variety of unwanted side effects, some of which can be quite severe. These side effects are, in part, observed because the NMDA receptors do not just signal for cell death but also play an important role in its vitality. Treatment for these conditions might be found in blocking NMDA receptors not found at the synapse. Ligands [ ] Agonists [ ]. The major endogenous agonist of the glycine co-agonist site of the NMDAR. Activation of NMDA receptors requires binding of or (aspartate does not stimulate the receptors as strongly). In addition, NMDARs also require the binding of the co- for the efficient opening of the ion channel, which is a part of this receptor. Has also been found to co-agonize the NMDA receptor with even greater potency than glycine. It is produced by, and is enriched in the same areas as NMDA receptors. Removal of D-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that D-serine can be released both by neurons and astrocytes to regulate NMDA receptors. NMDA receptor (NMDAR)-mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast unbinding kinetics, increasing channel open probability with depolarization. This property is fundamental to the role of the NMDA receptor in and, and it has been suggested that this channel is a biochemical substrate of, where it can act as a coincidence detector for membrane depolarization and synaptic transmission. Figure 6: Chemical structure of neramexane, second generation memantine derivative. An example of memantine derivative is which was discovered by studying number of aminoalkyl, with memantine as the template, as NMDA receptor antagonists. Neramexane, which can be seen in figure 6, binds to the same site as memantine within the NMDA receptor associated channel and with comparable affinity. It does also show very similar bioavailability and blocking kinetics as memantine. Neramexane went to for four indications, including Alzheimer's disease. Partial agonists [ ]. (NMDA), a synthetic partial agonist of the main site of the NMDAR. (NMDA), which the NMDA receptor was named after, is a partial agonist of the active or glutamate recognition site. 3,5-Dibromo-L-phenylalanine, a naturally occurring halogenated derivative of, is a weak partial NMDA receptor agonist acting on the glycine site. 3,5-Dibromo-L-phenylalanine has been proposed a novel therapeutic drug candidate for treatment of neuropsychiatric disorders and diseases such as, and neurological disorders such as and. Other weak partial agonists of the glycine site of the NMDA receptor such as (GLYX-13) and (NRX-1074) are now viewed for the development of new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities. Examples [ ] • (ACC) – synthetic glycine site partial agonist • () – naturally occurring glycine site partial agonist found in • – synthetic glycine site weak partial agonist • – synthetic glutamate site partial agonist • (NMDA) – synthetic glutamate site partial agonist Positive allosteric modulators include: • (NRX-1074) – synthetic weak partial agonist of an allosteric site of the glycine site • (GLYX-13) – synthetic weak partial agonist of an allosteric site of the glycine site Antagonists [ ]. A synthetic general anesthetic and one of the best-known NMDAR antagonists. Antagonists of the NMDA receptor are used as for animals and sometimes humans, and are often used as due to their properties, in addition to their unique effects at elevated dosages such as. When certain NMDA receptor antagonists are given to rodents in large doses, they can cause a form of called. NMDA receptor antagonists that have been shown to induce Olney's lesions include,, and (a metabolite of ), as well as some NMDA receptor antagonists used only in research environments. So far, the published research on Olney's lesions is inconclusive in its occurrence upon human or monkey brain tissues with respect to an increase in the presence of NMDA receptor antagonists. Most NMDAR antagonists are or of the channel pore or are antagonists of the glycine co-regulatory site rather than antagonists of the active/glutamate site. Figure 7: Nitroglycerin donate ONO 2 group that leads to second generation memantine analog, nitromemantine. Include: • – endogenous weak negative allosteric modulator • – naturally occurring negative allosteric modulators of the polyamine site found in Modulators [ ] Examples [ ] The NMDA receptor is modulated by a number of and compounds: • have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect. • regulates the amount of -containing NMDA receptors on the synaptic membrane, thus affecting. • do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses. • modulates NMDA function through and. Significantly enhancing in the. • kinase enhances NMDA receptor currents. •, and not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. • and generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity. • 2+ is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb 2+ exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling. • Proteins of the class I are endogenous negative regulators of NMDAR-mediated currents in the adult hippocampus, and are required for appropriate NMDAR-induced changes in trafficking and NMDAR-dependent and and. • The activity of NMDA receptors is also strikingly sensitive to the changes in, and partially inhibited by the ambient concentration of H + under physiological conditions. The level of inhibition by H + is greatly reduced in receptors containing the NR1a subtype, which contains the positively charged insert Exon 5. The effect of this insert may be mimicked by positively charged polyamines and aminoglycosides, explaining their mode of action. • NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called 'redox modulatory site.' Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as,, and the essential nutrient. Development of NMDA receptor antagonist [ ] The main problem with the development of NMDA antagonist for neuroprotection is that the physiological NMDA receptor activity is essential for normal neuronal function. Complete blocking of all NMDA receptor activity therefore results in adverse side effects such as, agitation and. To be clinically accepted the NMDA receptor antagonist must block excessive activation without blocking the normal function. Figure 3 shows simplified models of various types of NMDA receptor antagonists, which will be discussed further. Competitive NMDA receptor antagonists [ ] NMDA receptor antagonists, which were developed first, are not a good option because they compete and bind to the same site (NR2 subunit) on the receptor as the agonist, glutamate, and therefore block normal function also. They will block healthy areas of the brain prior to having an impact on pathological areas, because healthy areas contain lower levels of than pathological areas. These antagonists can be displaced from the receptor by high concentration of glutamate which can exist under excitotoxic circumstances. Uncompetitive NMDA receptor antagonists [ ]. Figure 4: The chemical structures of MK-801, phencyclidine and ketamine, high affinity uncompetitive NMDA receptor antagonists. Uncompetitive NMDA receptor antagonists however block within the ion channel at the Mg 2+ site (pore region) and in that way prevent excessive influx of Ca 2+. Uncompetitive block refers to a type of block that increased concentration of glutamate cannot overcome and is dependent upon prior activation of the receptor by the agonist, i.e. It only enters the channel when it is opened by agonist. The Mg 2+ block itself is too transient and flickery and therefore doesn't block excessive Ca 2+ influx to the extent necessary to prevent neurological toxicity. High affinity antagonists for the Mg 2+ site are on the other hand good excitotoxicity blockers, such as MK-801. They block open ion channels but the problem is when the ion channels close they get trapped inside resulting in undesirable side effects because of blocking normal as well as excessive activity. MK-801 cannot be given to humans because of that long dwell time in the channels and its blocking causes drowsiness and even coma. It's therefore considered to be clinically unacceptable., which has slightly shorter dwell time but still too excessive, causes hallucination and is therefore not a good agent either for neurodegenerative diseases. Ketamine is another example of drug with slightly shorter dwell time but still excessive and it is used as. Chemical structures of MK-801, Phencyclidine and Ketamine can be seen in figure 4. Memantine and related compounds [ ]. Figure 5: Chemical structures of memantine (right) and amantadine (left). Because of these adverse side effects of high affinity blockers the search for clinically successful NMDA receptor antagonists for neurodegenerative diseases continued and focused on developing low affinity blockers. However the affinity could not be too low and dwell time not too short (as seen with Mg 2+) where membrane depolarization relieves the block. The discovery was thereby development of uncompetitive antagonist with longer dwell time than Mg 2+ in the channel but shorter than MK-801. That way the drug obtained would only block excessively open NMDA receptor associated channels but not normal neurotransmission. Memantine is that drug. It is a derivative of amantadine which was first an anti-influenza agent but was later discovered by coincidence to have efficacy in Parkinson's disease. Chemical structures of memantine and amantadine can be seen in figure 5. The compound was first thought to be or but was later found to be an NMDA receptor antagonist. Memantine is the first drug approved for treatment of severe and more advanced, which for example anticholinergic drugs do not do much good for. It helps recovery of synaptic function and in that way improves impaired memory and learning. In 2015 memantine is also in trials for therapeutic importance in additional neurological disorders. Many second-generation memantine derivatives have been in development that may show even better neuroprotective effects, where the main thought is to use other safe but effective modulatory sites on the NMDA receptor in addition to its associated ion channel. Structure activity relationship (SAR) [ ]. Figure 8: Structure activity relationship (SAR) of amantadine and related compounds Memantine (1-amino-3,5-dimethyladamantane) is an aminoalkyl cyclohexane derivative and an atypical drug compound with non-planar, three dimensional tricyclic structure. Figure 8 shows SAR for aminoalkyl cyclohexane derivative. Memantine has several important features in its structure for its effectiveness: • Three-ring structure with a bridgehead amine, -NH 2 • The -NH 2 group is protonated under physiological pH of the body to carry a positive charge, -NH 3+ • Two methyl (CH 3) side groups which serve to prolong the dwell time and increase stability as well as affinity for the NMDA receptor channel compared with amantadine (1-adamantanamine). Despite the small structural difference between memantine and amantadine, two adamantane derivatives, the affinity for the binding site of NR1/NR2B subunit is much greater for memantine. In measurements memantine has an of (2.3+0.3) µM while amantadine has an IC 50 of (71.0+11.1) µM. The binding site with the highest affinity is called the dominant binding site. It involves a connection between the amine group of memantine and the NR1-N161 binding pocket of the NR1/NR2B subunit. The methyl side groups play an important role in increasing the affinity to the open NMDA receptor channels and making it a much better neuroprotective drug than amantadine. The binding pockets for the methyl groups are considered to be at the NR1-A645 and NR2B-A644 of the NR1/NR2B. The binding pockets are shown in figure 2. Memantine binds at or near to the Mg 2+ site inside the NMDA receptor associated channel. The -NH 2 group on memantine, which is protonated under physiological pH of the body, represents the region that binds at or near to the Mg 2+ site. Adding two methyl groups to the -N on the memantine structure has shown to decrease affinity, giving an IC 50 value of (28.4+1.4) µM. Second generation derivative of memantine; Nitromemantine [ ] Several derivatives of Nitromemantine, a second-generation derivative of memantine, have been synthesized in order to perform a detailed (SAR) of these novel drugs. One class, containing a nitro (NO 2) group opposite to the bridgehead amine (NH 2), showed a promising outcome. Nitromemantine utilizes memantine binding site on the NMDA receptor to target the NO x (X= 1 or 2) group for interaction with the S- nitrosylation/redox site external to the memantine binding site. Lengthening the side chains of memantine compensates for the worse drug affinity in the channel associated with the addition of the –ONO 2 group Therapeutic application [ ] Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases. It is, however, important to preserve physiological NMDA receptor activity while trying to block its excessive, excitotoxic activity. This can possibly be achieved by uncompetitive antagonists, blocking the receptors ion channel when excessively open Memantine is an example of uncompetitive NMDA receptor antagonist that has approved indication for the neurodegenerative disease Alzheimer's disease. In 2015 memantine is still in clinical trials for additional neurological diseases. Receptor modulation [ ] The NMDA receptor is a non-specific cation channel that can allow the passage of Ca 2+ and Na + into the cell and K + out of the cell. The (EPSP) produced by activation of an NMDA receptor increases the concentration of Ca 2+ in the cell. The Ca 2+ can in turn function as a in various. However, the NMDA receptor cation channel is blocked by Mg 2+ at resting membrane potential. Magnesium unblock is not instantaneous, to unblock all available channels, the postsynaptic cell must be depolarized for a sufficiently long period of time (in the scale of milliseconds). Therefore, the NMDA receptor functions as a 'molecular '. Its ion channel opens only when the following two conditions are met: glutamate is bound to the receptor, and the postsynaptic cell is depolarized (which removes the Mg 2+ blocking the channel). This property of the NMDA receptor explains many aspects of (LTP) and. NMDA receptors are modulated by a number of endogenous and exogenous compounds and play a key role in a wide range of (e.g., ) and processes (e.g., ). Clinical significance [ ] NMDAR antagonists like,,,,, and are used as. These and similar drugs like and also produce,, and effects and are used as. NMDAR inhibitors, including ketamine, (JNJ-54135419), (GLYX-13), (NRX-1074), (AV-101), and (CERC-301, MK-0657), are under development for the treatment of, including and. In addition, ketamine is already employed for this purpose as an off-label therapy in some clinics., a low-trapping NMDAR antagonist, is approved in the and for the treatment of moderate-to-severe Alzheimer's disease, and has now received a limited recommendation by the UK's for patients who fail other treatment options. Cochlear NMDARs are the target of intense research to find pharmacological solutions to treat. NMDARs are associated with a rare disease,, that usually occurs due to cross-reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in. These are known as. Compared to like, the NMDAR antagonist phencyclidine can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers, in what has led to the. Experiments in which rodents are treated with NMDA receptor antagonist are today the most common model when it comes to testing of novel schizophrenia therapies or exploring the exact mechanism of drugs already approved for treatment of schizophrenia. NMDAR antagonists, for instance,,, and have been extensively investigated for the treatment of -mediated in situations like and, but were unsuccessful in. See also [ ]. Abstract During T cell activation, the engagement of costimulatory molecules is often crucial to the development of an effective immune response, but the mechanism by which this is achieved is not known. Here, it is shown that beads attached to the surface of a T cell translocate toward the interface shortly after the start of T cell activation. This movement appears to depend on myosin motor proteins and requires the engagement of the major costimulatory receptor pairs, B7-CD28 and ICAM-1–LFA-1. This suggests that the engagement of costimulatory receptors triggers an active accumulation of molecules at the interface of the T cell and the antigen-presenting cell, which then increases the overall amplitude and duration of T cell signaling. ![]() 2 MHC–TCR interaction. Structures for the extracellular portions of MHC–peptide complexes, TCRαβ modules and the trimolecular MHC–peptide–TCR complex, are known from X-ray crystallography 5. TCRδε and TCRγε modules form extracellular disulfide-linked immunoglobulin domains, but no high-resolution structures are available. Stoichiometries other than that shown have been proposed. The cytoplasmic domains of the δ, ε, γ and ζ subunits carry 1–3 copies of the characteristic immunoreceptor Tyr-based activation motif (ITAM, blue boxes) YxxLx 6–8YxxL. Tyr residues in these sequences are phosphorylated by membrane-associated kinases upon receptor engagement. The relatively large cytoplasmic domains of the ζζ module might form a membrane-associated helical structure involved in signal transduction 48. Abbreviations: MHC, major histocompatibility complex; TCR, T-cell antigen receptor. ![]() ![]() 3 Soluble oligomeric major histocompatibility complex (MHC)–peptide complexes for studying T-cell activation processes. (a–d)Schematic diagrams of various MHC oligomerization strategies. (e–i)Scale models of oligomer components. Colors are consistent for the various species throughout all panels. (e) Ribbon diagram of the MHC–peptide complex, with αβ subunits in green, and bound antigenic peptide shown in yellow. Flexible β-subunit connecting peptide region (eight residues) is shown in red. MHC oligomers have been made through attachments to the α or β subunit termini, with linkers of up to 12 residues. (f) Antibody (IgG) ribbon diagram with antigen-binding domain (F ab) in purple, constant (Fc) domain in orange and flexible hinge region in red. MHC–peptide dimers have been produced as IgG–MHC complexes (a) 17,18. (g) Ribbon diagram of antibody Fc domain, used to prepare chimeric Fc–MHC dimers (b) 19,20. (h) Streptavidin (SA) ribbon diagram (blue), with biotin-binding sites used to link biotinylated MHC–peptide complexes 21 shown as yellow circles. SA-linked MHC dimers, trimers and tetramers (c) have been produced by this method. The exact valency of such complexes can be difficult to determine, particularly for streptavidin–phycoerythrin conjugates, which are large aggregates 26. (i) Peptide-based synthetic tetrameric cross-linker (xlink) shown as a ball-and-stick model, with reactive maleimide groups used to attach MHC monomers indicated by arrows, and fluorescent probe indicated by asterisk. MHC dimers, trimers and tetramers (d) have been prepared by this strategy 23,24. All structural diagrams (e–i) are drawn to the same scale. Cell 73, 209-212. Wilson, D.B., Wilson, D.H., Schroder, K., Pinilla, C., Blondelle, S, Houghten, RA., and Garcia, KC. Specificity and degeneracy of T cells. Mol Immunol 40, 1047-1055. Wulfing, C., and Davis, M.M. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. (2002), Flow cytometry used for the analysis of calcium signaling induced by antigen-specific. T-cell receptor. Movement triggered by costimulation during T. T-cell activation by the B7 costimulatory pathway. In 1970 Bretscher and Cohn put forth the two-signal model of lymphocyte activation to explain self/nonself dis- crimination (1). This model proposes that T-cell activation requires two independent signals. The first is transduced through the T-cell receptor (TCR) after. ![]() The net inward movement of F. Complexes at the IS during early phases of T cell activation. Cytoskeletal remodeling in T cell receptor signaling. The CH27 cell is substantially larger than the T cells. The T cell intracellular calcium concentration is overlaid in a false color scale from blue (low concentration) to red (high concentration) to mark the onset of T cell activation, set to time 0:00 min. Although the beads, one of which is marked with an arrow, are bound to the. ![]() Arrows indicate attachment points. 4 Large-scale membrane rearrangements during T-cell activation. (a) Fluorescent microscopy of interaction between a T cell and a supported bilayer carrying labeled MHC–peptide complexes (green) and ICAM adhesion molecules (red). The view is normal to the membrane interface. Image adapted with permission from Grakoui et al. 33 © 1999 American Association for the Advancement of Science. (b) Schematic diagram of molecular interactions at the immunological synapse. MHC–peptide complexes and TCRs cluster in the center, and are surrounded by adhesion molecules such as ICAM and LFA-1. Video microscopy movies available on the web include: formation of the immunological synapse 33 (), cytoskeletal movements and the synapse 49 () and differential clustering of CD3 and CD4 (Ref. Abbreviations: MHC, major histocompatibility complex; TCR, T-cell antigen receptor. Well, in a minute, I’m going to tell you how you can get some free satellite music for your travels. How Did They Deactivate My Radio When My Subscription Ran Out? Your satellite radio provider can authorize and de-authorize your radio at will, especially if you haven’t been paying your bill. Each radio has a unique radio ID that is used for the purpose of being able to activate or deactivate it. These ”activate” or “kill” codes are sent via satellite as part of the data stream that your satellite radio receives. So when your free 3-month subscription ended, like mine did. A signal was likely sent that effectively de-authorized your radio and boom, your channels were all gone, but maybe not ALL gone. We’ll get to that in a minute? Are There Any Hacks to Get All of my Channels Back for Free? Well, not exactly, that would be stealing and illegal, but you can get some free Sirius/XM satellite music and I’m about to explain how to do it. It can be a real problem on the Internet. Check out our article: for information on how to not get sucked into all that link bait madness. Ok, ok, I promised you a 'hack' to get you some free music, I guess it's time I delivered on my promise: How to Get Free Music on Your Sirius / XM Satellite Radio: 1. Select the XM/Sirius source button from your vehicle's radio. There is usually a button that says 'XM' or 'Sirius/XM'. ![]() ![]() Tune Your XM Radio to Channel 1 or Your Sirius Radio to Channel 184 When your subscription ran out, you probably remember seeing that your XM radio would only tune to channel '1' (or 184). This channel usually displays as 'XM PREVIEW' and may have your radio ID number displayed as well. When my XM subscription ran out a couple of years ago, this channel was filled with 10 to 20-second advertisements on a loop and was just wall to wall ads and didn't have any content on it at all. I remember thinking 'OK, well I guess that's it then, bye, XM'. Channel 1 was basically designed to be a nothing channel that was only used for the purposes of letting you know that you were getting a good signal, and it would just continually tell you to subscribe, not worth listening to AT ALL. On March 12, 2015, THAT ALL CHANGED!! XM/Sirius Tweeted: 'Hear without a subscription! Now available for free on all Sirius and XM radios. Sirius channel 184 and XM channel 1!' Finally, that stupid mind numbing preview channel that was all just ads on a loop IS GONE and has been replaced with actual content!! The channel is now called 'HITS 1' and is FREE and actually has decent MUSIC ON IT. Not parts of songs, but WHOLE SONGS, with not any actual commercials (for products anyway)!! Other than some subscription pitches after maybe every third or fourth song, you actually have real satellite music in your car again!! ![]() I've heard as many songs as 8 in a row without interruption. They even have a pretty decent morning show on the station as well. How to activate Sirius radio? Please enjoy the discussion forums below and share your experiences with the 200,000 current, new and past BMW owners. This is important: Your radio needs to be powered on and tuned to Channel 184 for Sirius radios or Channel 1 for XM and SiriusXM radios. Make sure your antenna has a clear view of the sky before sending a refresh signal. Simply tune to Channel 4 to verify your signal. How to activate Sirius radio? BMW - How to activate Sirius radio? To activate a new subscription for Sirius and I have had no luck. The music genre is pretty much pop top 40 type stuff, but it's actually a great little free channel now that you can listen to from coast to coast, and the only 'hack' you really need to access it is just to press your XM/Sirius button and start listening again! ![]() ![]() Free Capital One Activate Card Telephone Software, Capital One Quicksilver Credit Card 6 Things To, How To Activate A Capital One Credit Card Sapling, Capital One Journey Student Rewards Credit Card Login, Capital One Journey Student Rewards Credit Card Login, Capital One Card Activation Www Capitalone Activate, Archives Bertylbrasil, Activate Capital One Card Customer Service Phone Number, Www Capitalonecardservice Login General Motors, Free Capital One Activate Card Telephone Software Smartphone Soon, 2018 is coming soon. A new year will most likely also be invaded new smartphones of. So, what features whiz that would be the trend next season? If couple of years earlier a smartphone with a sizable screen (above 5 inches) dominate the market, now the smartphone with the full screen barely bezel (bezeless) and double cameras precisely the most sought by many people. Actually, these technology trends are merely present via premium smartphones aimed at top of the class. So to state, the premium-grade smartphone market still dominates this trend. So, whether smartphone technology trends in 2010 will continue sustainable in 2018? Will it be entry-level Will smartphones also follow an identical trend? See how big industry with the trend, it's no wonder many leading vendors intensively introduce this feature on its flagship. Just say it iPhone X, Samsung Galaxy Note 8, Google Pixel 2, Oppo F5, Vivo V7 Plus, and several others. Smartphone trend throughout the lastyear it will conical to a number of advanced features. We shall review for you personally 6 Technology that Will Become Trend in 2018 1. Middle-Class Will Using Bezeless Screen Bezeless is the biggest trend that gets attention throughout 2017. It 's not impossible smartphone screen trends bezeless (with a 2: 1 screen ratio or 18: 9) will continue within the next year. However, if this year the screen bezeless only comes through the premium class, next year bezeless smartphone screen actually be present in the segment medium. Unfortunately not disclosed which manufacturer will carry the bezeless screen in the centre class. But if talking about the rumors that circulated, one of many alleged players is Samsung. Known, the tech giant origin of Ginseng Country should indeed be preparing a series of classes medium, Galaxy A5, which will be rumored to be carrying the display bezeless display Galaxy S8 Galaxy S8 and Note 8. So, besides Samsung, can there be another vendor who is also preparing an identical step? You will find definitely some, so people think next year 's full-screen smartphone is not just expensive. USB Type-C Herry also said, could be more new smartphones that come with a USB Type-C port in 2018. This indicates Micro-B or 2.0 USB port will no longer be described as a trend. 'That may inevitably be some or perhaps many smartphones come with a Type-C USB port. USB type this 1 many usefulness and obviously better as opposed to Micro-B ', such as USB Type-C can be used in alternating position, different from 2.0 which can only be utilized in the up position. Furthermore, USB Type-C can be claimed to be faster to greatly help document transfer process and can charge faster, though not supported by Fast Charging capabilities. Face Recognition Fingerprint scanner was no longer considered as a sophisticated feature on the smartphone. In reality, this feature had become a tendency over the last few years. IPhone 5s arguably become pioneers. Then, that trend will replace the fingerprint is none apart from facial scan feature aka Face Recognition, or also often called facial scanning. This feature once was adopted in a number of premium classes released in 2017, some on we demonstrate to them like iPhone X and Samsung Galaxy Note 8. Face Recognition is also present on middle-class smartphones, like the Oppo F5 and Vivo V7. 'It's not the possible method of opening the smartphone screen with the face area can be the trend of numerous vendors in preparing new services with this technology in the next year. Dual DSLR Dual Camera Speaking of dual cameras which have end up being the trend of smartphone 2017, this trend will continue for quite some time forward, or even in the long term. 'The configuration is just like the Samsung Galaxy Note 8 or some other series with two dual cameras, one lens for telephoto mode, and another a wide-angle. With your capabilities, the captured photo effects can lead to professional camera shooting like DSLR or mirrorless. Bye-bye 3.5mm Jack Headphone! The absence of a 3.5mm headphone jack hole will also be a popular trend. In fact, this really is already done Apple on the iPhone 7 and 7 Plus since 2016 ago. 'It took quite a while for many vendors to finally obtain it follow Apple 's 'footsteps 'to eliminate the headphone hole on its newest product. In 2017 also already exist some, such as Pixel 2, Xiaomi Mi 6, HTC U11. Later, the newest smartphone without a 3.5mm headphone jack hole will count on wireless technology. Not impossible, some of which will follow Apple 's release step special wireless earphones for iPhone without headphone jackholes. Without Home Button Along with the bezeless trend, the physical home button is predicted to be lost on the newest smartphone lineup in years front. Instead, the smartphone screen may be embedded fingerprint to open the screen. 'iPhone X already first, but he 's depending on FaceID (face scanning technology). Some are among smartphone vendors will likely follow Apple. Vivo has also introduced Under Display Fingerprint Scanning technology right. Which means this smartphone won't use the physical home button, open the smartphone just need to touch the screen, '.Thus, without the house button, the smartphone will in actuality include the screen intact. For alternatives open the screen, users can make the most of features Face Recognition, Iris Scanning, and embedded fingerprint directly below the screen in Vivo. On this website we display some, and will also review Plus Minus iPhone possible it is likewise useful for you for extra information. IPhone is just a revolutionary phone by Apple Inc., and the initial generation begun to be marketed on June 29, 2007 in America, costing the US $ 499 for 4GB model and the US $ 599 for 8GB model. The following generation was named iPhone 3G, was launched in lots of countries on July 11, 2008, priced at the US $ 199 for the 8GB model and the US $ 299 for a 16GB model. While the third generation called iPhone 3GS appeared on June 17, 2009, the price tag on US $ 199 for 16GB model and the US $ 299 for the 32GB model. IPhone Specs How could be the specification? The iPhone camera has a capacity of 2-megapixel resolution for the very first generation iPhone and iPhone 3G, and 3.2 megapixels for iPhone 3GS. ![]() However, iPhone debutants and 3G do not have to record capabilities video, except by making use of the additional software. There are about 100 thousand applications that may be put on iPhone latest product. This app is sold on iTunes computer or in the Apps Store. IPhone users may even buy and download apps contained in the Apps Store directly provided a maximum of 10MB. The operating system on the iPhone works on the lightweight version of Mac OS X that is practical, without any 'junk components '. The system occupies about 250MB space. ![]() The operating system could be updated periodically via iTunes for free. Gadgets which are touted as 'The Smartest Phone 'isn't suddenly famous as, however it took almost no time since the initial iPhone was launched. The 2nd generation of iPhone is spread to numerous states on July 11, 2008, and priced the US $ 199 for 8GB models and the US $ 299 for the 16GB model. Phone activation is an option, but you’ll need to call this number: 1 (800) 678-7820. Activate Your Card Online. Although customers with accounts in Canada can only activate their cards via telephone, U.S. Customers can use the Capital One activation portal to activate their credit cards with Capital One. Visit capitalone/activate, activate your new Capital One card, so that you can enroll in Online banking and manage you account in an easy way. Generation third or also called iPhone 3GS, thrown to the gadget market on June 17, 2009, be valued price US $ 199 for model 16GB and the US $ 299 for the 32GB model. IPhone 3G is fairly popular among gadgets in differing of the world. With many different additional applications, this Apple product directly becomes the closest competitor Blackberry in the class of smartphones. However, the iPhone 3G has some shortcomings, ie unable to perform cut and paste operations. Though it appears simple, editing is important. After iPhone 3G features to get and copywriting disappears in this gadget. In addition, the iPhone also does not have MMS facilities. Needless to say, this problem is difficult Apple users, because, without MMS, gadgets cannot send photos or pictures directly. Other than that, iPhone also does not have the capacity to record video. As a system that has a degree of outer sophistication ordinary, the shortcoming to record video is quite strange. Another drawback, when the center iPhone users using apps like Twitter or instant messaging, iPhone owners cannot read inbox messages on a typical basis concise and fast. An additional, the famous iPhone battery is wasteful. The applications used to cause this gadget quickly come to an end of energy. Whilst the advantages of Apple iPhone is to have a revolutionary touchscreen and instantly accompanied by many vendors. However, there is no-one to match the iPhone technology. In addition, support 3rd Party Apps may also be greatly, though not entirely free. Another plus could be the stylish design, in addition to the screen large with very clear picture quality. Excellence iPhone touchscreen technology that utilizes a brand new interface mechanism - also referred to as multitouch - is really worldwide. Actually, what sort of multitouch on the iPhone? IPhone has super sensitive screen against touch, which is layered 'capacitive 'material. This causes the screen to differentiate between location and movement constant on multilocation. Because it relies heavily on this 'capacitive 'material, the iPhone screen can just only be active with the touch of the fingertips. That's, the screen is difficult to use if the consumer is using a stylus or wearing a holster nonconductive. Touchscreen on the iPhone will detect touch through 1 or 2 methods which can be 'mutual capacitance 'and self-capacitance '.Through the 'mutual capacitance 'method, the 'capacitive 'circuit uses 2 types the layer material, which is your website for current career paths, and a area for current signal censor sensors. 'Self-capacitance 'utilizes the electrode layer attached to the 'sensor capacitance 'circuit. Both wills send data in the form of electrical pulses to the processor. More info Once you've an iPhone, users must register to obtain AT & T service for phone activation. After active, the consumer can illuminate the screen by pressing the tiny button in the bottom of the screen. Four phone icons, mail, safari, and iPod will be at the bottom of the screen. While on top screen there's a row of icons, which is a menu hint for a variety of functions such as for instance texts, maps, weather, clock, calendar, photo albums, cameras, YouTube, stock reports, notes, and settings. A lot of attractive features that can be added on iPhone, like - for example - various kinds of games. These various applications may be obtained at Apple 's web store, and most are special apps for iPhone and iPod Touch. Before entering 2018, as a start we will start discussing Smartphone Flagship will most likely Make an Uproar in the beginning of the new year: 1. Nokia 9 The most effective distinct Nokia Android smartphone range is rumored to be supporting multimedia features. Nokia 9 itself reportedly is likely to be built with Qualcomm Snapdragon 835 processor and 4GB RAM and 64GB of internal memory. Supports multimedia, making Nokia 9 is going to be designed with dual-camera Carl-Zeiss and 12MP resolution. Of Nokia also think about the 4K video features that are mandatory for the upcoming 2018 guys. Nokia 6 (2018) Underneath there's an update from the Nokia smartphone range. Nokia 6 (2018) reportedly will use the screen contemporary with a rate of 18: 9 and is intended for the mid-end class market with affordable prices. In this line, Nokia reportedly will contend with Xiaomi and Motorola who have been fighting in this market. Nokia 6 (2018) will use Snapdragon 630 and supported with 4GB of RAM and 32GB of internal memory. Samsung Galaxy S9 and Galaxy S9 + The flagship smartphone certainly offers a different experience to its users. Samsung Galaxy S9 and Galaxy S9 + was reported provides some updates. Includes the usage of the latest Qualcomm Snapdragon processor 845. The improvement is the use of dual vertical cameras on the back. Fingerprint problem in the previous generation will be fixed. Samsung Galaxy S9 and Galaxy S9 + will use it camera really easy to reach. OnePlus 6 Just released OnePlus 5T, do not make brand smartphone origin China stop innovation. As known, OnePlus 5T has already been utilising the 18: 9 ratio screen and will continue on OnePlus 6. The headlines can also be OnePlus 6 will utilize the best processor Qualcomm Snapdragon 845. Needless to say, the performance of the gameplay will increasingly fast. Xiaomi Mi 7 Xiaomi Mi 7 became the most anticipated smartphone in 2018 by netizens. Since this smartphone is expected to be the first to use the Qualcomm Snapdragon 845 processor. Uniquely, Xiaomi Mi 7 this can work with a dual camera selfie resolution of every 16MP. With the support of lowlight mode and features bokeh, will Mi 7 compete with another selfie smartphones? Xiaomi Mi Mix 3 Mi Mix Xiaomi smartphone line is built with an attractive design. Well reportedly Xiaomi Mi Mix 3 already leaked on the net will work with a dual vertical camera setting that looks just like the iPhone X. Xiaomi Mi Mix 3 seems to be released in mid to late 2018. Are you going to wait for the clear presence of the smartphone these guys? Xiaomi Redmi Note 5 Xiaomi Redmi Note 5 is likely to be released in January 2018. Just as the line Redmi Note previously, this smartphone will use widescreen supported with a large 4000mAh battery. Xiaomi Redmi Note 5 will bring an 18: 9 ratio screen that uses FullHD + resolution (2160 x 1080 pixels). Not even known whether Xiaomi Redmi Note 5 will carry dual camera technology or not. IPhone (2018) iPhone X much discussed in 2017 is apparently the inspiration of Apple 's smartphone in the future. Reportedly Apple will prepare three models of iPhone 2018 with a display of bezel-less and notch that is characteristic. For cut prices, Apple provides the iPhone 6.1 with a TFT-LCD screen. While another two models will using OLED panels of 6.5 inches and 5.8 inches. What would you call her name? Innovation in the smartphone market certainly will not stop before the above things. Needless to say, there are many more innovations which are increasingly being prepared and kept tight by vendors to surprise smartphone consumers in future. 6 Reasons why you should use PagePlusDirect.com: • Proven track record - we have successfully activated tens of thousands of devices! • Activations and Ports are FREE! (be sure to ) • If you have trouble programming your phone, call us toll-free on our activation help line (Number provided in Confirmation E-Mail) • Professional and courteous assistance from AMERICAN operators in the USA. • We know how to get your port completed FAST! (usually within 1/2 hour) • Open 7 days a week for your convenience ( EVERY day of the year!) Instructions for 4G LTE Users: • Do NOT put your Selectel Wireless 4G SIM Card in the device until you receive an e-mail confirmation from us that it is safe to do so. • Be sure you choose a monthly plan of $20.00 or higher. ![]() • To use this form, you *MUST* purchase the SIM Card from us (PagePlusDirect.com). How to Find your ESN / MEID / IMEI: Your phone's ESN/MEID/IMEI can usually be found on the back of the phone AFTER you remove the battery (it will NOT be on the battery!) or in your phone's 'Settings' menu, usually under 'About Phone' or 'Phone Info.' • Please do NOT use the ESN/MEID/IMEI from the box your phone came in - some sellers recycle their boxes, so it could be wrong. • The number is usually under or above the barcodes. It is NOT the pESN, FCC ID or the S/N. • It may be labeled as DEC or HEX or IMEI (for 4G Phones). ![]() It can also be found in the phone's settings menu, usually under 'About Phone' or 'Phone Info.' • On some newer 4G phones, the IMEI can only be found by removing the battery (i.e., Samsung). Below is a Guide on how to activate a cell phone on Alltel Wireless that you purchased on eBay from the comfort of your home and without the need to go to a Alltel Store. It will always be a 15 digit number. Carrier: Compatibility: Important Notes: Compatible CDMA 3G and 4G Devices The GOLD STANDARD!! The 3G and 4G Compatible CDMA devices from one carrier will work on the Selectel Wireless Network. If you are not sure which carrier this is, please. Prepaid Devices will NOT work - see for details. Alltel Branded NOT compatible AT&T NOT compatible Boost Mobile NOT compatible Cricket NOT compatible Metro PCS NOT compatible Sprint NOT compatible Straight Talk Not Compatible T-Mobile NOT compatible TracFone NOT compatible US Cellular NOT compatible Virgin Mobile NOT compatible. Below is a Guide on how to activate a cell phone on Alltel Wireless that you purchased on eBay from the comfort of your home and without the need to go to a Alltel Store. Its easy, simple and fast. If you find this guide helpful, please click 'Yes' in the blue title bar below the guide. Thanks for reading. Two Steps Before You Call To Activate: 1. Get the ESN Number of the Phone. Take the battery off of the phone and look for the ESN number on the label the battery was covering. Models vary, but all of them either show the ESN as an 11 digit number in Decimal format (sometimes abbreviated DEC) or in Hexadecimal format which is a combination of letters and numbers that is 8 digits in length. Alltel can work with either one. It is not the serial number which is usually designated “S/N” or the FCC ID number. ESN Number is always below the battery ESN Number is on a label Alltel can use either the ESN, HEX, or DEC Number 2. Make sure the phone is fully charged. You don't want the phone to die when it starts programming because the battery dies. Also, fully charging the battery helps to prolong and enhance the battery’s performance (repeated, short and incomplete charging of your battery will diminish its capacity). Transferring your existing contract service to the phone you just bought. Call 1-800-Alltel1 (1-800-255-8351) and at the prompt enter your 10 digit phone number. When the Customer Service person answers the phone, tell him/her that you would like to activate your phone number on another cell phone. You will be asked some security questions, and then they will ask for the ESN number of the phone that you want to switch your service to. It takes about 30 seconds and then they will ask you to turn your phone off and back on and dial *228 and press send. Your phone will be programmed over the air in about 60 seconds. Please Read: We do not recommend taking the phone into any Alltel Wireless Store, the people do not get paid to switch your phone number to a new phone and sometimes they see it as a big bother. They tend to tell you a wide variety of things designed to either (1) get you to buy a phone from them, or (2) get you to leave the store without activating your phone. Also, the average representative is only trained on the few models that the store sells and sometimes that are just not familiar enough with the phone to do the activation. The best trained people are found when you call in at the above number. Quick Dial Codes To pay your bill from your phone: Press #PAY To get minutes of use: Press #MOU To get minutes of use via text: Text the word MINUTE to short code 696-467 (MYMINS) *611 and Send: It connects you to Alltel Customer Service free of charge If you found this guide helpful, please click yes below and we look forward to you coming to see us again. Thanks for reading. JustCellular on ebaY. ![]() I recently think about using page plus as my backup cell phone plan. The reasons are 1. The coverage of verizon network coverage. ![]() The newly rolled out $80 for 2000 minutes last a year plan. Something I worry about: Page plus sub-hell customer services and their unstable/inaccurate billing system. Finally decide to give it a try. The phone I picked is a Palm Pre. Here is the procedures to use a Palm Pre with page plus standard plan. Most of the work is to setup the phone. I bought my Palm Pre off craigslist for $60. Right after the deal, I bought a page plus activation off ebay from kittywireless. Their hard work and awesome customer service helped my stay away from page plus customer service daemons. Kitty activated my phone really quick and sent me the procedure for me to do on my phone in less than an hour. Note: This site was designed with Cascading Stylesheets for layout & design. You are seeing this note either because those Stylesheets didn't reach your machine. Sprint will not activate the Palm Pre on the Sero Plan! You'll have purchase the 'Simply Everything' Plan! It sucks that dedicated customers like us can't use it on. ![]() To activate the phone line: • Tap the right low corner of the screen. Choose “Emergency Call”, so I can dial a number out. The “Customer Service” call won’t allow me to modify the number to dial. • Revmove the 911 number, and put the number sent from kitty. It’s *22890 or *228. *22890 should program the phone automatically. • If the phone shows ‘connecting’ but no ‘connected’ for long time, hangup and wait for at least 15 minutes. • Repeat step 2. • Now the Palm Pre is activated. Because my standard pageplus plan does not provide data access, now the issue is to bypass the palm profile setup on the phone (Palm Activation). If you have data from page plus, you can go ahead setup your palm profile. • Download Palm WebDoctor from. • Download PlamOS Quick Install from. • Download the activation bypass tool from palm. • Run the PalmOS Quick Install first. It will take care of the driver problem on Windows XP. • Run WebDoctor, see if it can see the Palm Pre, even in recovery mode. • Follow the procedure to put the phone in recovery mode, and run the activation bypass tool as ‘java -jar devicetool.jar’. For details, read the bypass the activation. • Run WebOSQuickInstall. Search for Preware and install it. Since I bypassed the phone activation and ended up no palm profile, I cannot use the app catalog and updates. With Preware, I can install apps and updates. • I am ready to go. • Extra works: • Google weatherman, see if you can find a free ipkg copy of their old verion. The newer 2.1 one costs only $1.99. • Install facebook beta 1.5 from Preware. On the first run, Plam Pre sync with all facebook contacts. • Install InternalZ from Preware. • Install Dr. Battery from Preware. • Sync my google account with my Palm Pre. Hallo, I disconnected defective palm 755 p and activate Palm Pre Plus. After I remove the 911 and put the number sent from Pages Plus the phone wont sing in: “ Use the email address and password to created profile. I can call any phone when I choose remove Emergency Call and put phone when I wish to call. But nobody can ring to me. On procedure above I stop on point 3. I can not take a file. When I took from different side, then I stopped in point 5. ( Checking system Novacomd Connect your phone directly with your USB cable. Do not remove the battery or disconnect your phone during this process. ) How I can created my profile and password or skip it I have not to application the theses of access in telephone. I ask about help. There is an easy way and the way I posted. The easy way to contact the dealer you used. They should activate the data service for you, so you can setup the profile. If you stopped at step 3, that means your phone was not ready yet. You may have to wait for awhile and try dial *22890 again. On my case, I waited about 2 hours to get the *22890 passed through. I would not recommend you try “the other way”. It’s kind of risky, and you may brick your phone. However, if you really want to try it. You may have to put your phone into recovery mode. This tip is only for devices running webOS 1.x. (This will not work on webOS 2.x devices,; we will have a separate 2.x tip in the near future) When you activate a webOS 1.x device, the first thing the phone does is search for a cellular signal or SIM card (for GSM phones). Even if you have an active Wi-Fi connection available, if it is not an active device on your cellular account you will not be able to do much more than just turn the phone on. If your phone is a GSM device and you have a friend with an active SIM card, you should see if you could borrow it to activate your device. Once activated, just take out the SIM card out and the device will run just fine. Otherwise, there is a developer tool available that will allow you to bypass the activation requirements, thus allowing you to use your phone as a Wi-Fi only device. Unfortunately, there are a number of limitations of developing on an Unactivated Devices. You are unable to log in to a Palm Profile, access the App Catalog, get any OTA webOS updates, or use the Phone or SMS functionality. Here comes Homebrew to the rescue! Specifically, developer Arthur Thornton to the rescue! He has created a patch that will allow you to create or login to a Palm profile on a activation-bypassed device, thus removing all the limitations above with the exception of providing Phone/SMS functionality. Continue reading after the break to learn how to bypass the activation and then log in to your profile. To bypass activation: • Visit on the webOS Developer Center website • Under the section 'Running the Activation-Bypass Tool', download the activation-bypass tool (direct link ) to your computer • Follow the directions a little earlier on that page to boot your device into recovery mode • Once in recovery mode, run the activation-bypass tool from the command line by issuing the following command: 'java -jar devicetool.jar'. (for example, to access the command line on a Windows PC, press the 'Start' button, choose 'Run' and type 'cmd'. Navigate to the directory you saved the bypass tool.) • The device will reboot. • Once the device boots, it will already be in developer mode. Just activate Wi-Fi and the device will be ready to use, subject to the limitations of non-activation. To log in to an existing Palm Profile (or to create a new one): • If you haven't already, activate the Wi-Fi on your device and log in to a Wi-Fi network • Plug in your device to a computer and select 'Just Charge'. • It should already be in developer mode, so all you need to do is load up webOS Quick Install and tap on the 'feeds' button (the bottom button on the right-hand side). Select patches and do a search for the 'Enable Profile Creation - Activation Bypassed' patch. Install the patch (it if asks you to install other dependant patches, install those, too) • Then do a search for the 'Show FirstUse App' patch and install that patch, too. • • Once the phone is back up, you should see a new app called 'First Use'. Open that app and follow the steps to log in or create a new profile. • At the end of the process, you will get to a screen saying 'Setup Complete' with a standard webOS spinning progress circle. Manually again. • When the phone comes back up, you will have full access to the device, the App Catalog, and everything else that does not require a cellular connection or phone number. Unfortunately, none of your apps will be automatically re-downloaded from the App Catalog if you are using an existing Profile. You can still go into the App Catalog and download them all for free, as your Palm Profile will have a record of all your app purchases. Otherwise, if you need help restoring from a previous device, be sure to check out our before resetting your device and logging in to your profile. March 13 2013 by in,, Do you want to lose weight? Here’s number 16 of my 18 best tips. All of the published tips can be found on the page. Before we get started, here’s a short recap of the tips so far: The first and most crucial piece of advice was to. ![]() ![]() The next were,,,,,, and,,, eating, stocking up on, using and finally,. This is number sixteen: 16. Get into optimal ketosis Warning: Not recommended for type 1 diabetics, see below. We’ve now arrived at tip number 16. If you’re still having trouble losing weight, despite following the 15 pieces of advice listed above, it might be a good idea to bring out the heavy artillery: optimal ketosis. Many people stalling at weight plateaus while on a low carb diet have found optimal ketosis helpful. So how does this work? A quick run-through: The first tip was to eat low carb. This is because a low-carb diet, allowing your fat deposits to shrink and release their stored energy. ![]() This tends to cause you to want to consume less calories than you expend – without hunger – and lose weight. Several of the tips mentioned above are about fine-tuning your diet to better this effect. Tag: Foods That Activate Ketones. Ballabgarh India Dementia Review. Plants and oils that were scientifically proven to activate ketones, and in turn, improve. Video course Do you know exactly how to eat a low-carb and high fat diet (LCHF)? This is required for ketosis. If not the easiest way is watching this high quality 11-minute video course on how to eat LCHF, and the most important things to think about. Sign up for our free newsletter and you’ll get instant access to it. The newsletter arrives once a week with unbiased information. Your email is kept 100% private. To unsubscribe just press “unsubscribe” at the bottom of any newsletter. Maximum effect from an LCHF diet How do you know you’re getting the maximum hormonal impact from your low-carb diet? You do that by achieving what’s known as “optimal ketosis”. Ketosis Ketosis is a state at which the body has an extremely high fat-burning rate. Even the brain runs on fat, via ketone bodies. These are energy molecules in the blood (like blood sugar) which become fuel for our brains after being converted from fat by the liver. To encourage ketone production, the amount of insulin in your bloodstream must be low. The lower your insulin, the higher your ketone production. And when you have a well-controlled, sufficiently large amount of ketones in your blood, it’s basically proof that your insulin is very low – and therefore, that you’re enjoying the maximum effect of your low-carbohydrate diet. That’s what’s called optimal ketosis. Measuring ketones Today, there are reasonably-priced gadgets available for measuring ketone levels at home. One needle prick of the finger, and in just a few seconds you’ll know your blood ketone level. Blood ketones are best measured on a fasted stomach in the morning (before breakfast, that is). Here are a few pointers on how to interpret the result: • Below 0.5 mmol/L is not considered “ketosis”. At this level, you’re far away from maximum fat-burning. • Between 0.5-1.5 mmol/L is light nutritional ketosis. You’ll be getting a good effect on your weight, but not optimal. • Around 1.5 – 3 mmol/L is what’s called optimal ketosis and is recommended for maximum weight loss. • Values of over 3 mmol/L aren’t neccessary. That is, they will achieve neither better nor worse results than being at the 1.5-3 level. Higher values can also sometimes mean that you’re not getting enough food. For type 1 diabetics, it can be caused by a severe lack of insulin, see below. Ketones in urine Ketone levels can also be measured in a more old-fashioned way, with urine test sticks (sold prescription-free in pharmacies or ). Ketone sticks give less reliable results for several reasons, and the above recommendations can’t be straightforwardly applied to them. They are, however, much cheaper. My personal experience Feel free to read my accounts of a two-month personal trial: • • • Although I was quite happy with my weight before these trials, they resulted in a further loss of 4.5kgs (10 pounds) and 7cm (3 inches) around my waist – without additional exercise or even the slightest resemblance of hunger. How to achieve optimal ketosis Many who firmly believe they are eating a strict low-carb diet are surprised when they measure their blood ketones. They may be at around only 0.2 or 0.5 – quite far off from the sweet spot! The trick here is not only to avoid all obvious sourced of carbohydrate (sweets, bread, spaghetti, rice, potatoes), but also to be careful with your protein intake. If you eat large amounts of meat, eggs and the like, the excess protein will converted into glucose in the body. Large amounts of protein can also raise your insulin levels somewhat. This compromises optimal ketosis. The secret to getting around this is usually to eat your fill with more fat. For example, if you have a bigger helping of herb butter to your steak, you might not feel like having a second steak, and instead feel satisfied after the first one. A popular trick people use to ingest more fat is “fat coffee” (sometimes called “Magic Bullet Coffee” or MBC). It involves adding one tablespoon of butter and one tablespoon of coconut oil to your (morning) coffee, and requires a food blender for the right texture. More fat in your food will fill you up more. This will ensure you eat less protein, and even less carbohydrate. Your insulin will drop and, hopefully, you’ll be able to reach optimal ketosis. And that’s when many a stubborn weight plateau is overcome. If it doesn’t work Being in optimal ketosis for a prolonged period of time (say, a month) will ensure that you experience the maximal hormonal effect from eating a low-carb diet. If this doesn’t result in noticeable weight loss, you can be certain that too many carbs are NOT part of your weight issue and not the obstacle to your weight loss. There are, in fact, other causes of obesity and being overweight. The next three tips in this series might help you. Try it Order a ketone meter online and start measuring. There are a few different models, the most popular one is probably the Precision Xtra ketone meter. Unfortunately these meters are all quite expensive to use, as the test strips can cost about $5 per test. With everything you need to check your blood ketone levels. More Learn much more about ketogenic diets here: Watch my video interview with the American doctor Peter Attia, on a strictly ketogenic low-carbohydrate diet: Read all the tips on the page. A word of warning If you have type 1 diabetes, you should not follow the above advice on optimal ketosis – it may be risky. If you have ketones in your blood at all, you must be sure that your blood sugar levels are normal. If they are, you’re in normal ketosis – just like the ketosis of healthy people who stick to a strict low carb diet. High blood sugar levels coupled with high blood ketones, on the other hand, will mean that you have a pathologically low level of insulin – something non-diabetics do not suffer from. This can lead to ketoacidosis – a potentially life-threatening condition. If this happens, you’ll need to inject more insulin; if you’re at all unsure of what to do, contact a medical professional. Coveting really high blood ketones for weight control is not worth the risk for type 1 diabetics. First to apicius, you suppress hunger aka ur Lepten hormone with fat. After you have fully reached a steady state of ketosis you can do a refeed once a week of say 400g of carbs. This will ramp up your motabilizm again. Look it up its true. I keep my carb below 30g a day even below 20 if I can. Also I work out a lot and replenish my glycogen stores once a week loook up the term cyclical keto diet ckd. To pentro- a TRUE keto diet is boring it's meat and fats that's it. You can't even eat onions the first couple weeks cause they have suger. Unless you are looking for more of a just low carb diet, but then you won't be in full ketosis. And the fat you eat will be stored on ur body, Your midacondria will choose to burn either carbs or fat for energy. If you burn fat you will not store fat, if you burn carb then the fat you are also ingesting with not burn off it will be stored. That's why if you do not do this diet properly it can harm you. I eat 200 grams of fat a day if I ate carbs that amount of fat could be catastrophic to my heart and organs. My blood pressure and everything would rise. Look up recipes online for fats bombs to keep it interesting. Lastly remember to use unrefined virgin coconut oil. The reason is it is an MCT versus most fats that are LCT Medium-chain tryglyceride and long-chain. Medium chain is broken down instantly and sent to liver for ketones for fast energy. Does not get stored on body. Long chain triglycerides take a while to break down. This may sound weird but go to bodybuilding.com and look up ketogenic videos. There is an hour long video on there. Great video and they also have great recipes in keto articles. Hi, I am fairly new to LCHF and a previous sugar addict, but am learning about the diet plan and sticking to a keto strict diet. I also intermittenly fast between 12-15 hours a day. I am happy to say I don't crave sugar anymore! I've lost 17 lbs in the month I have been on it. I drink a lot of coffee and use 1 packet of Spenda Naturals, which is an erythitol/stevia blend, in a cup with 1/2 tbsp. Measuring ketones in urine, my level was moderate about 3 hours after my last meal. I read on another keto blog that if erythitol was the 1st ingrediant, which it is in Stevia Naturals, that it has 0 net carbs. Is this true? Can erythitol keep you from reaching optimum ketosis? What is the best time to test ketones, after eating or after a fast? Hi Gentiann, thanks for replying! You may regret it!! I'm on a specific diet, through a company, recommended by my GP. All the food is provided, at a cost of course, and supplements are also provided! I have definitely struggled and I'm still learning! I'm not losing as fast as expected, and only just understood ketosis which is the ultimate aim! Apparently I came out of it after the tomatoe incident. I just miss tea, sounds daft, but I do, I have anxiety depression and it is one of my many crutches! I've not had sugar for over three wks and the other problem is. I have type 2 diabetes. My daughters wedding is in July, so I'm running out of time. One good thing, I've ordered a treadmill ??? Xx. I do not regret it.! Did you read DietDoctor site at all? You do not need to waste money on a diet company, because the LCHF diet is quite easy to implement and does not have to be expensive. It just requires some discipline for not buying the wrong food. If you have diabetes type 2 you can reverse it by following the Low Carb HIGH Fat diet strictly as many have done on this site. The problem with having meals delivered to you is that you are not learning how to be a long term low carb eater. Usually when people reach the desired weight and stop using this meal delivery service, they put back the weight.are you going to pay for such a service for the rest of your life? I hope you will try to read the diabetes section (and weight loss as well) on this site so you become well informed (it's free) and not dependant on a diet company. I wish you the best. Been low carbing since Jan 1. Lost 17 lbs so far. Combining low carb/ high fat with a 16 hour daily fast is the best thing I've done and the only thing that has ever worked. All my lchf food is consumed between noon and 8p. I go to bed at ten and actually sleep better too. My meals are typically salad for lunch with a tuna creations flavor of choice (they have a lot of flavors and are very reasonably priced). The salad is heavy on leafy greens and I do throw in half a dozen cherub tomatoes occasionally. I'll have an avocado for a snack around three or four o'clock and a good protein in the evening like a steak or tilapia. I always use fresh veggies on the side like buttery asparagus with fresh lemon juice and fresh steamed bean beans. Avoid canned vegetables! Buy frozen veggies if you have to. The cravings for carbs are mostly gone and people are noticing a difference in my appearance. I check my urine often and maintain moderate ketosis almost all of the time. Last night, I ordered a supreme pizza from pizza hut and ate only the toppings and about 8 wings and I was still in ketosis this morning and had lost two pounds. It doesn't have to be boring. If you love wings, this diet is perfect for you. Just do a reasonable amount of research on the place you're buying from. No fast food wings. Wing stop and buffalo wild wings are A-okay! They key is the 16 hours of fasting. This activates a mechanism in your body that burns fat to provide you the energy you need to find food. It's an ancient part of your makeup that goes back to when humans were mostly hunter gatherers. Hope this makes sense and helps you out! Good luck to you! I have a question for anyone who is doing the LCHF eating plan. I started on Jan 30th, I lost 8 lbs in 10 days. After one cheat meal and another week of LCHF eating, I lost 4 lbs. The following weekend, things went crazy and I wasn't able to stick closely to my eating plan as I had been. I went off balance 2-12 days and gained the 2 lbs back. Got strict again on week 3, lost 4 lbs. The following week, lost 1 more lb. Total lost by end of February (4 weeks) was 15 lbs. First week in March and through today, I have not lost any further weight. My energy level is good, the inflammation in my joints is gone as well after cutting out sugars and carbs. I'm not yet to a good weight to exercise or do much walking (have lower back injury and a hip issue) but had hoped to get the other 16 lbs off this month. Here we are 10 days in, and not moving. I have two questions actually: 1) Any suggestions on getting the fat burning loss kicked in again? And 2) Through this whole process, I have had BM issues, completely different from before I started this eating plan. Where as I would go 2-3 per day before, it became once in 2 days and that was assisted by an oral laxative. Now, it's a problem because it's gone on to 3 days, and laxatives are not working. I drink mostly unsweet tea and water. Recently I discovered Diet Coke made with Splenda, which I've had a total of 2 in a week. (I cannot do other sweeteners because I'm allergic to Aspartame), and I have 1-1/2 cups coffee with Splenda and half n half in the mornings. I eat salads almost daily, so I am getting fiber. I eat a lot of fresh or frozen veggies such as squash, zucchini, asparagus, cauliflower, broccoli, avocado a couple times a week. Salad consists of iceberg lettuce, 3 cherry tomatoes and a few sliced cucumbers. A lot of chicken, either in fajita mean, or boneless skinless breasts, rotisserie shaved chicken breast, rib eye steak, pork chops. I try to eat 2 scrambled eggs with ham, or bacon, or sausage 4-5 mornings a week. What do I need to do to get my colon expelling waste on a daily basis again? Oh, and a third question.when counting my carbs per day, I have been doing total carbs (around 20 but sometimes a bit over), not net. How much difference in the weight loss process does it make if it's on net carbs as opposed to total? Should it always be total carbs? And I have been keeping my protein around 50ish per day, fat and sodium much higher. Calories around 1,000 per day. Ann, Stop counting calories! You wouldn't have to even worry about counting carbs if you just monitor your foods and be conscious about what you eat. LCHF will mean more calories but they are calories your body will instantly burn off. Intermittent fasting will also fire up your ketosis. Please read my other two posts right above yours. Just remember, no bread, pasta or dairy. Lots of water. When counting carbs, deduct the dietary fiber from the total carbs and you'll get the net carbs. Net carbs are what you want to count. You may not be getting enough carbs if going by total carbs. Good luck - Josh. I have lost 16 pounds in the past 5 weeks on LCHF diet, plus intermittent fasting daily. I gave up grains completely and have noticed I suddenly have vivid dreams at night and also many skin rashes have disappeared. I am a 47 year old female and I was 65 pounds overweight, so I still have a long way to go. In the past 10 days, my weight loss has substantially slowed down. I just took a urine ketone test with results at 4.0, which is supposed to be high. I wonder if I should test for diabetes? Any thoughts on this? Also, I am eating avocodos, fish, nuts, bacon, tamari, lots of vegetables and different meats - moderate dairy and cheese. It took 9 days to lose 1.5 pounds. I feel this is a bit slow considering how overweight I am and that my diet has changed dramatically. I only went completely off wheat in the last two weeks. Prior to that, I ate 1 ezekial muffin a day and was achieving faster results. Any thoughts or suggestions? Hello guys need reassurance please!! I started lchf a month ago and IF just 10 days back. I've been fasting for 17-18 hrs zero food and liquid intake (religious reasons)! I usually break my fast with 2 glasses of water with apple cider vinegar at 7pm then a keto/lchf dinner online recipe (usually some protein, low carb veggies in some heavy cream sauce r sour cream and cheese mix. I don't over eat) around 8pm then by 10 or 11pm I take a bullet proof coffee adding a lil whip cream, heavy cream, vanilla extract, butter and coffee! By midnight or 1am I'm not really hungry but I need to eat before I sleep so I don't starve I usually do 3 boiled eggs, with a spoon of store bought mayo, a lil mustard and 2 small cucmber pickles. Sometimes I also munch on a few pepperonis and beef salami (Hebrew national brand) slices while I prepare the eggs! My Keto urine test is usually on the light to dark purple side. I also drink a few glasses of water to catch up! Can someone please advice if I'm on the right track to loosing weight? I'm definitely under 25grams of carbs! Should I cut down on fats to lose more I haven't really lost any weight maybe a half inch on my waist! I'm 4'11 and 135lbs that 150cm and around 62kgs. Want to loose 12-15 lbs! I use to log my daily intake to make sure I hit my macros always below the carb and fat and might be a lil over in protein some days! Am I on the right track or should I start extended fasts to switch things up? You can have as much tea with full fat milk as you like, just don't eat loads of carbs - tomatoes are packed with sugar - you will not go into ketosis eating those, it's simple, no bread, no pasta, no rice, no cereal of any kind, no sugar of course, no fruit juice, very limited (or no) citrous fruit. What you CAN eat:- meat (the fattier the better), dairy, nuts and leafy veg - that's it - you will go into ketosis within two days and will not feel at all hungry, fat will fall off you. The closest thing to grain you can eat is buckwheat - but even then I wouldn't touch it until the ideal body composition is obtained as it is still carb rich even though it's not actually a cereal. Most nutritionists and doctors are stuck with the modern fad that (dietary) fat is bad - it's not, cholesterol levels are completely irrelevant too. Just stop eating carbs and you will be healthier and slimmer for the rest of your life. I have been using your site for some time now it’s my daily to go site for the last 4 months I am doing the lchf way of eating how ever I have a problem getting in ketosis I have set as goal to eat less than 20gr usable carbs a day and usually I am between 10-15. I also pay a close attention to protein and try not to eat more than 60gr a day I am 119kg and i am in desperate need to loose some (aka a lot of weight).i lost three in the past two months I bought the ketostixs and for the last two months they are usually some sort of pink-purple which would mean I am in ketosis but for the last month I bought a blood meter and it seems to be stuck at 0.4mmol/l am I in ketosis or not? Is there anything else I can try? Thank you in advance for your reply. Is there anyone that's having a problem getting into ketosis? Yesterday was my one year anniversary of doing the keto diet. No matter what I do I cannot get keto adapted I just came off a three day fast and I'm still at only,4. My liver keeps spitting out sugar and my blood sugars range in the high 90s. I am not cheating I am not doing anything I'm not supposed to be doing, my liver is fighting me has anyone had this happen? I'm so frustrated I've been trying for so long. I thought if you did it correctly it would definitely work for you and apparently that's not always the case. Hello I am a user and promotor for Keto-os. I have been with my company for almost a year. Your absolutely right about Keto putting your body into Ketosis in about 30 mins from the time you shake it up. I have lost 45 lbs of fat and since I started I now have my husband and children on the product. My daughter who has epilepsy has been on it and with the low carb lifestyle we had cut the amount of pills she takes daily. I'm not speaking from any medical stand at all, I'm not a doctor and make no medical claims, just our personal expirenece with the product. My energy level, sleep habits and all around health has absolutely improved and we were failrly healthy before and living even better today. Get in touch with me if you have any questions or would like to talk more. Hi Angela, my understanding after being keto for 10 months (since september) is that weight loss is not a straight line there are a few stages where weight loss will stall for a couple of weeks. For veryone the reasons will differ I can only speak from my own experience. Initially for the first month I was limiting to a low sugar diet about 40 grams carb per day mostly from cranberries and vegetables. Your weight loss 6lbs in a week is extremely fast although I suspect it could be more if you drank less fluid but you know best how much fluid you need. As always observe and adjust you will learn many different ways to tweak keto as you go on especially in combination with intermittent fasting. My weight loss in body fluid anything from 60 to 120 grams per day. It was then I discovered dietdoctor and started the keto diet. No ketostix but after 2 weeks had a week long bout of diarrhoea as my microbiome adjusted to the new diet after 40 years of eating bread and fruit it was quite a change. Started to sleep really well at night out within 10 minutes no effort at all. My first 2 week stall was a couple of months later after losing 6 kilos no idea why but the body was up to something or maybe I was eating too much dairy did not keep a exact record. Another 3 week stall occured after new year I took up a series of several 4 day intermittent fasting within a month (see Jason Fung) and really enjoyed the noradrenaline boost and leptin satiety that kept me free from thinking about food. Proceeded to lose another 8 kilo got BMI down to 22. After that 8 kilo loss I felt fine for a while but then mysteriously started to get periods of cravings especially in the evenings I would eat nuts, olives, beef jerky non stop and yo yo up and down 2 kilos as I desparately tried to control my apetite.. The reason for craving I can not exactly be sure as I only measured my weight do not a a ketostix or glucose meter. However one conclusion I have come to s that with weight loss their is less adipose tissue secreting the leptin hormone. The body can cope with this in several ways their are so many pathways but I guess that the adipose tissue is lagging and has to adjust to fewer cells pumping out the same amount of leptin and maybe the adipose receptors have to be more sensitive to L cell PYY signals from the small intestine which is a signal telling the adipose that food has been eaten so produce some leptin. What ever the reason I now avoid nuts not because they make me eat more nuts but they often are the start of a snaking binge that has me eating olives, jerky, cheese, etc. Your experience will be your own don't worry you certainly wont starve on the keto diet and there lots of opportunity to tweak it to your own liking. Look out for the metabolic health benefits its all worth it. P.S Angela it may also take you about a month to become keto adapted which is why your ketosis is still measuring low. Even after adaptation ketosis is only about 50% as there is always a baseline level of glucose due to lypolysis the reverse flow of fat to the liver to be converted to glucose and free fatty acids. The baseline glucose level in healthy people is steady but in people with type 2 diabetes the liver can be overwelmed with the triglycerides flow as the adipose tissue will also be insulin resistent, a sort of double push back. This is the dawn phenomenon and even in people who are pre diabetic they will feel the effects of the high blood glucose (hyperglycemia) above baseline. The Memory Repair Protocol Book Review – Is The Memory Repair Protocol Guide By Martin Reilly really the solution to your problem? Do you know that you can have anything in The Memory Repair Protocol PDF experience? 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