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"Q:\n\nWhat are ASP.NET Core Static Web Assets?",
"\n\nThere is a lot of hidden magic that occurs in HostBuilder.",
"ConfigureWebHostDefaults() (that eventually calls ConfigureWebDefaults). ",
"I would like to understand it better as there is no documentation that I can find about it.",
"\nThis code seems to be loading some static files. ",
"What are static web assets and why do we need them? ",
"Is this something to do with embedding static assets into libraries for Blazor?",
"\nbuilder.",
"ConfigureAppConfiguration((ctx, cb) =>\n{\n if (ctx.",
"HostingEnvironment.",
"IsDevelopment())\n {\n StaticWebAssetsLoader.",
"UseStaticWebAssets(ctx.",
"HostingEnvironment, ctx.",
"Configuration);\n }\n});\n\nA:\n\nStatic Web Assets are static files made available from a Razor Class Library (RCL):\n\nAn RCL may require companion static assets that can be referenced by the consuming app of the RCL. ",
"ASP.NET Core allows creating RCLs that include static assets that are available to a consuming app.",
"\n\nUseStaticWebAssets inserts additional file providers (instances of StaticWebAssetsFileProvider), using a manifest file ({environment.",
"ApplicationName}.StaticWebAssets.xml if not set via IConfiguration) to determine a list of mappings from path to base path. ",
"\nAs an example, when using the ASP.NET Core Identity UI RCL, the manifest file for your app looks something like this:\n<StaticWebAssets Version=\"1.0\">\n <ContentRoot BasePath=\"/Identity\" Path=\"\\path\\to\\.nuget\\packages\\microsoft.aspnetcore.identity.ui\\3.0.0\\staticwebassets\\V4\" />\n</StaticWebAssets>\n\nThis all ends up with a CompositeFileProvider being set for the IWebHostEnvironment.",
"WebRootFileProvider. ",
"This composite provider does two things:\n\nProcesses the wwwroot/ static files as usual (assuming default configuration).",
"\nDelegates any files requested from wwwroot/Identity to the extracted NuGet package content folder for the Identity UI.",
"\n\nAs the code snippet from your question shows, this only happens when running in the Development environment. ",
"When your app is published, the files in question get copied up into the wwwroot folder, as though they were part of your app.",
"\n\n"
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[
"Where'd the time go?? ",
"Since my original thread had no activity for 14 months and I now have a deadline, it's time to start a new build thread. ",
"We are hosting Thanksgiving for my family this year (~25 people), and the theater needs to be ready by then. ",
"I am shooting for 11-1 to allow time for \"testing\", but will accept 11-15. ",
"Time to get crackin'!",
"\n\nMy original design thread is still in my signature for those who care to look back at ancient history. ",
"The room is in our basement, and the rough framed dimensions are 21' 4 L x 12' 11 W x 9' H. Here are a few pics of the space as it stands today.",
"\n\nEntry\n\nScreen Wall\n\nBack\n\nYeah, those are the same pics as the original thread...\n\nI took advantage of the theater layout service from Dennis quite a few months ago. ",
"Here's the design that I will finally be working toward. ",
"Of course I'm assuming no major changes in HT design philosophy in the last year and a half since I got these...\n\nEntry door wall.",
"\n\nOpposite wall (looking through entry door).",
"\n\nScreen wall\n\nFloor\n\nI am very happy with the design and instructions that came with it. ",
"I know it's been said many times on this forum, but if you are struggling with the design, Dennis is a great resource.",
"\n\nI have 2-20 amp dedicated circuits run to the space, and have an electician friend coming over this weekend to bounce a few things off of, then the fun begins.",
"\n\nSince the room is already studded, I plan on clips and channel on the ceiling and walls to decouple plus DD+GG (Ted, you will be getting an email in the next few days).",
"\n\nEven though I haven't been working on the theater, I have kept my eyes open for good deals on equipment. ",
"Here's the list of what I have so far.",
"\n\nAPC J10 Power Conditioner\n\nSony BDP-N460 Blu-ray Player\n\nEmotiva ERM-6.2 LCR Speakers\n\nEmotiva ERD-1 Side and Rear Surrounds\n\nLogitech Harmony 900 Remote\n\nLutron Grafik Eye 3106\n\nI will try to take as many pics as I can to document the build and share them here. ",
"As I will be doing the overwhelming majority of this work myself, I want to thank everyone in advance for answering all the questions that I will have along the way. ",
"Wish me luck, and let me know your thoughts on the space!",
"\n\nI've always had the Panasonic 4000 in the back of my mind, but now I'm considering the 7000. ",
"I'm not really into the 3D side of things, but the it looks like it would do the trick for me. ",
"I won't be ordering one until September anyway, so I have some time.",
"\n\nCouple of quick wiring questions. ",
"I plan on running as much of the cabling as possible through the soffits. ",
"This includes electrical and A/V. Seems to me like I could get almost all of it in there and only have 1 or 2 penetrations for wiring. ",
"Is there any reason why I wouldn't want to do that?",
"\n\nPlanning on 3 screen wash cans, 6 cans in the soffit (3 on each side), rope light around soffit (in tray with crown molding) and 4 wall sconces (2 on each side). ",
"Does that seem like light overkill for a room this size that will be mostly inhabited in the dark? ",
"Do I need the sconces, or do you think the 6 cans plus 3 screen and rope lights be enough light for the room? ",
"Black will be the predominant color in the room with gold accents (Iowa Hawkeyes/Pittsburgh Steelers colors)\n\nOne more question (for now). ",
"I will be using an APC J10 power conditioner/battery backup for the equipment. ",
"Would the sub get power from the J10 too, or from its own outlet? ",
"Would still be on the same 20 amp circuit. ",
"Plan to powerbridge for the projector, and can do the same for sub if it should be on the J10 too.",
"\n\nPlanning on 3 screen wash cans, 6 cans in the soffit (3 on each side), rope light around soffit (in tray with crown molding) and 4 wall sconces (2 on each side). ",
"Does that seem like light overkill for a room this size that will be mostly inhabited in the dark? ",
"Do I need the sconces, or do you think the 6 cans plus 3 screen and rope lights be enough light for the room?",
"\n\nMy room is a similar size, and I've got more can lights and even with them on full it's not bright enough to read in the room comfortably. ",
"Depending on your choice of sconces they can throw a lot of light into the room, but if you've got the can lights around the perimeter like I do, the seating area can be quite dim.",
"\n\nQuote:\n\nOne more question (for now). ",
"I will be using an APC J10 power conditioner/battery backup for the equipment. ",
"Would the sub get power from the J10 too, or from its own outlet? ",
"Would still be on the same 20 amp circuit. ",
"Plan to powerbridge for the projector, and can do the same for sub if it should be on the J10 too.",
"\n\nI ran the romex from the PowerBridge to both my projector and to the front wall to power the speakers/sub as well. ",
"But if you've got a UPS, I wouldn't put the sub on that. ",
"May be best to just use a point solution for surge protection on the sub.",
"\n\nThanks Jeff. ",
"I kind of figured that for the lighting, but it's good to hear your experience. ",
"I wouldn't plug the powerbridge for the sub into the UPS section of the J10, just for surge protection.",
"\n\nThat's a good thought, and I'll add that to my \"what I would do different\" hindsight list...\n\nI ran a single PowerBridge from my rack, which terminated at the Projector location, but the romex continues on to the front of the room to pick up the sub/speakers/screen. ",
"So if I chose to add a UPS to the PJ, the sub/speakers would also be on that run.",
"\n\nBetter choice would have been two PowerBridge inlets at the rack, one run to the PJ, the other to the front speakers/sub. ",
"That way the PJ link could be fed by the UPS, while the speaker/sub inlet could be on surge-only.",
"\n\nMade some progress this w/e. Sorry for the cell phone quality pics. ",
"Will take HQ pics when there is more exciting progress...\n\nRemoved corner angle studs and relocated HVAC return to back of room. ",
"Started insulating rear wall as there will be no cable runs on this wall outside of the shell.",
"\n\nRelocated HVAC supplies to front of room and started insulation in areas where there will be no cabling.",
"\n\nFully insulated side wall since no cabling outside of the shell on that side.",
"\n\nNext up is a couple cable runs that need to be done before more insulation in certain spots. ",
"I have decided to mount the Grafik Eye in the front column so that also cuts down on pre-DW cabling.",
"\n\nCouple of questions. ",
"What gauge of speaker wire is recommended? ",
"I have some leftover 14 gauge inwall rated, but will get 12 if that would be better. ",
"LCR are Emotiva 6.2 (4ohm) don't know the sub yet. ",
"Would like to run it in conduit in case it needs to be replaced down the road. ",
"The local Lowes only had 3/4\" flexible carlon tubing, seemed like that would be a tight fit for LCR & sub cables on the front wall. ",
"What size conduit do you use, and where is a good place to order from?",
"\n\nAlso, you can see a cleanout in the lower left corner of the first pic. ",
"This is for the bar sink on the other side of the wall. ",
"Nothing else drains here (the vertical is just a vent). ",
"Does it make sense to create access for this cleanout? ",
"The drain is only 2 feet on the other side of the wall. ",
"Would be no problem to snake through the drain if it was ever needed. ",
"Thoughts?",
"\n\nNot a lot of progress last night, but enough to feel like I did something.",
"\n\nRan power to the rack area.",
"\nRan romex to the sub location for powerbridge.",
"\nGreat Stuffed a few more spots that needed it.",
"\nTried to make a complete list of things that need to be done before DW. ",
"If I can keep chipping away during the week, I should be able to make good progress on the weekends.",
"\n\nThere won't be any progress tonight though. ",
"Heading to Iowa City for the first round NIT basketball game between my Hawkeyes and the Dayton Fliers!",
"\n\nSome decent progress this weekend inbetween events and family things, just not all that photo worthy.",
"\n\n- Drilled more holes in studs and ran almost all the romex that needs to be done before DW. ",
"Only have one more to run for the Grafik Eye wall station. ",
"Going to go with the NTGRX-1S. No need to get fancy here, and I already have the 14/2 to run to it from the 3106 location.",
"\n- Ran the conduit for LCR & Sub cables. ",
"Nobody local had the carlon flex conduit any larger than 3/4\", so I went with sealtite at 1-1/4\". ",
"I have to think that the carlon is much easier to work with, but the sealtite will be fine.",
"\n- Hung more insulation on the walls. ",
"Just a few spots left to do, then I can move on to the ceiling insulation.",
"\n- Had a great conversation with Ted at the Soundproofing Company last week. ",
"Order will be placed this week.",
"\n\nOne thing I forgot to talk to Ted about is an upstairs return that runs in one of the joist spaces. ",
"Here is a pic:\n\nHas anyone done anything special for these, or have you just left them alone since they will be outside the DD+GG envelope?",
"\n\nOne thing I forgot to talk to Ted about is an upstairs return that runs in one of the joist spaces. ",
"Here is a pic:\n\nHas anyone done anything special for these, or have you just left them alone since they will be outside the DD+GG envelope?",
"\n\nIf it is completely outside the DD+ GG and not touching the drywall then you should be fine. ",
"If you really want to you could add some pipe wrap to it to add more mass (sold by the soundproofing company) but I did not do that and have not experienced any problems.",
"\n\nI'm not an expert plumber but I can say that there are two waste stacks in my basement that are behind walls with no access. ",
"They were like that when we bought the house and I don't know what the code says about it but when I asked the home inspector what he thought the random \"bump out\" on one of the walls was he said that it was probably a waste stack and didn't seem to have any concerns with it being there.",
"\n\nI've always had the Panasonic 4000 in the back of my mind, but now I'm considering the 7000. ",
"I'm not really into the 3D side of things, but the it looks like it would do the trick for me. ",
"I won't be ordering one until September anyway, so I have some time.",
"\n\nIf you are not into 3D then the RS45 would be one of the projectors at the top of my list. ",
"Much brighter (almost twice) in best image mode compared to the Panny 7000. ",
"With that size screen, paired with an RS45, I would consider a microperf StudioTek 130. ",
"If we can help you, let us know.",
"\n\nI don't have any advice for you as I am really a newbe to this myself, but as we have just watched our first movie in our room - I can say that it is a rewarding experience!",
"\n\nGood luck - have fun - and enjoy the journey, as it is more than half of the experience.",
"\n\nNick\n\nThanks Nick. ",
"The journey is definitely fun now that there are signs of progress. ",
"Just need to keep moving forward.",
"\n\nQuote:\n\nOriginally Posted by aaustin\n\nIf it is completely outside the DD+ GG and not touching the drywall then you should be fine. ",
"If you really want to you could add some pipe wrap to it to add more mass (sold by the soundproofing company) but I did not do that and have not experienced any problems.",
"\n\nI'm not an expert plumber but I can say that there are two waste stacks in my basement that are behind walls with no access. ",
"They were like that when we bought the house and I don't know what the code says about it but when I asked the home inspector what he thought the random \"bump out\" on one of the walls was he said that it was probably a waste stack and didn't seem to have any concerns with it being there.",
"\n\nGood to hear you didn't have issues with your return. ",
"I have some extra foil tape, so I may just make sure it is sealed up really good and put some extra insulation there.",
"\n\nI decided not to worry about the sink cleanout. ",
"I have the location marked if it needs attention in the future. ",
"I really don't think it will be a problem since the sink is 2 feet away (knocking on wood and rubbing a rabbit's foot).",
"\n\nQuote:\n\nOriginally Posted by AV Science Sales 5\n\nIf you are not into 3D then the RS45 would be one of the projectors at the top of my list. ",
"Much brighter (almost twice) in best image mode compared to the Panny 7000. ",
"With that size screen, paired with an RS45, I would consider a microperf StudioTek 130. ",
"If we can help you, let us know.",
"\n\nThanks for the suggestions. ",
"I'll be doing a lot of research on the projectors and will let you know if I run into any questions. ",
"I am planning on a Seymour AV Center Stage XD screen.",
"\n\nOK, apparently my Google-fu powers are on the fritz again. ",
"I can't seem to find anywhere to purchase hat channel or Nailor bar diffusers. ",
"Not getting a responce from Lowes or HD, and my local HVAC guy didn't know what a Nailor bar diffuser was. ",
"Any suggestions?",
"\n\nI found hat channel in stock at HD. ",
"It was next to the drywall material. ",
"They only carried 10' sections instead of 12' sections but I plan to make it work. ",
"Also were considerably cheaper than the special order 12' pieces at local Menards (less than 1/2 the price). ",
"Walked out with 30 pieces for less than $60.",
"\n\nOn the screen, I too am planning to use the Seymour XD material but I think I am going to get the frame and material from Jamestown home theater. ",
"They had a pretty competitive price for the kit. ",
"Probably half the cost of the larger name companies.",
"\n\nOK, apparently my Google-fu powers are on the fritz again. ",
"I can't seem to find anywhere to purchase hat channel or Nailor bar diffusers. ",
"Not getting a responce from Lowes or HD, and my local HVAC guy didn't know what a Nailor bar diffuser was. ",
"Any suggestions?",
"\n\nI found hat channel in stock at HD. ",
"It was next to the drywall material. ",
"They only carried 10' sections instead of 12' sections but I plan to make it work. ",
"Also were considerably cheaper than the special order 12' pieces at local Menards (less than 1/2 the price). ",
"Walked out with 30 pieces for less than $60.",
"\n\nOn the screen, I too am planning to use the Seymour XD material but I think I am going to get the frame and material from Jamestown home theater. ",
"They had a pretty competitive price for the kit. ",
"Probably half the cost of the larger name companies.",
"\n\nMy kind of shopper! ",
"Guess I'll do some walk-ins instead of Internet searches. ",
"Luckily Lowes, HD and Menards are all close together. ",
"Thanks!",
"\n\nI personally had no luck finding hat channel at my local Lowes or home depot. ",
"I ended up calling a local building supply warehouse and they knew exactly what I was talking about. ",
"They called it \"metal drywall furring channel\". ",
"I think it was about $7 for a 12 foot piece.",
"\n\nAlso make sure that it is 25 gauge and has a hemmed edge for the clips.",
"\n\nIf I read the forum rules correctly, I am obligated to post this next pic.",
"\n\nOrdered Tuesday, and delivered Thursday. ",
"If anyone doesn't know by now, Ted and John at the Soundproofing Company are fantastic!",
"\n\nI'm a week or so away from using the GG, but got to play with the putty pads last night. ",
"That allowed me to finish insulating the walls. ",
"Tonight I start the ceiling insulation. ",
"Can't wait for this part to be done...\n\nThanks Nick. ",
"The journey is definitely fun now that there are signs of progress. ",
"Just need to keep moving forward.",
"\n\nGood to hear you didn't have issues with your return. ",
"I have some extra foil tape, so I may just make sure it is sealed up really good and put some extra insulation there.",
"\n\nI decided not to worry about the sink cleanout. ",
"I have the location marked if it needs attention in the future. ",
"I really don't think it will be a problem since the sink is 2 feet away (knocking on wood and rubbing a rabbit's foot).",
"\n\nThanks for the suggestions. ",
"I'll be doing a lot of research on the projectors and will let you know if I run into any questions. ",
"I am planning on a Seymour AV Center Stage XD screen.",
"\n\nAnother point to consider, if it is going to be fall before you are ready, wait for the new models to come out.",
"\n\nSitting here having a nice pale ale homebrew and thought I should post an update. ",
"I am done with insulation (until I need to do more insulation). ",
"Next step is the front soffit (which will need insulation, dangit!!), ",
"and then I can put the clips and channel up and be ready for drywall.",
"\n\nScreenwall\n\nBackwall\n\nFront Soffit Area\n\nOrdered the door this week. ",
"Masonite Safe'n Sound solid core 1-3/4\" thick, 80\"x36\". ",
"I will make the jambs myself, so just ordered the slab. ",
"Will be here by April 8. ",
"Also have a drywall lift coming this weekend from a friend who just finished his basement. ",
"Saved him from putting it on Craigslist and me from buying one off of Craigslist...\n\nThings are looking good! ",
"Keep up the pace, and you'll make it for sure.",
"\n\nI have a question for you. ",
"I noticed in your plans the angled corners in the rear of the room. ",
"Then I see in your most recent pictures that only one of the corners \"has to\" be that way. ",
"Obviously symmetry dictates the other match - no argument there. ",
"And surely there is something important behind the one required cut corner. ",
"The question I have is did you get any notes or an impression from The Erskine Group about the impact of this shape on your acoustic design? ",
"I have an opportunity to extend the length of my room in the center, and I'm trying to weigh the costs and benefits.",
"\n\nThings are looking good! ",
"Keep up the pace, and you'll make it for sure.",
"\n\nI have a question for you. ",
"I noticed in your plans the angled corners in the rear of the room. ",
"Then I see in your most recent pictures that only one of the corners \"has to\" be that way. ",
"Obviously symmetry dictates the other match - no argument there. ",
"And surely there is something important behind the one required cut corner. ",
"The question I have is did you get any notes or an impression from The Erskine Group about the impact of this shape on your acoustic design? ",
"I have an opportunity to extend the length of my room in the center, and I'm trying to weigh the costs and benefits.",
"\n\nHey Fred. ",
"The wet bar on the other side of the wall dictated the one corner, and the other corner was angled to match. ",
"There really wasn't an explanation given by DE, and to be honest I didn't think to ask what impact those corners would have. ",
"I'm sure there is some acoustical explanation as to how it will affect the room, just don't know what it would be. ",
"Maybe someone else can chime in here."
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"Nowadays visual disability compensation, as for other disabilities, is mainly contingent on the patient's obtaining an allowance for a third party, but this is increasingly related to the concept of autonomy in the main activities of everyday life. ",
"This concept cannot be applied to visual handicaps. ",
"A special allowance, however, which need not be i..."
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"Airborne SUV comes crashing down onto police cruiser: VIDEO\n\nA Tennessee police officer escaped with only minor injuries after an SUV went airborne and landed on his police cruiser. ",
"Dashboard footage showed the SUV hit rocks in the roadway, going airborne and then flying out of the frame before impact.",
"\n\nBRISTOL, Tenn. -- A Tennessee police officer escaped with only minor injuries after an SUV went airborne and landed on his police cruiser.",
"\n\nThe accident, which was caught on camera, happened around 6:30 a.m. Wednesday in Bristol, a city on the Tennessee-Virginia border. ",
"Local officials said the officer was responding to a rock slide that had blocked Raytheon Road when he radioed in that he was involved in an accident.",
"\n\nDashboard footage showed the SUV driving toward the cruiser in the oncoming lane as it hit the rocks in the roadway. ",
"It went airborne and then flew out of the frame before impact.",
"\n\nAfter he was freed from his cruiser, the officer was taken to a nearby hospital with minor injuries. ",
"The driver of the SUV refused medical transport, police said."
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"T3NS: Three-Legged Tree Tensor Network States.",
"\nWe present a new variational tree tensor network state (TTNS) ansatz, the three-legged tree tensor network state (T3NS). ",
"Physical tensors are interspersed with branching tensors. ",
"Physical tensors have one physical index and at most two virtual indices, as in the matrix product state (MPS) ansatz of the density matrix renormalization group (DMRG). ",
"Branching tensors have no physical index, but up to three virtual indices. ",
"In this way, advantages of DMRG, in particular a low computational cost and a simple implementation of symmetries, are combined with advantages of TTNS, namely incorporating more entanglement. ",
"Our code is capable of simulating quantum chemical Hamiltonians, and we present several proof-of-principle calculations on LiF, N2, and the bis(μ-oxo) and μ-η2:η2 peroxo isomers of [Cu2O2]2+."
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"Valrubicin\n\nValrubicin (N-trifluoroacetyladriamycin-14-valerate, trade name Valstar) is a chemotherapy drug used to treat bladder cancer. ",
"Valrubicin is a semisynthetic analog of the anthracycline doxorubicin, and is administered by infusion directly into the bladder.",
"\n\nIt was originally launched as Valstar in the U.S. in 1999 for intravesical therapy of Bacille Calmette-Guérin (BCG)-refractory carcinoma in situ of the urinary bladder in patients in whom cystectomy would be associated with unacceptable morbidity or mortality; however, it was voluntarily withdrawn in 2002 due to manufacturing issues. ",
"Valstar was relaunched on September 3, 2009.",
"\n\nSide effects\nBlood in urine\nIncontinence\npainful or difficult urination\nUnusually frequent urination\n\nReferences\n\nCategory:Anthracyclines\nCategory:Topoisomerase inhibitors\nCategory:Trifluoromethyl compounds\nCategory:Acetamides\nCategory:Withdrawn drugs"
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"\n478 Pa. 327 (1978)\n386 A.2d 956\nCOMMONWEALTH of Pennsylvania\nv.\nSebastian Thomas YOST, Appellant (two cases).",
"\nSupreme Court of Pennsylvania.",
"\nArgued January 13, 1977.",
"\nDecided April 28, 1978.",
"\n*328 *329 *330 Anthony D. Miele, Williamsport, for appellant.",
"\nSamuel C. Ranck, Dist. ",
"Atty., ",
"R. Michael Kaar, Asst. ",
"Dist. ",
"Atty., ",
"for appellee.",
"\nBefore EAGEN, O'BRIEN, ROBERTS, POMEROY, NIX and MANDERINO, JJ.",
"\n\nOPINION\nO'BRIEN, Justice.",
"\nAppellant, Sebastian Yost, of Shamokin, was convicted in the Court of Common Pleas of Northumberland County, in a case arising from the deaths of three Shamokin girls, Margaret Long, 16, her sister, Sharon, 15, and Carol Taylor, also 15.",
"\nYost was convicted of murder of the first degree in the death of Sharon Long, murder of the second degree in each of the other two deaths, and criminal conspiracy. ",
"He was sentenced to imprisonment for life for murder of the first degree, ten-to-twenty years on each count of murder of the second degree, and five-to-ten years for conspiracy. ",
"All sentences were to run consecutively. ",
"He appeals the judgments of sentence.",
"\nThe facts surrounding this appeal are as follows. ",
"The three girls disappeared the evening of July 19, 1973. ",
"On October 6, 1974, their bodies were discovered in a wooded area near Shamokin. ",
"They were identified on the basis of personal effects at the scene, an examination by Dr. Halbert *331 Fillinger, a forensic pathologist, and the identification of an orthodontic appliance belonging to Sharon Long.",
"\nThe police were led to the bodies by Robert Reichwein, who reported that Yost had shown them to him and Albert Patti, Jr., after telling them that he (Yost), Ronald Scandle and Joseph Ziemba killed the girls. ",
"Both Reichwein and Patti testified at trial that Yost made the admission and took them to the scene.",
"\nTestifying against Yost after a guilty plea, Joseph Ziemba gave the following account of the events relating to the disappearance and death of each of the victims. ",
"He (Ziemba), Yost and Scandle picked up the victims on the night of their disappearance while riding around Shamokin in Scandle's car. ",
"They took them to a spot near the site where the bodies were found. ",
"When they had been there for a time, an argument broke out, which led to violence. ",
"The girls were killed at Yost's suggestion. ",
"Yost himself strangled Sharon Long. ",
"The bodies were taken to the spot where they were found, which was in a wooded ravine, and left there. ",
"The following day, a deodorizing solution was purchased at a hardware store and applied to the bodies, which were then covered with debris.",
"\nSharon Johns, an acquaintance of all of the involved parties, testified that she was with the victims on the night of their disappearance, that they were picked up as stated by Ziemba, and that she declined an invitation to accompany them. ",
"Robert Jones, proprietor of the hardware store, identified Scandle and Ziemba as purchasers of the deodorizing solution.",
"\nYost testified that he was with certain members of his family on the night of the victims' disappearance. ",
"Other members of the family testified that Yost was with them. ",
"Yost testified in detail about his activities on that day. ",
"He explained his ability to remember what happened by stating that it was the day his infant daughter was released after being hospitalized. ",
"His testimony concerning his daughter's hospitalization and release was corroborated from hospital records. ",
"Yost admitted knowledge of details of the manner *332 of the victims' deaths. ",
"He claimed that he learned what he knew from Ziemba and from rumors that were circulating around the Shamokin area.",
"\nAppellant first argues that the evidence is insufficient to sustain his convictions. ",
"We do not agree.",
"\nIn Commonwealth v. Rose, 463 Pa. 264, 344 A.2d 824 (1975), this court reiterated our standard review in judging the sufficiency of the evidence:\n\"The test of sufficiency of the evidence is whether, viewing the evidence in the light most favorable to the Commonwealth and drawing the proper inferences favorable to the Commonwealth, the trier of fact could reasonably have found that all of the elements of the crime had been established beyond a reasonable doubt. ",
"Commonwealth v. Robson, 461 Pa. 615, 625, 337 A.2d 573, 578 (1975); Commonwealth v. Boyd, 461 Pa. 17, 24, 334 A.2d 610, 613 (1975); Commonwealth v. Murray, 460 Pa. 605, 608, 334 A.2d 255, 257 (1975). ",
"Moreover, it is the province of the trier of fact to pass upon the credibility of witnesses and the weight to be accorded the evidence produced. ",
"Commonwealth v. Robson, supra; Commonwealth v. Murray, supra; Commonwealth v. Smith, 457 Pa. 638, 326 A.2d 60, 61 (1974); Commonwealth v. Paquette, 451 Pa. 250, 257, 301 A.2d 837, 841 (1973). ",
"The fact-finder is free to believe all, part, or none of the evidence. ",
"Commonwealth v. Robson, supra; Commonwealth v. Smith, supra.\"",
"\nIn this case, there is testimony that appellant was a party to a plan to kill the victims and hide their bodies, that he participated in the killings, and that he strangled Sharon Long. ",
"We find that the evidence will sustain the verdict. ",
"Appellant contends that the evidence is insufficient because of the conflict between the Commonwealth's evidence and his testimony.",
"\nAs stated in Rose, supra, a \"fact-finder is free to believe all, part, or none of the evidence,\" and credibility is also within the province of the factfinder. ",
"Given the above test, there existed sufficient evidence to sustain appellant's convictions.",
"\n*333 Appellant argues that the verdict is contrary to law. ",
"He bases his argument on the premise that a verdict is illegal if it is against the express instructions of the trial judge. ",
"Commonwealth v. Jones, 303 Pa. 551, 154 A. 480 (1931).",
"\nOur review of the charge in the instant case reveals that the trial judge instructed the jury on all possible verdicts, including murder of the first degree, murder of the second degree, and criminal conspiracy, the crimes that appellant was found guilty of. ",
"We find no merit in appellant's allegation of error.",
"\nAppellant next argues that the trial judge improperly charged the jury that he had the burden of proof concerning his alibi defense. ",
"We do not agree.",
"\nThe charge of the trial judge states in relevant part: \". . . ",
"the burden is on the Commonwealth to prove, beyond a reasonable doubt, . . . ",
"every ingredient (of the crime). . . . ",
"This burden never shifts. . .\"",
"\nLater, referring specifically to the alibi defense, he said:\n\"Obviously the defendant cannot be guilty unless he was at the scene. . . . [",
"His] evidence that he was not present, either by itself or together with other evidence, may be sufficient to raise a reasonable doubt of his guilt in your minds. ",
"If you have a reasonable doubt, . . . ",
"you must find him not guilty.\"",
"\nThe above charge clearly established that the Commonwealth had the burden to prove beyond a reasonable doubt all elements of the crimes charged. ",
"See Commonwealth v. Hilbert, 476 Pa. 288, 382 A.2d 724 (1978). ",
"The trial judge in the above-quoted portion of the charge did not shift the burden to appellant to prove his alibi defense, but merely instructed the jury as to how to use the evidence appellant introduced at trial. ",
"We find no error.",
"\nAppellant next claims that the trial court erred in refusing to allow him to call several witnesses. ",
"Appellant proposed to have these witnesses testify that unnamed persons *334 had told them these unnamed persons had knowledge of the killings because they had taken part in the slayings. ",
"During appellant's offer of proof, he stated that he was not introducing the statements for their truth, but rather simply to show that the statements were made. ",
"The trial court refused appellant's offer on grounds of either relevance or a violation of the hearsay rule.[1]\nDuring his offer of proof, appellant did not show how the mere fact that these statements were made tended to prove either his guilt or innocence. ",
"Because of this, the statements did not meet the test of relevancy. ",
"The only way which the statements could have been relevant was to show someone's admission of complicity in the slaying. ",
"In that case, however, the statements would have been offered to prove the truth of the matter asserted and thus been inadmissible hearsay. ",
"In any case, the trial court did not err in refusing to allow the testimony.",
"\nCertain questions that the defense desired to ask appellant were also excluded on the basis of hearsay. ",
"Counsel proposed to ask appellant whether Ziemba told him details of the alleged crime and made threats against him. ",
"Appellant again argues that he was offering to prove only that statements were made. ",
"We reject this contention because the purpose in this instance, as well, was to put the blame on someone other than appellant, thus making it inadmissible hearsay.",
"\nWhile cross-examining Joseph Ziemba, appellant was not permitted to question him on the details of a previous incident in which Ziemba was convicted of corrupting the morals of a minor and deviate sexual intercourse. ",
"Appellant contends that he should have been permitted to pursue such questioning to impeach Ziemba's credibility. ",
"A witness may be impeached on the basis of past convictions, but only if the convictions involve crimes of dishonesty or *335 false statements. ",
"Commonwealth v. Katchmer, 453 Pa. 461, 309 A.2d 591 (1973). ",
"Sex crimes may not be used to impeach the credibility of a witness. ",
"See McIntosh v. Pittsburgh Rwys. ",
"Co., 432 Pa. 123, 247 A.2d 467 (1968), where we held that a pandering conviction was not a proper basis for impeachment.",
"\nIn cross-examining Robert Reichwein, the defense desired to question the witness as to whether appellant had any prior record of sexual offenses. ",
"It was not permitted to do so. ",
"Appellant claims that this was error. ",
"His sole contention in support of his claim is that this case falls within the ambit of Commonwealth v. Zapata, 455 Pa. 205, 314 A.2d 299 (1974), where we held that the defense may introduce evidence of the defendant's prior criminal record if the Commonwealth would be able to introduce such evidence against the defendant for impeachment purposes. ",
"Under Katchmer, supra, and McIntosh, supra, the Commonwealth could not introduce evidence of prior sex crimes, so Zapata is not applicable and the question was properly excluded.",
"\nAppellant claims that the trial judge erred in admitting, over his objection a black and white photograph taken at the grave site of the skeletal remains of Sharon Long. ",
"He alleges that it was gruesome and inflammatory and not of significant evidentiary value. ",
"The trial court has discretion on the admission of photographs, but it is an abuse of discretion to admit photographs that are unduly gruesome so as to inflame the passions of the jury, if the photographs do not have sufficient evidentiary value to compensate for their inflammatory potential. ",
"We so held in Commonwealth v. Scaramuzzino, 455 Pa. 378, 317 A.2d 225 (1974), where we found it to have been error to admit fourteen color slides of the body of a homicide victim. ",
"The slides were bloody and explicit, and we did not find them to be of significant value in understanding the case. ",
"The Court held that the probative value must outweigh the prejudicial effect of such photographs.",
"\n*336 A photograph of a corpse is less objectionable if it is in black and white and the body is shown in a less gruesome manner. ",
"Commonwealth v. Petrakovich, 459 Pa. 511, 521, 329 A.2d 844 (1974). ",
"We set forth the applicable standard in Petrakovich as follows:\n\"We have consistently held that the question of admissibility of photographs of a corpse in homicide cases is a matter within the discretion of the trial judge, and only an abuse of that discretion will constitute reversible error. ",
"Commonwealth v. Woods, 454 Pa. 250, 311 A.2d 582 (1973); Commonwealth v. Sullivan, 446 Pa. 419, 286 A.2d 898 (1971) (opinion in support of order); Commonwealth v. Chasten, 443 Pa. 29, 275 A.2d 305 (1971); Commonwealth v. Robinson, 433 Pa. 88, 249 A.2d 536 (1969); Commonwealth v. Powell, 428 Pa. 275, 241 A.2d 119 (1968); Commonwealth v. Novak, 395 Pa. 199, 150 A.2d 102 (1959); Commonwealth v. Peyton, 360 Pa. 441, 62 A.2d 37 (1948). ",
"When the trial judge is confronted with gruesome or potentially inflammatory photographs, the test for determining their admissibility which he must apply is `whether or not the photographs are of such essential evidentiary value that their need clearly outweighs the likelihood of inflaming the minds and passions of the jurors.' ",
"Commonwealth v. Powell, supra, 428 Pa. at 278-279, 241 A.2d at 121; Commonwealth v. Peyton, supra, 360 Pa. at 450, 62 A.2d at 41. ",
"A photograph which is not deemed to be inflammatory, however, may be admitted so long as it has relevance and can assist the jury's understanding of the facts of the case before it. ",
"Commonwealth v. Claitt, 454 Pa. 313, 311 A.2d 922 (1973); Commonwealth v. Smalls, 449 Pa. 15, 295 A.2d 298 (1972); Commonwealth v. Morgan, 448 Pa. 494, 295 A.2d 77 (1972).\"",
"\nWe find that the photograph in question here was properly admitted. ",
"The trial judge admitted a single black and white photograph of a skeleton at the grave site. ",
"It was not bloody, nor was it obvious from the photograph that any violence had occurred. ",
"Anyone who did not examine it carefully might not be aware at all that it depicted human *337 remains. ",
"The skeleton does not appear so prominently as to be readily identifiable without a close look. ",
"A human skull is discernible, however, if a close examination is made. ",
"The photograph should not be viewed as particularly inflammatory. ",
"By providing an example of how the bodies were situated at the grave site, it illustrated what happened to the victims, thereby aiding in understanding the alleged crime. ",
"We deem that sufficient to render it admissible under the circumstances of this case. ",
"See Commonwealth v. Snyder, 408 Pa. 253, 182 A.2d 495 (1962).",
"\nAnother alleged error was the trial court's refusal to allow the question \"whether or not, Albert, you have had a severe drug problem?\" ",
"during the cross-examination of Albert Patti. ",
"Appellant argues that it was a proper question because it had a bearing on Patti's credibility. ",
"The purpose was to show that Patti was not mentally stable at the time that Yost allegedly admitted to him that he killed the victims. ",
"If Patti's mental condition at that time had been impaired so as to affect his ability to remember what he saw or heard, evidence as to his condition would be relevant. ",
"Commonwealth v. Ware, 459 Pa. 334, 329 A.2d 258 (1974). ",
"Such impairment may be shown on the basis of use of drugs or alcohol at such time, but questions on their use at other times are impermissible. ",
"Commonwealth v. Duffy, 238 Pa.Super. ",
"161, 353 A.2d 50 (1975). ",
"After the objection to the disallowed question was sustained, appellant was permitted to question Patti on his use of drugs at the particular time of the alleged admission. ",
"Patti said that at the time he was taking Proloxin, a tranquilizer prescribed for a nervous condition, and was not taking heroin, cocaine, or Tolwyn, a synthetic form of morphine. ",
"Having been allowed to ask such questions, appellant was not denied any right that he had to attempt to impeach on the basis of drug use. ",
"The disallowed question would have brought out any drug problem that Patti might have had at an irrelevant time and was, therefore, properly excluded.",
"\nAppellant alleges that he was not tried by twelve competent jurors. ",
"Appellant argues that because one juror *338 became ill and had to be hospitalized after the verdict, he was entitled to a new trial. ",
"Appellant would be entitled to a new trial only if the record showed that he had been denied the essential features of a jury trial. ",
"Commonwealth v. Fugmann, 330 Pa. 4, 198 A. 99 (1938). ",
"A juror should not be so physically infirm as to be unable to properly discharge his or her duties. ",
"Commonwealth v. Brown, 231 Pa.Super. ",
"431, 332 A.2d 828 (1974). ",
"We find no denial of appellant's rights in this case. ",
"Nothing in the record indicates that the juror was ill during the trial or that she in any way failed or was unable to discharge her duties. ",
"Her being taken ill afterward is, therefore, irrelevant. ",
"See also Commonwealth v. Thomas, 465 Pa. 442, 350 A.2d 847 (1976).",
"\nFinally, appellant claims that his trial attorneys were incompetent because they did not move for a change of venue. ",
"The record shows that they originally intended to do so. ",
"They thought there was a reasonable chance of success because Shamokin is a small town and the alleged crime was publicized in the local media after the discovery of the victims' bodies. ",
"The matter was discussed thoroughly with Yost, who agreed that the motion should be made. ",
"Counsel abandoned the idea after the denial of a motion by Roland Scandle for a change of venue in his trial. ",
"They decided they could not secure a change of venue if Scandle could not succeed in his motion. ",
"Yost was advised of this and agreed with counsel's assessment of the situation.",
"\nA decision by counsel not to take a particular action does not constitute ineffectiveness if it is based on a reasonable conclusion that there will be no benefit and is not caused by sloth or ignorance of available alternatives. ",
"Commonwealth v. Twiggs, 460 Pa. 105, 331 A.2d 440 (1975). ",
"It was reasonable to conclude that a motion for change of venue would have been fruitless. ",
"Because of counsel's careful consideration of the matter, we find no sloth or ignorance. ",
"Counsel is presumed competent and appellant has the burden to prove otherwise. ",
"Com. ",
"ex rel. ",
"Washington v. *339 Maroney, 427 Pa. 599, 235 A.2d 349 (1967).[2] Under the facts of the instant case, appellant has not carried his burden to show that counsel was incompetent.",
"\nHaving considered all of appellant's allegations, we find no error.",
"\nJudgments of sentence affirmed.",
"\nPOMEROY, J., files a concurring opinion.",
"\nROBERTS, J., concurs in the result.",
"\nMANDERINO, J., files a dissenting opinion.",
"\nJONES, former C.J., took no part in the consideration or decision of this case.",
"\nPOMEROY, Justice, concurring.",
"\nI concur in the decision of the Court. ",
"I am unable, however, to agree fully with the rationale of the opinion upholding the admission of the photograph taken at the gravesite and supposedly depicting skeletal remains. ",
"The picture, which I have examined, appears to me to have had but marginal relevancy; it proved little or nothing as to the conduct or state of mind of the defendant, nor, so far as I can see, did it supply or corroborate any other element of the case that the Commonwealth had to prove. ",
"But if on this account the admission of the photograph was error, I believe the error was harmless; I can see no prejudice to any interest of appellant's which would justify reversal.[*]",
"\n*340 The Court concludes that the challenged photograph was admissible as both relevant and non-prejudicial. ",
"In so doing, the majority purports to apply the test enunciated in Commonwealth v. Petrakovich, 459 Pa. 511, 329 A.2d 844 (1974). ",
"Because in my view the language of the majority opinion is not an accurate application of our holding in that case, I feel constrained to write this separate statement.",
"\nAs Mr. Justice O'Brien notes, the challenged photograph is a single black and white picture showing the area where the victim's skeletons were found; the remains themselves are barely discernible. ",
"I should think that these characteristics of the exhibit are answer enough to any assertion, such as that made by Mr. Justice Manderino in dissent, that photographs of human remains must be deemed inflammatory per se. ",
"The majority, however, places reliance on its appraisal that \"[t]he photograph should not be viewed as particularly inflammatory.\" ",
"Ante at 337. ",
"In making this statement the majority seems to overlook the fact that the Petrakovich test consists of two steps, viz., ",
"determining whether a photograph proffered as an exhibit is inflammatory or not, and, if it is, proceeding to determine whether it has such evidentiary value that its \"need clearly outweighs the likelihood of inflaming the minds and passions of the jury.\" ",
"Petrakovich, supra, 459 Pa. at 521, 329 A.2d at 852, quoting Commonwealth v. Powell, 428 Pa. 275, 279, 241 A.2d 119, 121 (1968). ",
"Instead, the majority seems to be saying that a photograph's evidentiary value is to be balanced in each case against various subtle gradations of inflammatory potential. ",
"With this I cannot agree; to view the Petrakovich test in this manner is to adopt in part the notion that \"photographs are inflammatory per se\" a conclusion that Petrakovich explicitly rejected. ",
"See, 459 Pa. at 522, 329 A.2d 844. ",
"See also, Commonwealth v. Hilton, 461 Pa. 93, 101, 334 A.2d 648, 650 (1975) (Pomeroy, J., concurring, joined by Jones, C.J., and Eagen, O'Brien, and Nix, JJ.).",
"\nIn the instant case the conclusion is inescapable that the photograph which was admitted simply was not inflammatory at all; indeed, the \"skeletal remains\" were barely distinguishable *341 as such. ",
"Thus the inquiry in passing on admissibility becomes whether the photograph \"has relevance and can assist the jury's understanding of the facts of the case before it.\" ",
"Petrakovich, supra, 459 Pa. at 521, 329 A.2d at 849.",
"\nWhile, as stated above, I have some difficulty in finding relevance, the trial court was clearly correct in not excluding the exhibit because of any gruesome or emotionally exciting aspect. ",
"Thus I concur in this Court's upholding of the challenged ruling.",
"\nMANDERINO, Justice, dissenting.",
"\nOnce again this Court is asked to review a claim that it was error for the trial court to admit an inflammatory photograph of a corpse. ",
"See Commonwealth v. Smith, 477 Pa. 505, 384 A.2d 1202 (1978) (Manderino, J., dissenting); Commonwealth v. Norris, 477 Pa. 239, 383 A.2d 912 (1978) (Manderino, J., dissenting); Commonwealth v. Sullivan, 472 Pa. 129, 371 A.2d 468 (1977); id. at 489-91 (Roberts & Manderino, JJ., ",
"concurring and dissenting). ",
"Once again the majority finds no error in admitting such photographs. ",
"Although I have already expressed the view that recent decisions of this Court make it difficult to construct a case where a new trial is granted because of the admission of inflammatory photographs, Commonwealth v. Sullivan, 472 Pa. 129, 371 A.2d 468, 497-501 (1977) (Manderino & Roberts, JJ., ",
"concurring and dissenting), I must express my dismay and disagreement with the reasoning employed by the majority in this case.",
"\nThe trial court admitted a photograph of the skeletal remains of one of the deceased. ",
"The majority is forced to conclude that the photograph is inflammatory, although it does so reluctantly, stating that the photograph is not \"particularly inflammatory.\" ",
"Even under the test a majority of this Court adopted in Commonwealth v. Petrakovich, 459 Pa. 511, 521, 329 A.2d 844, 849 (1974), a standard with which I continue to disagree, the pictures are therefore inadmissible unless \"of such essential evidentiary value that their need *342 clearly outweighs the likelihood of inflaming the minds and passions of the jury.\" (",
"Emphasis added).",
"\nBy no stretch of the imagination can it be said that this photograph had \"essential evidentiary value.\" ",
"The majority holds this photograph admissible because it \"[provided] an example of how the bodies were situated at the gravesite, [and] illustrated what happened to the victims, thereby aiding in understanding the alleged crime.\" ",
"The flimsiness of this purported relevance is self-apparent. ",
"A skeleton cannot possibly illustrate \"what happened to the victims.\" ",
"Death was by strangulation, and I am at a loss to understand how a skeleton can illustrate strangulation. ",
"I am also at an utter loss to comprehend the relevance of \"how the bodies were situated.\" ",
"There is absolutely no issue in this case even remotely related to the situation of the victims' bodies. ",
"Not only was this photograph lacking in \"essential evidentiary value,\" this photograph had no relevance whatsoever. ",
"Under any test ever articulated by this Court for reviewing a trial court's discretion in admitting photographs of corpses, to admit this photograph was an abuse of that discretion. ",
"I dissent.",
"\nNOTES\n[1] At trial, the court refused to allow the testimony on grounds of relevancy. ",
"In the opinion filed which supported the denial of post-verdict motions, the court held that the testimony was inadmissible hearsay.",
"\n[2] Scandle was convicted in Lebanon County after being granted a change of venue in a second petition after Yost's trial. ",
"The reason for granting the change of venue may have been that Yost's trial generated publicity that made a fair trial on charges from the same incident impossible in Northumberland County. ",
"In any event, the denial of Scandle's first motion made the withdrawal of Yost's motion reasonable at the time.",
"\n[*] The trial court gave the jury cautionary instructions about the pictures, thus reducing to a minimum any possible prejudice to the defendant. ",
"See Commonwealth v. Martinez, 475 Pa. 331, 380 A.2d 747, 752-53 (1977) (Pomeroy, J., concurring). ",
"The court also excluded three other black and white photographs of the gravesite because they were cumulative.",
"\n"
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"Q:\n\nHome folder encrypted, hacker has physical access - safe to ssh to it?",
"\n\nA computer runs Ubuntu with home folder encryption. ",
"It is switched on but not logged in. ",
"Another computer connects to it over SSH, allowing browsing of the home folder through the terminal. ",
"Can a hacker with physical access now read the home folder data?",
"\n\nA:\n\nThe root user has full access to any encrypted home folders while those users are logged in. ",
"Someone with physical access to the computer can modify the kernel to give themselves root access and access the files that way.",
"\nThe SSH server can see any passwords entered, and the SSH server executable can be modified by someone with physical access to provide the password to them.",
"\n\n"
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"[leer.eps]{} gsave 72 31 moveto 72 342 lineto 601 342 lineto 601 31 lineto 72 31 lineto showpage grestore\n\n------------------------------------------------------------------------\n\n[**Michael Reiterer, Eugene Trubowitz**]{} [Department of Mathematics, ETH Zurich, Switzerland]{} [**Abstract:**]{} Recently, Christodoulou [@Chr] proved that trapped spheres can form in evolution, through the focusing of gravitational waves, from a generic initial state. ",
"His work is the motivation for the present paper, in which we consider the same physical problem, using very different mathematical methods. ",
"Our approach is based on a controlled “far field expansion”. ",
"By a systematic use of scaling symmetries, we regularize Christodoulou’s singular “short pulse method”, rigorously track vacuum solutions by the far field expansion and exhibit trapped spheres that first appear deep inside the far field region. ",
"Our presentation is self-contained. ",
"In the final section, we present a detailled outline of the construction of another, more subtle, expansion that allows us to continue the solutions beyond the far field region to within any fixed “finite distance” from the (expected) singularity. ",
"From a methodological perspective, the underlying aim of this paper is the development of a general method for constructing solutions to the vacuum Einstein equations by controlled expansions.",
"\n\nAnderson, L. and Rendall, A.D., Commun. ",
"Math. ",
"Phys. **",
"218**, (2001) 479-511 Belinskii, V.A., Khalatnikov, I.M., Sov. ",
"Phys. ",
"JETP **36**, (1973) 591-597 Belinskii, V.A., Khalatnikov, I.M., Lifshitz, E.M., Adv. ",
"in Phys. **",
"31**, (1982) 639-667 Bondi, H., van der Burg, M.G.J. and Metzner, A.W.K., Proc. ",
"Roy. ",
"Soc. ",
"Lond. ",
"A **269**, (1962) 21-52 Chandrasekhar, S., *The Mathematical Theory of Black Holes* (Oxford U., 1983) Christodoulou, D., *The Formation of Black Holes in General Relativity* (EMS, 2009) Christodoulou, D. and Klainerman, S.,\\\n*The Global Nonlinear Stability of the Minkowski Space*, (Princeton U., 1993) Friedrich, H., Proc. ",
"R. Soc. ",
"Lond. ",
"A **375**, (1981) 169-184 John, F., *Partial Differential Equations* (Springer, 1978) 139 Newman, E. and Penrose, R., J. Math. ",
"Phys. **",
"3**, (1962) 566-578 Penrose, R., Phys. ",
"Rev. Lett. **",
"14**, (1965) 57-59 Szekeres, P., J. Math. ",
"Phys. **",
"13**, (1972) 286-294 Taylor, [M.]{} E., *Partial Differential Equations III* (Springer, 1997) 360-370 Taylor, [M.]{} E., *Partial Differential Equations I* (Springer, 1996) 434-439\n"
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"To link to the entire object, paste this link in email, IM or documentTo embed the entire object, paste this HTML in websiteTo link to this page, paste this link in email, IM or documentTo embed this page, paste this HTML in website\n\n\"Georgie White: Woman of the Rivers.\" ",
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"Frank Gaffney has emerged as one of the DC-beltway’s most outspoken critics of American Muslims, purveying conspiracy theories about the infiltration of the Muslim Brotherhood into the highest levels of the U.S. government and birther accusations about Barack Obama’s eligibility to serve as president. ",
"But even while drawing criticism from civil rights organizations, Gaffney, who served as acting Assistant Secretary of Defense in 1987, has continued to find sources of funding for his organization, the Center for Security Policy, managing a budget of over $3.5 million in 2013.",
"\n\nSalon acquired a copy of the Center for Security Policy’s donor rolls, listing the organization’s biggest donors. ",
"And while far from providing the lion’s share of funding, six of the U.S.’ biggest aerospace and defense contractors are supporters of Gaffney’s organization.",
"\n\nAdvertisement:\n\nThe document, which details contributions to the Center for Security Policy during the 2013 tax year, includes donations from: Boeing ($25,000); General Dynamics ($15,000); Lockheed Martin ($15,000); Northrup Grumman ($5,000); Raytheon ($20,000); and General Electric ($5,000).",
"\n\nA number of institutional donors with a history of supporting Islamophobia, including the Lynde & Harry Bradley Foundation and the Sarah Scaife Foundation, are also contributors, but the aerospace industry’s decision to support Gaffney’s highly controversial work is unusual due to his reputation as a member of the fringe, anti-Muslim far-right.",
"\n\nGaffney, who serves as president of the Center for Security Policy, emerged as one of the most high-profile propagators of conspiracy theories about Obama’s country of birth and his -- alleged -- agenda to undermine the U.S. government. ",
"In a 2008 Washington Times column, titled: “The Jihadist Vote,” Gaffney questioned “whether Mr. Obama is a natural born citizen of the United States, a prerequisite pursuant to the U.S. Constitution” and postulated that \"there is evidence he was born in Kenya rather than, as he claims, Hawaii.\"",
"\n\nAdvertisement:\n\nAnd Gaffney’s assertions become even more extreme when he discusses the influence of a subversive Muslim agenda within the U.S. In a 2010 column for Breitbart.com, Gaffney argued that the Missile Defense Agency logo “appears ominously to reflect a morphing of the Islamic crescent and star with the Obama campaign logo” and is part of a “worrying pattern of official U.S. submission to Islam.”",
"\n\nGaffney has even gone as far as to suggest that a House committee, based on Sen. Joseph McCarthy’s House Committee on Un-American Activities, should be formed to investigate the Muslim Brotherhood’s alleged infiltration of the U.S. government. “",
"So pervasive now is the MB’s [Muslim Brotherhood’s] ‘civilization jihad’ within the U.S. government and civil institutions that a serious, sustained and rigorous investigation of the phenomenon by the legislative branch is in order,” wrote Gaffney in 2011. “",
"To that end, we need to establish a new and improved counterpart to the Cold War-era’s HUAC [House Un-American Activities Committee] and charge it with examining and rooting out anti-American – and anti-constitutional – activities that constitute an even more insidious peril than those pursued by communist Fifth Columnists fifty years ago.”",
"\n\nSince 2011, Gaffney has repeatedly claimed that Huma Abedin – an aide to Hillary Clinton during her tenure as Secretary of State – was a Muslim Brotherhood operative, a charge so outlandish that Sen. John McCain (R-AZ), House Speaker Rep. John Boehner (R-OH) and Sen. Marco Rubio (R-FL) all condemned it. ",
"These comments and others led civil rights organizations to denounce Gaffney’s demonization of American Muslims.",
"\n\nAdvertisement:\n\nMark Potok, a senior fellow at the Southern Poverty Law Center told Salon, \"I cannot imagine why any legitimate business would fund a man like Frank Gaffney. ",
"The man is a propagandist and a defamer of perfectly innocent people. ",
"It's shocking that any business would give this man money.\"",
"\n\nAnd the Anti-Defamation League characterizes the Center for Security Policy as “a neo-conservative think tank that has pioneered the anti-Shariah hysteria by publishing materials regarding the threat of an Islamic takeover of the U.S.”\n\nAdvertisement:\n\nWhen asked about their donations to the Center for Security Policy and Gaffney’s record of anti-Muslim statements, most of the companies emphasized that their contributions were directed to a dinner honoring the late Chairman of the House Defense Appropriations Subcommittee Bill Young. (",
"The Center for Security Policy also corroborated that explanation.)",
"\n\nWilliam Philbin, the Center for Security Policy’s Senior Vice President for Operations told Salon, “these folks gave us money to help our annual awards dinner… It’s not uncommon for folks like that to buy sponsorships or help us defray costs of the awards dinner.” ",
"Corporate donors, including representatives from General Dynamics, Northrup Grumman, Lockheed Martin, and Raytheon confirmed their participation, with a GE spokesperson adding that the company “sees diversity and inclusiveness as an essential part of our productivity, innovation and competitive advantage.” (",
"It’s unclear what GE’s comment about diversity is a reference to.) ",
"Gordon Johndroe, Vice President of Worldwide Media Relations at Lockheed Martin did make clear to Salon that they had participated in the award dinner but that Lockheed Martin “does not have an ongoing relationship with the Center for Security Policy.”",
"\n\nAnd Michael Doble, Director of Corporate Public Relations at Raytheon, told Salon, “In 2013, we purchased our final table for the dinner which honored the late Representative Bill Young of Florida, a long-time supporter of our men and women in uniform. ",
"We discontinued all other support of CSP in 2012 and have no plans to provide further funding to the organization.\"",
"\n\nAdvertisement:\n\nBut, unlike the other companies, Boeing spokesperson Gayla Keller acknowledged that “Boeing provided general support to the Center for Security Policy in 2013.”",
"\n\nResponding to a question about Gaffney’s views on the Obama administration and Islam, Keller said, “Boeing supports organizations such as the Center for Security Policy because of work they do on issues of importance to our company. ",
"Boeing’s support of the Center for Security Policy does not mean that we share all of the views expressed by the organization or individuals working for, or leading, the organization.”",
"\n\nBoeing did not respond to a question about its support of Gaffney’s organization in years preceding 2013 but, in 2008, The Washington Note’s Steve Clemons noted that Gaffney acknowledged receiving money from Boeing.",
"\n\nAdvertisement:\n\nAt the time, Clemons asked “one of Boeing’s top DC-based officials whether he knew if Frank Gaffney was a consultant or adviser to the firm.” ",
"The official responded, “I don’t know – but I can’t possibly believe that that would be the case. ",
"That just can’t be true. ",
"No way. ",
"I’ll check it out right away.” ",
"The official didn’t get back to him."
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"Advanced Tips\n\nMost learning is done by following a good player around, healing them and, watching how they play.",
"Inside domes all beams are COMPLETELY negated.",
"It's a good idea to disable \"Self spell on self click\" in Keybindings. ",
"If you don't have middle mouse, rebind it.",
"Switch to a Fire Ward when you're on Fire. ",
"Switch to a Ward when you're Wet.",
"If Mines are lain under you, DON'T MOVE! (",
"hit the stomp moving button) Stepping off them detonates them. ",
"Ward the damage before you move or before they are detonated.",
"Chain cast spells by quickly queuing elements, and reclicking and holding Right/Middle Click.1 Lightning Ward will prevent any Lightning mini-stuns.",
"You cannot have an Wall and an Barrier out at the same time. ",
"will go through every wall but, the one with the same element you chose for DON'T dome if you're getting healed. ",
"prevents Steam damage. ",
"and Rock Wards block Ice damage.",
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"The Society for Pediatric Epidemiologic Research is an open- membership society comprised of researchers from a variety of backgrounds, all of whom share an interest in the epidemiology of normal and abnormal growth and development of children, from their conception through adolescence. ",
"The purpose of the Society is to foster research in this discipline by encouraging communication and exchange of ideas and research results between established investigators, as well as between new and established investigators. ",
"In its eleven years of existence, has met these goals successfully, and its annual meeting has become the primary congregating point of researchers in the fields of perinatal and pediatric epidemiology. ",
"Three popular features of the meeting are the Student Prize Paper, the International Prize Paper and the Keynote Address. ",
"The Society currently funds 100% of the transportation, hotel and other costs of these awards. ",
"This request is for the NICHD to assist the Society by assuming funding of the transportation and hotel costs of these awards, thereby assuring the continued development of young investigators in pediatric and perinatal epidemiology into the next century."
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"Effects of vaccination against reproductive diseases on reproductive performance of beef cows submitted to fixed-timed AI in Brazilian cow-calf operations.",
"\nThe objectives were to assess incidence of pregnancy losses, associate this outcome with immunization programs against reproductive diseases, and evaluate the effects of vaccination against bovine herpesvirus-1 (BoHV-1), bovine viral diarrhea virus (BVDV), and Leptospira spp., ",
"on reproductive efficiency of Brazilian cow-calf operations. ",
"In experiment 1, 7614 lactating Nelore cows from 18 ranches were assigned to the same estrus synchronization and fixed-time AI protocol (ESFTAI; Days -11 to 0). ",
"Pregnancy status was determined with transrectal ultrasonography on Days 30 and 120 after AI. ",
"Pregnancy loss was deemed to have occurred when cows were pregnant on Day 30 but nonpregnant on Day 120. ",
"Incidence of pregnancy loss across all ranches was 4.1%; pregnancy losses were detected (P < 0.10) in 14 ranches but not detected (P > 0.11) in four ranches. ",
"Pregnancy loss was lower (P ≤ 0.02) in ranches that vaccinated against BoHV-1, BVDV, and Leptospira spp. ",
"compared with ranches that did not vaccinate, or only vaccinated against Leptospira spp. ",
"In experiments 2 and 3, lactating Nelore cows (N = 1950 and 2793, respectively) from ranches that did not have a history of vaccinating against reproductive diseases (experiment 2), or only vaccinated against Leptospira spp. (",
"experiment 3), were assigned to the same ESFTAI used in experiment 1. ",
"Within each ranch, cows received (VAC) or not (CON) vaccination against BoHV-1, BVDV, and Leptospira spp. ",
"at the beginning of the ESFTAI (Day -11) and 30 days after (Day 41) AI. ",
"In experiment 2, VAC cows had greater (P ≤ 0.05) pregnancy rates compared with CON on Days 30 and 120. ",
"In experiments 2 and 3, pregnancy loss was reduced (P ≤ 0.03) in primiparous VAC cows compared with CON cohorts. ",
"In experiment 4, 367 primiparous, lactating Nelore cows previously vaccinated against Leptospira spp. ",
"were assigned to the same ESFTAI used in experiment 1. ",
"Cows received VAC, or the same vaccine 30 days before (Day -41) and at the beginning (Day -11) of the ESFTAI (PREVAC). ",
"Pregnancy rates on Days 30 and 120 were greater (P ≤ 0.05) in PREVAC cows compared with VAC cows. ",
"In conclusion, pregnancy losses affected reproductive and overall efficiency of Brazilian cow-calf operations, and might be directly associated with BoHV-1, BVDV, and Leptospira spp. ",
"infections. ",
"Hence, vaccinating cows against these pathogens, particularly when both doses are administered before fixed-time AI, improved reproductive performance in Brazilian cow-calf systems."
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"Concise Construction of the ACDE Ring System of Calyciphylline A Type Alkaloids by a [5+2] Cycloaddition.",
"\nA concise route for construction of the ACDE ring skeleton in calyciphylline A type alkaloids was developed using an intramolecular [5+2] cycloaddition reaction of an oxidopyrylium species bearing a tetrasubstituted olefin. ",
"Key to the success of this reaction was the combination of acid and base, which accelerated the construction of this skeleton containing a spiro ring and vicinal quaternary carbon centers. ",
"The resultant tricyclic ADE ring compound was converted to an ACDE ring model through C-H oxidation and an aza-Wittig reaction."
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"Q:\n\nWhy doesn't this ruby code compare regex?",
"\n\nif string == /\\s{1,}/ or string == /\\n{1,}/\n puts \"emptiness...\"\nend\n\nA:\n\nTo test a String against a Regex, you can do any of five things:\n1: Use String#match:\n' '.match /\\s{1,}/ # => #<MatchData:0x118ca58>\n'f'.match /\\s{1,}/ # => nil\n\n2: Use Regex#match:\n/\\s{1,}/.match ' ' # => <MatchData:0x11857e4>\n/\\s{1,}/.match 'f' # => nil\n\n3: Use String#=~:\n' ' =~ /\\s{1,}/ # => 0\n'f' =~ /\\s{1,}/ # => nil\n\n4: Use Regex#=~:\n/\\s{1,}/ =~ ' ' # => 0\n/\\s{1,}/ =~ 'f' # => nil\n\n5: Use Regex#=== (this is what is used in case statements):\n/\\s{1,}/ === ' ' # => true\n/\\s{1,}/ === 'f' # => false\n\nNote: String#=== doesn't do what you want:\n' ' === /\\s{1,}/ # => false\n'f' === /\\s{1,}/ # => false\n\nA:\n\nWhen comparing with regexes in Ruby, you should use the '=~' comparison instead of '=='.",
"\nTry that and see if it gives you what you expect.",
"\n\n"
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"For sexy Korean Curls like SNSD, UNIX It's Magic! ",
"Hot roller set is perfect for short to long hair. ",
"Used even by professional hair stylists, it gives a salon finish with minimal effort.",
"\n- Perfect for short to long hair as it has 3 barrel size.",
"\n- used only afew times as boyfriend prefers straight hair and I prefer to retain said boyfriend by looking fleek \n-9/10 c ...\n\nNOW ONLY $49 (Usually $189) but only few sets left. ",
"Watch Demo video at www.myroyalshop.com/babyliss.",
"\nFeatures: – Ceramic curl chamber for smooth and shiny curl creation – 3 heat settings; 190°C, 210°C and 230°C for long lasting results on different hair types – Powerful heating system ready to use in seconds with ultra-fast heat recovery – Curl direction control for either a uniform or natur ...\n\nJapanese brand Ion hair brush - made in Korea\nKeep hair healthy, soft, smooth n in beautiful condition even with daily styling.",
"\nCan curl and straight hair with the benefits of its titanium plate technology.",
"\nOnly used twice. ",
"Purchased fm hair salon."
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"The Greek AMA Recommends Reducing EMFs/RFs To Protect Public Health\n\nThe Athens Medical Association of Athens, Greece, held a conference April 1st regarding “Non-Ionizing Radiation and Its Effects on Human Health” where scientific lectures were presented along with 16 recommendations to reduce exposures and human health adverse effects. ",
"Question: Why hasn’t the American Medical Association done the same? ",
"Good question?",
"\n\nHere are those 16 Recommendations for Wireless Use Safety:\n\nUse your cell phone with caution and make brief calls as necessary\n\nChildren under the age of 14 should make limited use of cell phones\n\nDo not put your cell phone in contact with your head\n\nDo not use your cell phone inside a car, train, aeroplane, or elevator\n\nGeorge Patoulis MD, President of the Athens Medical Association, said that AMA, “in emphasizing its role and duties as guardian for public health, has taken steps to encourage and promote this open discussion dealing with the delicate issues of electromagnetic radiation. ",
"Mr. Patoulis stressed that all local authorities and all medical associations are obliged to adopt and apply the best possible practices available in today’s world, aiming primarily at the protection of our fellow citizens.” [",
"2]\n\nHow interesting to read Dr. Patoulis’s remarks! ",
"Do you think we’ll ever read something similar from an American Medical Association’s president? ",
"Hint: Don’t hold your breath! ",
"Remember how doctors used to promote cigarettes [3]? ",
"One has to wonder how trade associations can be so doggone stupid, especially medical ones, who ought to know better, that is, if they weren’t ‘subsidized’ by vested interest lobbyists or sales reps.",
"\n\nIMMEDIATE measures must be taken in order to protect the public, and especially children, from the electromagnetic radiation of mobile telephone masts.” [",
"4] The residents of Apostolos Andreas in Limassol planned a demonstration over the immediate removal of a mobile telephone mast from their area, which was next to a school of over 1,500 pupils. [",
"4] Can you imagine that type of demonstration ever happening in the USA where consumers either don’t know or don’t care about the effects of EMFs/RFs from microwaves affecting their children’s health?",
"\n\nHere’s a less than five minute video in Greek with English subtitles featuring precious Greek children emphasizing the Cyprus National Committee on Environment and Children’s Health advice about wireless exposures.",
"\n\nOne of the physicians at the Greek AMA meeting, Dr Stella Canna Michaelidou, called for “awareness and education among health professionals, teachers and parents, and for new legislation or biological criteria to evaluate at least children’s exposure” [1]. ",
"When will that happen in the USA?",
"\n\nHere is Truthstream Media’s video about cell towers being erected on school buildings, or near or on school grounds in the USA. ",
"One in ten cell towers/sites emits electromagnetic frequencies well above ‘safety’ limits!",
"\n\n“Wi-Fi is a known weaponized frequency,” says Deborah Tavares citing Dr Barrie Trower, an eminent British Wi-Fi researcher and former Royal Navy Microwave Weapons Expert and former debriefer for UK Intelligence Services.",
"\n\nCatherine J Frompovich (website) is a retired natural nutritionist who earned advanced degrees in Nutrition and Holistic Health Sciences, Certification in Orthomolecular Theory and Practice plus Paralegal Studies. ",
"Her work has been published in national and airline magazines since the early 1980s. ",
"Catherine authored numerous books on health issues along with co-authoring papers and monographs with physicians, nurses, and holistic healthcare professionals. ",
"She has been a consumer healthcare researcher 35 years and counting."
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"The Duke of Sussex has spoken passionately about the environment on day four of his visit to southern Africa. ",
"As he planted trees with schoolchildren on the first stop in Botswana, Prince Harry said that the science explaining climate change couldn’t be denied by anyone, including world leaders.",
"\n\nThe Duke of Sussex made specific references to the wave of recent protest movements by young people demanding action on the environment. ",
"He had particular words of support for the actions of teenage climate change activist Greta Thunberg, who was also named as one of the ‘Forces for Change’ in the September edition of British Vogue edited by the Duchess of Sussex. ",
"As he planted trees with young people in Chobe Forest Tree Reserve, Harry said ‘‘this last week, led by Greta, the world’s children are striking. ",
"It’s a race against time and one which we are losing – everyone knows it, there’s no excuse for not knowing that”.",
"\n\nThe prince went on to say ”I think the most troubling part of it is that I don’t believe there is anybody in this world that can deny science, undeniable science and facts. ",
"Science and facts that have been around for the last 30, maybe 40 years…I genuinely don’t understand how anyone in this world…you, us, children, leaders….no one can deny science otherwise we are living in a very, very troubling world”.",
"\n\nHarry’s words came at the start of a busy day in Botswana which will also see him dedicate a new part of the Queen’s Commonwealth Canopy. ",
"The area of forest to be celebrated today spans Botwana’s borders with three other countries – Namibia, Zambia and Zimbabwe. ",
"The Duke of Sussex will then head to Angola where he will join a demining camp to see the ongoing work against land mines.",
"\n\nHis time in Angola will also see him visit the stretch of land that his mother, Diana, Princess of Wales, walked along in January 1997 as she began her campaign to highlight the dangers of landmines and bring about change to ban the weapons for good."
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"BlueStacks Android-apps-on-Windows tops 10 million downloads\n\nThe BlueStacks app player for Windows was released in beta form a little more than a year earlier. ",
"The software launched in beta towards the end of March 2012 and as of today it looks like the company is celebrating a new milestone. ",
"It seems they have crossed the 10 million download mark.",
"\n\nFor those keeping track, the BlueStacks app player wasn’t released for the Mac until December 2012. ",
"Putting the Mac release to the side, it looks like the 10 million download mark has surpassed the expectations of everyone from the company. ",
"In fact, the BlueStacks employee with the closest guess was still off by roughly 9 million.",
"\n\nBlueStacks CEO Rosen Sharma said the employees all took bets on where they would be after the first year. ",
"According to Sharma, the employee that was the closest had guessed a few hundred thousand. ",
"In addition to sharing the milestone number, BlueStacks is also working to get a new version of Android up and running.",
"\n\nThere hasn’t been any specific release dates revealed just yet, however a Jelly Bean version is expected to arrive in the not-to-distant future. ",
"Otherwise, the other side of the 10 million download milestone is the amount of active users. ",
"Sadly the company didn’t share this number. ",
"Instead, the senior VP of marketing did refer to that number as being “spooky high.” ",
"That said, anyone here a BlueStacks user?"
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"The Seasteading Institute, committed to the ongoing development of ocean communities, has just announced the winners of their first annual design content. ",
"Could people really end up living in these hypothetical off-shore communities?",
"\n\n\n\n\nThe design contest had five categories: Overall, Best Picture, Aesthetics, Personality, and Community Choice. (",
"The winners from each category are shown in this post in that particular order, so the first design up top is the Overall winner, the one to the right is Best Picture, and so on.) ",
"With prizes ranging from $250 to $1000, the design contest attracted both amateur and professional architects from around the world, as the winners hailed from such far-flung locales as Estonia, Hungary, Brazil, and Minnesota.",
"\n\n\n\n\n\n\n\n\n\n\nSeasteading, a term derived from combining \"sea\" and \"homesteading\", is a general term given to the notion of either converting existing structures, such as old boats or disused oil rigs, or custom-building new ones to allow people to live in the middle of the ocean. ",
"Generally, this also includes the interrelated goal of establishing a sovereign state on the open seas, away from any existing governmental structures on dry land. ",
"Patri Friedman and Wayne Gramlich - whose 1998 article \"Seasteading – Homesteading on the High Seas\" is generally given credit for popularizing the term - founded the Seasteading Institute in 2008 in order to better organize the seasteading effort.",
"\n\n\n\n\n\n\n\nPerhaps the most famous - and, to some extent, the only - example of successful seasteading is the microstate of Sealand, which started life as the World War II sea fort HM Fort Roughs. ",
"Located six miles off the coast of Suffolk, Sealand was occupied by Roy Bates and his family in 1967. ",
"Crowning himself Prince Roy, Bates declared the disused fort to be the independent Principality of Sealand. ",
"Although the \"country\" is only the size of about two tennis courts, the Bates family has lived on the desolate fort for much of the last four decades. ",
"As one might well imagine, Sealand's history is about as eccentric as it origins, including an attempted invasion by a group of German and Dutch entrepreneurs in 1978, which forced the exiled Prince Roy to take up arms to reclaim his country. (",
"How that hasn't become a movie yet is completely beyond me.)",
"\n\n\n\n\n\n\n\n\nSealand's story is well worth reading up on, as it's just about the only topic I know of that can make the differences between de jure and de facto diplomatic recognition absolutely fascinating. ",
"Still, the question remains what, if any, long-term viability seasteading has. ",
"The success of the Bates family at least suggests it's possible to exist out on the open sea with limited government oversight (although the British government did still handle all the mail sent to Sealand), and the Seasteading Institute has raised over 500,000 dollars in support of their work. ",
"Of course, whether that would be enough to build even a fraction of any of these designs is an open question. ",
"In the meantime, at least we can take some small comfort in the fact that, should Waterworld ever prove terrifyingly realistic, at least a few people will be well prepared.",
"\n\n\n[The Seasteading Institute]\n\nIf you liked this post, you might want to browse io9's other posts on architecture and concept art."
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"In this Tutorial I want to show you, how you can program your Arduino with an Android device. ",
"It is very simple and cheap.",
"\n\nRequirements:\n\nA USB-A to USB-B cable\n\nA USB-Host cable (OTG cable)\n\nAn Arduino\n\n1 LED (for testing)\n\nA Android device with Android 4.0.0+ (or with host aviability)\n\nSoftware: ArduinoDroid from the Google Play store\n\nConnections:\n\nJust plug the USB-A to USB-B cable into the female USB of the Host cable. ",
"Then plug the USB-B plug into the Arduino and the Micro USB into the Android device.",
"\n\nArduinoDroid – Arduino IDE\n\nThe app takes about 210Mb as it contains IDE, compiler and uploader. ",
"Make sure you have enough free space in internal storage and it can’t be installed on sd card because of Android security policy.",
"\n\nFeatures:\n\n* open/edit Arduino sketches\n\n* example sketches and libraries included\n\n* code syntax highlighting with themes support *\n\n* code complete *\n\n* real-time diagnostics (errors and warnings) and fixes *\n\n* sketch navigator *\n\n* tiny built-in software keyboard *\n\n* compile sketches (no root required)\n\n* upload sketches (Arduino Uno/Uno_r3, Duemilanove, Nano, Mega 2560, Leonardo, Micro/Pro Micro, Pro, Pro Mini, Yun, Esplora, Robot Control, Robot Motor boards are supported, android devices with USB-host support required)\n\n* serial monitor\n\n* works offline (no internet connection required)\n\n* Dropbox support\n\n* Google Drive support\n\n* material design\n\nApp blog:\n\nhttp://www.arduinodroid.info\n\nTroubleshooting:\n\nhttp://www.arduinodroid.info/p/troubleshooting.html\n\nAdvanced paid features (marked with *) review:\n\nhttp://www.arduinodroid.info/p/advanced-features.html\n\nDownload Now\n\nTest Arduino Board\n\nArduinodroid is an IDE, a compiler and an uploader for Arduino, it also uses the host mode to upload sketches, which you can write directly in the app.",
"\n\nAfter you wrote a code, you can compile it with the “Lightning-Button”, that needs some time, but works good.",
"\n\nwhen its compiled you can press the upload button (the to the right).",
"\n\nThe upload should take only seconds.",
"\n\nAfter that my Arduino started the new code –> It worked very good!",
"\n\nFor testing I used the “Blink” sketch.",
"\n\nHere Special THANK YOU to Anton Smirnov who created the apps for Android!",
"\n\nhttps://play.google.com/store/apps/developer?id=An…\n\nI hope you like this post. ",
"Do you have any questions? ",
"Leave a comment down below!",
"\n\nThanks for reading. ",
"If you like this post probably you might like my next ones, so please support me by subscribing my blog.",
"\n\nExplore some ESP32 Tutorials:\n\n\n\nYou may like also:\n\nUpvote on Reddit\n\nLike this: Like Loading..."
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"Q:\n\nSphere Plane Intersection Circle Radius?",
"\n\nHow would one find the radius of the circle that's the intersection of a sphere and a plane ?",
"\nIt is some how associated with distance from the center of the sphere.. Distance from plane to center of sphere is 0, then the radius of circle is the radius of the sphere. ",
"If distance is equal to radius of sphere then it would simply be a point, radius = 0. ",
"Would it be possible to find the radius of the circle using only the distance between the plane and center of sphere?",
"\nAlso knowing the radius of the sphere.",
"\n\nA:\n\nThe answer to your question is yes: Let $O$ denote the center of the sphere (with radius $R$) and $P$ be the closest point on the plane to $O$. Then the distance $OP$ is the distance $d$ between the plane and the center of the sphere.",
"\nNow, if $X$ is any point lying on the intersection of the sphere and the plane, the line segment $OP$ is perpendicular to $PX$. So by the Pythagorean theorem we have:\n$R^2 = OX^2 = OP^2 + PX^2 = d^2 + PX^2 = d^2 + r^2$\nWhere $r = PX$ is the radius of the circle of intersection.",
"\nSo: $r = \\sqrt{R^2 - d^2}$\n\n"
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"Q:\n\nSharepoint List & Export to excel sheet\n\nI read that we can store list items limitation for sharepoint 2010 is 30 million . ",
"Is this true ? ",
"\nIf yes , then can i have 25 million records in sharepoint list , and use \"export to excel sheet\" and it will work fine ? ",
"\n\nA:\n\nYes this is true, as per technet. ",
"\n Items 30,000,000 per list Supported\n You can create very large lists using standard views, site hierarchies, and metadata navigation. ",
"This value may vary depending on the number of columns in the list and the usage of the list.",
"\n\nhttp://technet.microsoft.com/en-us/library/cc262787(v=office.15).aspx#ListLibrary\nBut milage vary as in the description mentioned that its depend how many columns of different type.",
"\nI dont have a list this much items, so only way to check is test it.",
"\nI dont think so it's good idea to have list with 25Million items, this will be big performance hit on your site.",
"\n\n"
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"In the construction of boilers and other heat exchange equipment, used in the power generation and chemical industries, there is a need for a device which can be used to form a seal for tubes, pipes and similar conduits which transport steam, liquid or gasses under pressure. ",
"The requirements for such devices include ease of installation, relatively low cost, and the ability to maintain a seal against leakage of steam, water or other gasses or fluids, over an extended period of time, with a high degree of reliability. ",
"One of the typical requirements for such tubes is that they have a relatively thin wall in order to maximize the rate of heat transfer through these tubes. ",
"This relatively thin wall structure results in an additional requirement for an effective tube plug. ",
"Such a device must not cut into the tube wall, or in any way weaken the structure of the tubes in order to prevent degradation of the tube's resistance to failure under pressures.",
"\nIt is an object of the present invention to provide a tube plug which can be quickly and easily installed in the end of a tube, usually within a heat exchanger tube sheet, to provide an effective leakproof seal.",
"\nAnother object of the present invention is to provide a tube seal capable of withstanding operational pressures.",
"\nAnother object of the present invention is to provide a tube plug which can provide a seal against both liquids and gasses.",
"\nAnother object of the present invention is to provide a tube plug which does not weaken the tube during or after installation.",
"\nStill another object of the present invention is to provide a tube plug comprising a relatively small number of simple component parts resulting in a relatively low manufacturing cost."
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"Model-independent method for fMRI analysis.",
"\nThis paper presents a fast method for delineation of activated areas of the brain from functional magnetic resonance imaging (fMRI) time series data. ",
"The steps of the work accomplished are as follows. ",
"1) It is shown that the detection performance evaluated by the area under the receiver operating characteristic curve is directly related to the signal-to-noise ratio (SNR) of the composite image generated in the detection process. ",
"2) Detection and segmentation of activated areas are formulated in a vector space framework. ",
"In this formulation, a linear transformation (image combination method) is shown to be desirable to maximize the SNR of the activated areas subject to the constraint of removing inactive areas. ",
"3) An analytical solution for the problem is found. ",
"4) Image pixel vectors and expected time series pattern (signature) for inactive pixels are used to calculate weighting vector and identify activated regions. ",
"5) Signatures of the activated regions are used to segment different activities. ",
"6) Segmented images by the proposed method are compared with those generated by the conventional methods (correlation, t-statistic, and z statistic). ",
"Detection performance and SNRs of the images are compared. ",
"The proposed approach outperforms the conventional methods of fMRI analysis. ",
"In addition, it is model-independent and does not require a priori knowledge of the fMRI response to the paradigm. ",
"Since the method is linear and most of the work is done analytically, numerical implementation and execution of the method are much faster than the conventional methods."
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"<?",
"php\n\n/*\n * This file is part of the Symfony package.",
"\n *\n * (c) Fabien Potencier <[email protected]>\n *\n * For the full copyright and license information, please view the LICENSE\n * file that was distributed with this source code.",
"\n */\n\nnamespace Symfony\\Contracts\\Translation\\Test;\n\nuse PHPUnit\\Framework\\TestCase;\nuse Symfony\\Contracts\\Translation\\TranslatorInterface;\nuse Symfony\\Contracts\\Translation\\TranslatorTrait;\n\n/**\n * Test should cover all languages mentioned on http://translate.sourceforge.net/wiki/l10n/pluralforms\n * and Plural forms mentioned on http://www.gnu.org/software/gettext/manual/gettext.html#Plural-forms.",
"\n *\n * See also https://developer.mozilla.org/en/Localization_and_Plurals which mentions 15 rules having a maximum of 6 forms.",
"\n * The mozilla code is also interesting to check for.",
"\n *\n * As mentioned by chx http://drupal.org/node/1273968 we can cover all by testing number from 0 to 199\n *\n * The goal to cover all languages is to far fetched so this test case is smaller.",
"\n *\n * @author Clemens Tolboom [email protected]\n */\nclass TranslatorTest extends TestCase\n{\n public function getTranslator()\n {\n return new class() implements TranslatorInterface {\n use TranslatorTrait;\n };\n }\n\n /**\n * @dataProvider getTransTests\n */\n public function testTrans($expected, $id, $parameters)\n {\n $translator = $this->getTranslator();\n\n $this->assertEquals($expected, $translator->trans($id, $parameters));\n }\n\n /**\n * @dataProvider getTransChoiceTests\n */\n public function testTransChoiceWithExplicitLocale($expected, $id, $number)\n {\n $translator = $this->getTranslator();\n $translator->setLocale('en');\n\n $this->assertEquals($expected, $translator->trans($id, ['%count%' => $number]));\n }\n\n /**\n * @dataProvider getTransChoiceTests\n */\n public function testTransChoiceWithDefaultLocale($expected, $id, $number)\n {\n \\Locale::setDefault('en');\n\n $translator = $this->getTranslator();\n\n $this->assertEquals($expected, $translator->trans($id, ['%count%' => $number]));\n }\n\n public function testGetSetLocale()\n {\n $translator = $this->getTranslator();\n $translator->setLocale('en');\n\n $this->assertEquals('en', $translator->getLocale());\n }\n\n /**\n * @requires extension intl\n */\n public function testGetLocaleReturnsDefaultLocaleIfNotSet()\n {\n $translator = $this->getTranslator();\n\n \\Locale::setDefault('pt_BR');\n $this->assertEquals('pt_BR', $translator->getLocale());\n\n \\Locale::setDefault('en');\n $this->assertEquals('en', $translator->getLocale());\n }\n\n public function getTransTests()\n {\n return [\n ['Symfony is great!', '",
"Symfony is great!', []],",
"\n ['Symfony is awesome!', '",
"Symfony is %what%!', ['%",
"what%' => 'awesome']],\n ];\n }\n\n public function getTransChoiceTests()\n {\n return [\n ['There are no apples', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 0],\n ['There is one apple', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 1],\n ['There are 10 apples', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 10],\n ['There are 0 apples', 'There is 1 apple|There are %count% apples', 0],\n ['There is 1 apple', 'There is 1 apple|There are %count% apples', 1],\n ['There are 10 apples', 'There is 1 apple|There are %count% apples', 10],\n // custom validation messages may be coded with a fixed value\n ['There are 2 apples', 'There are 2 apples', 2],\n ];\n }\n\n /**\n * @dataProvider getInternal\n */\n public function testInterval($expected, $number, $interval)\n {\n $translator = $this->getTranslator();\n\n $this->assertEquals($expected, $translator->trans($interval.' ",
"foo|[1,Inf[ bar', ['%count%' => $number]));\n }\n\n public function getInternal()\n {\n return [\n ['foo', 3, '{1,2, 3 ,4}'],\n ['bar', 10, '{1,2, 3 ,4}'],\n ['bar', 3, '[1,2]'],\n ['foo', 1, '[1,2]'],\n ['foo', 2, '[1,2]'],\n ['bar', 1, ']1,2['],\n ['bar', 2, ']1,2['],\n ['foo', log(0), '[-Inf,2['],\n ['foo', -log(0), '[-2,+Inf]'],\n ];\n }\n\n /**\n * @dataProvider getChooseTests\n */\n public function testChoose($expected, $id, $number)\n {\n $translator = $this->getTranslator();\n\n $this->assertEquals($expected, $translator->trans($id, ['%count%' => $number]));\n }\n\n public function testReturnMessageIfExactlyOneStandardRuleIsGiven()\n {\n $translator = $this->getTranslator();\n\n $this->assertEquals('There are two apples', $translator->trans('There are two apples', ['%count%' => 2]));\n }\n\n /**\n * @dataProvider getNonMatchingMessages\n * @expectedException \\InvalidArgumentException\n */\n public function testThrowExceptionIfMatchingMessageCannotBeFound($id, $number)\n {\n $translator = $this->getTranslator();\n\n $translator->trans($id, ['%count%' => $number]);\n }\n\n public function getNonMatchingMessages()\n {\n return [\n ['{0} There are no apples|{1} There is one apple', 2],\n ['{1} There is one apple|]1,Inf] There are %count% apples', 0],\n ['{1} There is one apple|]2,Inf] There are %count% apples', 2],\n ['{0} There are no apples|There is one apple', 2],\n ];\n }\n\n public function getChooseTests()\n {\n return [\n ['There are no apples', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 0],\n ['There are no apples', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 0],\n ['There are no apples', '{0}There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 0],\n\n ['There is one apple', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 1],\n\n ['There are 10 apples', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 10],\n ['There are 10 apples', '{0} There are no apples|{1} There is one apple|]1,Inf]There are %count% apples', 10],\n ['There are 10 apples', '{0} There are no apples|{1} There is one apple|]1,Inf] There are %count% apples', 10],\n\n ['There are 0 apples', 'There is one apple|There are %count% apples', 0],\n ['There is one apple', 'There is one apple|There are %count% apples', 1],\n ['There are 10 apples', 'There is one apple|There are %count% apples', 10],\n\n ['There are 0 apples', 'one: There is one apple|more: There are %count% apples', 0],\n ['There is one apple', 'one: There is one apple|more: There are %count% apples', 1],\n ['There are 10 apples', 'one: There is one apple|more: There are %count% apples', 10],\n\n ['There are no apples', '{0} There are no apples|one: There is one apple|more: There are %count% apples', 0],\n ['There is one apple', '{0} There are no apples|one: There is one apple|more: There are %count% apples', 1],\n ['There are 10 apples', '{0} There are no apples|one: There is one apple|more: There are %count% apples', 10],\n\n ['', '{0}|{1} There is one apple|]1,Inf] There are %count% apples', 0],\n ['', '{0} There are no apples|{1}|]1,Inf] There are %count% apples', 1],\n\n // Indexed only tests which are Gettext PoFile* compatible strings.",
"\n ['There are 0 apples', 'There is one apple|There are %count% apples', 0],\n ['There is one apple', 'There is one apple|There are %count% apples', 1],\n ['There are 2 apples', 'There is one apple|There are %count% apples', 2],\n\n // Tests for float numbers\n ['There is almost one apple', '{0} There are no apples|]0,1[ There is almost one apple|{1} There is one apple|[1,Inf] There is more than one apple', 0.7],\n ['There is one apple', '{0} There are no apples|]0,1[There are %count% apples|{1} There is one apple|[1,Inf] There is more than one apple', 1],\n ['There is more than one apple', '{0} There are no apples|]0,1[There are %count% apples|{1} There is one apple|[1,Inf] There is more than one apple', 1.7],\n ['There are no apples', '{0} There are no apples|]0,1[There are %count% apples|{1} There is one apple|[1,Inf] There is more than one apple', 0],\n ['There are no apples', '{0} There are no apples|]0,1[There are %count% apples|{1} There is one apple|[1,Inf] There is more than one apple', 0.0],\n ['There are no apples', '{0.0} There are no apples|]0,1[There are %count% apples|{1} There is one apple|[1,Inf] There is more than one apple', 0],\n\n // Test texts with new-lines\n // with double-quotes and \\n in id & double-quotes and actual newlines in text\n [\"This is a text with a\\n new-line in it. ",
"Selector = 0.\", '{",
"0}This is a text with a\n new-line in it. ",
"Selector = 0.|{1}This is a text with a\n new-line in it. ",
"Selector = 1.|[1,Inf]This is a text with a\n new-line in it. ",
"Selector > 1.', ",
"0],\n // with double-quotes and \\n in id and single-quotes and actual newlines in text\n [\"This is a text with a\\n new-line in it. ",
"Selector = 1.\", '{",
"0}This is a text with a\n new-line in it. ",
"Selector = 0.|{1}This is a text with a\n new-line in it. ",
"Selector = 1.|[1,Inf]This is a text with a\n new-line in it. ",
"Selector > 1.', ",
"1],\n [\"This is a text with a\\n new-line in it. ",
"Selector > 1.\", '{",
"0}This is a text with a\n new-line in it. ",
"Selector = 0.|{1}This is a text with a\n new-line in it. ",
"Selector = 1.|[1,Inf]This is a text with a\n new-line in it. ",
"Selector > 1.', ",
"5],\n // with double-quotes and id split accros lines\n ['This is a text with a\n new-line in it. ",
"Selector = 1.', '{",
"0}This is a text with a\n new-line in it. ",
"Selector = 0.|{1}This is a text with a\n new-line in it. ",
"Selector = 1.|[1,Inf]This is a text with a\n new-line in it. ",
"Selector > 1.', ",
"1],\n // with single-quotes and id split accros lines\n ['This is a text with a\n new-line in it. ",
"Selector > 1.', '{",
"0}This is a text with a\n new-line in it. ",
"Selector = 0.|{1}This is a text with a\n new-line in it. ",
"Selector = 1.|[1,Inf]This is a text with a\n new-line in it. ",
"Selector > 1.', ",
"5],\n // with single-quotes and \\n in text\n ['This is a text with a\\nnew-line in it. ",
"Selector = 0.', '{",
"0}This is a text with a\\nnew-line in it. ",
"Selector = 0.|{1}This is a text with a\\nnew-line in it. ",
"Selector = 1.|[1,Inf]This is a text with a\\nnew-line in it. ",
"Selector > 1.', ",
"0],\n // with double-quotes and id split accros lines\n [\"This is a text with a\\nnew-line in it. ",
"Selector = 1.\", \"{",
"0}This is a text with a\\nnew-line in it. ",
"Selector = 0.|{1}This is a text with a\\nnew-line in it. ",
"Selector = 1.|[1,Inf]This is a text with a\\nnew-line in it. ",
"Selector > 1.\", ",
"1],\n // esacape pipe\n ['This is a text with | in it. ",
"Selector = 0.', '{",
"0}This is a text with || in it. ",
"Selector = 0.|{1}This is a text with || in it. ",
"Selector = 1.', ",
"0],\n // Empty plural set (2 plural forms) from a .PO file\n ['', '|', 1],\n // Empty plural set (3 plural forms) from a .PO file\n ['', '||', 1],\n ];\n }\n\n /**\n * @dataProvider failingLangcodes\n */\n public function testFailedLangcodes($nplural, $langCodes)\n {\n $matrix = $this->generateTestData($langCodes);\n $this->validateMatrix($nplural, $matrix, false);\n }\n\n /**\n * @dataProvider successLangcodes\n */\n public function testLangcodes($nplural, $langCodes)\n {\n $matrix = $this->generateTestData($langCodes);\n $this->validateMatrix($nplural, $matrix);\n }\n\n /**\n * This array should contain all currently known langcodes.",
"\n *\n * As it is impossible to have this ever complete we should try as hard as possible to have it almost complete.",
"\n *\n * @return array\n */\n public function successLangcodes()\n {\n return [\n ['1', ['ay', 'bo', 'cgg', 'dz', 'id', 'ja', 'jbo', 'ka', 'kk', 'km', 'ko', 'ky']],\n ['2', ['nl', 'fr', 'en', 'de', 'de_GE', 'hy', 'hy_AM']],\n ['3', ['be', 'bs', 'cs', 'hr']],\n ['4', ['cy', 'mt', 'sl']],\n ['6', ['ar']],\n ];\n }\n\n /**\n * This array should be at least empty within the near future.",
"\n *\n * This both depends on a complete list trying to add above as understanding\n * the plural rules of the current failing languages.",
"\n *\n * @return array with nplural together with langcodes\n */\n public function failingLangcodes()\n {\n return [\n ['1', ['fa']],\n ['2', ['jbo']],\n ['3', ['cbs']],\n ['4', ['gd', 'kw']],\n ['5', ['ga']],\n ];\n }\n\n /**\n * We validate only on the plural coverage. ",
"Thus the real rules is not tested.",
"\n *\n * @param string $nplural Plural expected\n * @param array $matrix Containing langcodes and their plural index values\n * @param bool $expectSuccess\n */\n protected function validateMatrix($nplural, $matrix, $expectSuccess = true)\n {\n foreach ($matrix as $langCode => $data) {\n $indexes = array_flip($data);\n if ($expectSuccess) {\n $this->assertEquals($nplural, \\count($indexes), \"Langcode '$langCode' has '$nplural' plural forms.\");",
"\n } else {\n $this->assertNotEquals((int) $nplural, \\count($indexes), \"Langcode '$langCode' has '$nplural' plural forms.\");",
"\n }\n }\n }\n\n protected function generateTestData($langCodes)\n {\n $translator = new class() {\n use TranslatorTrait {\n getPluralizationRule as public;\n }\n };\n\n $matrix = [];\n foreach ($langCodes as $langCode) {\n for ($count = 0; $count < 200; ++$count) {\n $plural = $translator->getPluralizationRule($count, $langCode);\n $matrix[$langCode][$count] = $plural;\n }\n }\n\n return $matrix;\n }\n}\n"
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[
"Carrie Remake Coming From The Writer Of Spider-Man: Turn Off The Dark\n\nStephen King is arguably the greatest American author of the modern era and even his worst books are usually infinitely readable. ",
"That’s not always true of the movies based on his books though, they tend to be either hot or cold. ",
"A movie based on a Stephen King story is likely to be the greatest thing you’ve ever seen or something you’ll forget five minutes after you walk out of the theater. ",
"Carrie stands firmly rooted in the former. ",
"So, here comes the remake.",
"\n\nReally if you’re going to remake a Stephen King movie, someone should take a stab at one of the bad ones. ",
"Surely there’s something better to be done with Dolan’s Cadillac than… whatever that was… they did with it in 2007. ",
"I’d really like a better movie made out of Secret Window. ",
"Sorry Johnny Depp, everyone has already forgotten you were ever in that flick. ",
"Instead Hollywood has entered the “remake all of King’s most famous stuff to make money based on name recognition” phase. ",
"They’re already knee-deep in remaking It and now here comes Carrie, again.",
"\n\nThe original 1976 movie starred Sissy Spacek as an introverted high school girl who after being tormented and humiliated peers, develops psychic powers which manifest when she’s angry or upset. ",
"This new version THR says is being developed by a partnership between MGM and Screen Gems. ",
"Here’s the strangest part of this news: They’ve hired the guy who wrote the oft mocked, utterly disastrous Spider-Man: Turn off the Dark Broadway play to rewrite it.",
"\n\nHis name is Roberto Aguirre-Sacassa, and his involvement isn’t as bad as it sounds. ",
"Aguirre-Sacassa didn’t actually come up with that ill-conceived Spidey Broadway disaster, he was the guy they brought in at the last minute in an attempt to rewrite it and fix it. ",
"He also once wrote a few episodes of Big Love and has written for Marvel comics. ",
"He even did their comic book adaptation of King’s The Stand, which ought to tell you how he landed this job."
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"Pages\n\nMonday, November 24, 2014\n\nA lot of learning took place, as well as some mostly \"local\" sharing via Twitter (hashtag #edjewcon), Today's Meet and a shared Google doc during Silvia Tolisano's brilliant keynote, The 5 C's in Jewish Education.",
"\n\nThe day was great. ",
"We had hoped for a larger crowd, but the 10-4 timeline on a (snowy) Sunday may have deterred people. ",
"We also need to work more on branding. ",
"It seems clear that there is a lack of understanding. ",
"What IS edJEWcon? ",
"Is it a technology conference? (",
"No!)",
"\nI did put together a trailer to try to explain, in general, what edJEWcon is about.",
"\n\nIt felt like a successful session but not a conversation. ",
"One thing I really love about going to share my work at other schools or conferences is the perspective it affords me. ",
"In my day-to-day reality, I am motivated to work hard by an awareness of how much better I can be, how much more there is to learn and do. ",
"It is like climbing a huge mountain without stopping, only focused on how far there still is left to climb.",
"\nSharing my work elsewhere is akin to taking the time to stop and review how much I've already done, to look back and appreciate that I've actually come a long way. ",
"It's something I never take time to do unless I find myself sharing the process with others who are interested.",
"\n\nIt felt gratifying to share our student blogfolios and student-led conferences with the teachers in Cleveland. ",
"They were impressed by our students' capacity for reflective self-evaluation, as well as the evidence of digital literacy (hyperlinked persuasive blog posts; Creative Commons images, properly cited) they saw on the student blogs.",
"\n\nI am left with these questions, needing more thought and discussion:\nWhy is it so challenging to get the whole learn-reflect-share cycle happening? ",
"Is it worth the effort? ",
"How can we create a structure that supports the entire process?",
"\n\nHow do we continue to grow these experiences for maximum impact on the learning culture at our schools? ",
"How do we build and sustain a network that exists beyond the in-person experience?",
"\n\nMonday, November 3, 2014\n\nPersonalized learning is a hot topic in education right now, emerging as one of the \"new forms\" of the modern era.",
"\n\nHow could learning NOT get more personalized, what with all of the apps, devices, search engines, maker spaces, genius hours, contests, global projects and authentic opportunities for learning, prevalent in the modern world?",
"\n\nYet the old forms stick like glue, holding us back from exploring ideas of what education could and should look like. ",
"Structures like grades, schedules, age-groupings, testing, even school itself must be critically examined. ",
"Do they still make sense?",
"\n\nIt may be cliche, but the saying \"out of the box\" really speaks to me. ",
"I feel that the old forms gained popularity and still hang on because they represent the alluring idea that education can be boxed, measured, and standardized. [",
"We thought the same thing could be done with nutrition, and look at what we are learning about the unhealthfulness of factory foods.]",
"\n\nWhy do we love boxes?",
"\n\nChris Lehman says that students should never be the implied object of their own education. ",
"Do you teach subject content or do you teach kids? ",
"Kids are not standardized. ",
"We need to stop pretending and start speaking truth.",
"Truth: My students, despite being born in a roughly 365-day span, have vastly different abilities, needs, interests and motivations. ",
"They come to me at varying stages of physical, emotional and academic development. ",
"This impacts what they are able to do in my language arts classroom.",
"\n\nYou wouldn't know it by looking at most schools, but acknowledging and accepting this is the easy part. ",
"Once we accept that learning is developmental and students have different needs, what are we going to do about it?",
"\nHow do we get from point A (think rows of desks, worksheets. ",
"teacher-centered, everyone doing the same thing, compliance, grades, etc.) ",
"to these \"new forms\" that so many of us are envisioning and working to create? ",
"How does personalized learning work within the old-school constructs within which most of us are forced to work?",
"\n\nThe key is embracing and creating environments where open-ended, unboxed constructs provide students opportunity for \"choice and voice as opposed to chore and bore, documenting growth (which we do at my school through student blogfolios), formative assessment, and trying things to see what works for each child. ",
"The role of the teacher has totally changed to more individual coaching and conferencing.",
"\n\nMany people say that they want students to be able to learn according to their passions, personalities, abilities and interests, yet they are terrified to let go enough to allow this. ",
"Many of us, parents and educators alike, want it all. ",
"We want our students to be able to learn out of the box, but we want to keep the box, too. ",
"We are so afraid of what will happen without it. ",
"Will our children be prepared for college? ",
"How often do we stop and ask ourselves what it even means to be educated?",
"\n\nWe can not have it both ways. ",
"We must decide where we stand and what we believe. ",
"If we believe in a student-centered, personalized approach, we have to let go of some of the old ways of doing things. ",
"We have to understand that learning is developmental, that we learn through practice. ",
"We have to allow the roles of both teacher and students to evolve and change.",
"\n\nLearning is messy, messy, messy. ",
"Any attempt to make it un-messy squeezes kids into unnatural confines that work for some, but not all, students."
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"BARC scientist breakthrough in making sea water drinkable\n\nAround 13 states in the sub-continent have already been affected by severe drought. ",
"The sweet-water (potable) reserves are degrading day by day due to overuse of these resources and pollution . ",
"To prevent such decrease in water, a group of scientist from the state of Tamil Nadu has resorted for converting the salty sea-water into usable potable drinking water. ",
"Three-fourth of the world being covered with sea, this innovation is sure to be a boon for all the farmers suffering in the drought affected regions.",
"\n\nThis scientist from Bhabha Atomic Research Centre (BARC) have developed a filtration process which is capable of converting groundwater with arsenic and other heavy meatls like uranium into water which can quench ever growing thirst. ",
"The new method implemented in a projevt is calculated to produce 6.3 million litres of water each day to fulfill the need of the people. ",
"The main plant is located at Kalapakkam in the state of Tamil Nadu. ",
"The plant is designed to use the wastes from the nuclear reactor to steer clear the saltiness present in sea water. ",
"The sea-water is hence cleaned and the water is desalinated to make it appropriate for drinking!",
"\n\nKN Vyas, from BARC is reported to say that many such plants will be set up across the sea belts of West Bengal, Punjab, Rajasthan and Maharashtra to make purified water available to these states. ",
"He further claimed that the membranes designed to purify underground water will also be setup and they will deliver water at a minimum cost. ",
"Special filters designed by this scientist with thin membranes are distributed among households of Marthawada in Maharashtra affected by drought, so that they can separate even the most miniscule contaminants from the water and hence make it fit for drinking!"
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"The Last of Us Remastered’s Photo Mode provides players with the tools to explore the savage beauty Naughty Dog’s post-apocalypse world from a new angle. ",
"The following is a series of pictures that capture scenes of high action, quiet reflection and are otherwise striking. ",
"Another gallery, exploring the Easter Eggs and oddities of The Last of Us and DLC Left Behind, is available here."
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"Plan B Goes Back In Time\n\nA Comedy Variety Show\n\n(Archive)\n\nThis show has closed and tickets are no longer available.",
"\n\nJune 16, 2018\n\nGrab your plutonium for your flux capacitor and join us as Plan B Comedy returns to the Z with their monthly and FINAL sketch comedy show before we move to our new home. ",
"We love these guys and you will too. ",
"Come check out their unique brand of quick, smart, fun comedy."
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[
"Q:\n\nFor a political ruler is it better to be loved or feared?",
"\n\nLet's suppose the title question applies especially (but not exclusively) in the context of a leadership role (where the goal is to sustain power) and for simplicity let's say the choice is strictly binary. ",
"What advantages and disadvantages does fostering each feeling offer in keeping power according to political philosophers?",
"\n\nA:\n\nThe question was made famous by Machiavelli's Prince, where he also provided the answer:\n\n\"The answer is that one would like to be both one and the other; but because it is difficult to combine them, it is far better to be feared than loved if you cannot be both... So, on this question of being loved or feared, I conclude that since some men love as they please but fear when the prince pleases, a wise prince should rely on what he controls, not on what he cannot control. ",
"He must only endeavor, as I said, to escape being hated.\"",
"\n\nMachiavelli's position is motivated by his dim view of human nature (\"One can make this generalization about men: they are ungrateful, fickle, liars, and deceivers, they shun danger and are greedy for profit\") and psychological observations about influencing human behavior (\"fear is strengthened by a dread of punishment which is always effective\"). ",
"Bismarck, the unifier of Germany, declared in the same spirit in a speech from 1862:\n\n\"The position of Prussia in Germany will not be determined by its liberalism but by its power... Not through speeches and majority decisions will the great questions of the day be decided... but by iron and blood (Eisen und Blut)\". ",
"\n\nRussian poet Tyutchev responded romantically:\n\n\"From Lord's chalice overflowing with wrath\n The blood pours over the edge, and the West is drowning.",
"\n The blood will gush on you as well, our friends and brothers! —",
"\n Pull closer together, the Slavic world…\n “Unity, proclaimed the Oracle of our days, —\n Can only be soldered with iron and blood…”\n But we will try to solder it with love, —\n And we shall see what’s stronger…\" \n\nAlas, the Slavic world saw it soon enough, the hard way. ",
"But even Machiavelli already noted limitations of force and fear, for even they can be overcome by intense enough hate. ",
"This sentiment is seconded by a Spanish proverb anecdotally attributed to another political cynic mentoring a ruler, Talleyrand to Napoleon:\"Sire, you may lean on the bayonets, but you can not sit on them!\"",
"\nFrom modern perspective, Machiavelli perhaps underestimated,understandably for his simpler times, the possibilities of mental manipulation on a mass scale, which can instill \"love\" just as readily as fear. ",
"That realization was left to dystopias, like Orwell's 1984, the Nazi propaganda minister Goebbels and his communist counterparts. ",
"If we accept Machiavelli's core thesis, that a ruler should rely on what he controls, but take into account the last century's achievements in propagandistic brainwashing, with its more lasting effects and reduced resentments, we should probably take \"love\" over fear. ",
"But practitioners of such \"love\" never neglected fear either, as Orwell describes it:\n\n\"A hideous ecstasy of fear and vindictiveness, a desire to kill, to torture, to smash faces in with a sledgehammer, seemed to flow through the whole group of people like an electric current, turning one even against one's will into a grimacing, screaming lunatic.\"",
"\n\nA:\n\nSince Machiavelli has quite naturally come up (se sia meglio esser temuti piuttosto che amati) let's develop his line of thought. ",
"Machiavelli does not address this question in isolation but in the context of his concept of human nature informed as usual by reflection on Roman history and the Medici. ",
"\n\nHuman nature is also depraved and short sighted. '",
"As is demonstrated\n by all those who consider the well-ordered state - and history is full of\n examples - it is necessary for him who lays out a republic and arranges\n laws in it to presuppose that all men are evil and they will always act\n with the wickedness of their spirits whenever they have the chance.'",
"\n For Machiavelli, human wickedness is a consistent axiom that informs\n all of his analyses.",
"\nThe certainty of selfishness is not only something a lawgiver should\n bear in mind in a republican context but also equally central to the\n maintenance of princely governments. ",
"In II Principe, Machiavelli\n observes that princes should not always practise the traditional virtues\n because they are an ethical code that invites self-destruction in a world\n of permanently self-interested citizens. ",
"He concludes that it is better\n to be feared than loved 'because we can say this generally about men:\n they are ungrateful, fickle, simulators and dissimulators, shirkers of\n danger, eager for gain ... [and] because love is held by a chain of duty\n which, since men are bad, they break at every chance for their own\n profit, but fear is held by a fear of punishment that never abandons\n you'. ",
"The conviction of permanent human weakness is central to the\n Istorie florentine, the Capitolo dell ambizione and La Mandragola.",
"\nBecause men never do good except by necessity, fear becomes a\n crucial element in the proper configuration of the city. ",
"Machiavelli\n argues that the tyranny of the Tarquins had the beneficial effect of\n keeping the nobility humble, since they feared the Tarquins and\n therefore had to respect the people, who might not take the noble's\n side if treated badly. ",
"The people realised this only after the expulsion\n of the Tarquins. ",
"Since the people no longer had a powerful ally, the\n nobles were no longer compelled to respect them and spat 'out against\n the people the poison they had kept in their breasts, and injured them\n in any way they could'. ",
"In place of the expelled Tarquins, Rome\n needed an institution that the nobles would fear as much as they had\n Tarquinian autocracy - hence the creation of the Tribunes of the\n People, who not only had the power to forbid decrees by noble\n magistrates but also had the authority to have put to death anyone who\n obstructed the proper exercise of their office - in short, people whom\n the Roman nobles had very good reason to fear. ",
"Without such fear, they could \n always be counted on to rule according to destructive\n factional interests.",
"\nMachiavelli returns to the constitutive role of fear in his discussion of\n the importance of political renovation. ",
"By 'renovation', he refers to the\n process by which people's fear of transgressing the law is periodically\n re-established, and the most reliable process is draconian punishment,\n whether in ancient Rome or contemporary Florence. ",
"He praises the\n salutary effects on the Roman people of the republic's frequent use of\n the death penalty. ",
"In the Florentine example, Machiavelli notes that\n the Medici and their partisans often remarked that every five years they\n needed to retake the state or risk losing power. ",
"He then elaborates on\n the meaning of 'ripigliare': as the Mediceans used the term, it meant\n restoring that same sense of terror and fear in the people as they had\n initially inspired on first seizing the government. '",
"When the memory of\n such punishment disappears, men take courage to attempt innovations\n and to speak evil ...' John Najemy has argued that this passage\n parodies the concept of cycles, but nothing about it appears satirical - it\n is merely an extension of Machiavelli's frank recognition of the necessity\n of fear in a well-ordered state. (",
"Mark Jurdjevic, 'Machiavelli's Hybrid Republicanism', The English Historical Review, Vol. ",
"122, No. ",
"499 (Dec., 2007), pp. ",
"1238-9.)",
"\n\nMACHIAVELLI AND THE DIVERSITY OF POLITICS\nNote that Machiavelli does not address his question to politics in a crude or blank way. ",
"He weaves it through a variety of situations. ",
"His answer, he thinks, namely that it is better to be feared than loved, applies to republics as well as to princedoms and to conditions both of stability and of renovation. ",
"\nREFERENCES\nMark Jurdjevic, 'Machiavelli's Hybrid Republicanism', The English Historical Review, Vol. ",
"122, No. ",
"499 (Dec., 2007), pp. ",
"1228-1257.",
"\nJ. M. Najemy, 'Machiavelli and the Medici: The Lessons of Florentine History', Renaissance Quarterly, xxxv (1982), 551-76.",
"\nL. Strauss, Thoughts on Machiavelli, Glencoe, 1958. (",
"Don't be put off by the book's age; Strauss was an acute scholar whose work retains a good deal of value.)",
"\n\n"
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"Q:\n\nEmber component libraries\n\nI've come across a few Ember component libraries but don't see much activity in their repositories. ",
"This is raising some doubt as to whether I should use one in a brand new project.",
"\nAre people still using component libraries in new [Ember CLI] projects?",
"\nExample component libraries I've found:\n\nEmber Components\nEmber UI\nEmber Widgets\n\nAny experience with any of these lately? ",
"Any new kids on the block? ",
"\nOr are you creating your own components as required?",
"\n\nA:\n\nThere's not a perfect answer to this question. ",
"However, there are some factors I weigh when deciding whether or not to use a component library and which one:\n\nDo I need it? ",
"Ember has a number of built-in helpers (for example input helpers) that can often do what needs to be done.",
"\nHow many of the components that ship with the library will I use? ",
"There's nothing to gain by unnecessarily adding page weight, it will only degrade users' experience.",
"\nHow easy is each component to override/extend? ",
"In my experience, it's inevitable when using a component library that there will be something that doesn't work the way I need it to. ",
"So it's critical the components can be extended or overridden.",
"\nDoes the library ship with CSS? ",
"If so, is it well written and/or optional? ",
"Libraries that ship with their own styles can be a pain because the styles will likely not match the aesthetic of your application. ",
"How well the styles are written determines how much hacking you'll have to do in order to achieve the result you want.",
"\nHow active is the development and how many stars does it have on GitHub? ",
"If the library doesn't have a lot of active support, it's likely going to quickly get outdated. ",
"This can paint you into a corner if you want to upgrade ember itself and the component library is no longer compatible. ",
"It can be a significant effort to remove/replace one of these libraries.",
"\n\nThere are probably more things to consider, but my point is the decision should be well thought out and deeply question whether or not you need a component library at all.",
"\n\nI have used ember-material-lite extensively. ",
"It's a good option if you want to follow Google's Material Design spec. ",
"Another nice thing about it is you can easily override both the component JS and Handlebars files for each component in your application to extend/modify their behavior.",
"\n\n"
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"After years of hardship, America’s middle class has gotten some positive news in the last few months. ",
"The country’s economic recovery is gaining steam, consumer spending is starting to tick up (it grew at more than 4 % last quarter), and even wages have started to improve slightly. ",
"This has understandably led some economists and analysts to conclude that the shrinking middle phenomenon is over.",
"\n\nAt the risk of being a Cassandra, I’d argue that the factors that are pushing the recovery and working in the favor of the middle class right now—lower oil prices, a stronger dollar, and the end of quantitative easing—are cyclical rather than structural. (",
"QE, Ruchir Sharma rightly points out in The Wall Street Journal, actually increased inequality by boosting the share-owning class more than anyone else.) ",
"That means the slight positive trends can change—and eventually, they will.",
"\n\nThe piece of economic data I’m most interested in right now is actually a new report from Wallace Turbeville, a former Goldman Sachs banker and a senior fellow at think tank Demos, which looks at the effect of financialization on economic growth and the fate of the working and middle class. ",
"Financialization, a topic which I’m admitted biased toward since I’m writing a book about it, is the way in which the markets have come to dominate the economy, rather than serving them.",
"\n\nThis includes everything from the size of the financial sector (still at record highs, even after the financial crisis and bailouts), to the way in which the financial markets dictate the moves of non-financial businesses (think “activist” investors and the pressure around quarterly results). ",
"The rise of finance since the 1980s has coincided with both the shrinking paycheck of most workers and a lower number of business start-ups and growth-creating innovation.",
"\n\nThis topic has been buzzing in academic circles for years, but Turberville, who is aces at distilling complex economic data in a way that the general public can understand, goes some way toward illustrating how the economic and political strength of the financial sector, and financially driven capitalism, has created a weaker than normal recovery. (",
"Indeed, it’s the weakest of the post war era.) ",
"His work explains how financialization is the chief underlying force that is keeping growth and wages disproportionately low–offsetting much of the effects of monetary policy as well as any of the temporary boosts to the economy like lower oil or a stronger dollar.",
"\n\nI think this research and what it implies—that finance is a cause, not a symptom of weaker economic growth—is going to have a big impact on the 2016 election discussion. ",
"For starters, if you believe that the financial sector and non-productive financial activities on the part of regular businesses—like the $2 trillion overseas cash hoarding we’ve heard so much about—is a cause of economic stagnation, rather than a symptom, that has profound implications for policy.",
"\n\nFor example, as Turberville points out, banks and policy makers dealt with the financial crisis by tightening standards on average borrowers (people like you and me, who may still find it tough to get mortgages or refinance). ",
"While there were certainly some folks who shouldn’t have been getting loans for houses, keeping the spigots tight on average borrowers, which most economists agree was and is a key reason that the middle class suffered disproportionately in the crisis and Great Recession, doesn’t address the larger issue of the financial sector using capital mainly to enrich itself, via trading and other financial maneuvers, rather than lending to the real economy.",
"\n\nFormer British policy maker and banking regular Adair Turner famously said once that he believed only about 15 % of the money that followed through the financial sector went back into the real economy to enrich average people. ",
"The rest of it merely stayed at the top, making the rich richer, and slowing economic growth. ",
"This Demos paper provides some strong evidence that despite the cyclical improvements in the economy, we’ve still got some serious underlying dysfunction in our economy that is creating an hourglass shaped world in which the fruits of the recovery aren’t being shared equally, and that inequality itself stymies growth.",
"\n\nThe Leadership Brief. ",
"Conversations with the most influential leaders in business and tech. ",
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"Sign Up Now Check the box if you do not wish to receive promotional offers via email from TIME. ",
"You can unsubscribe at any time. ",
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"\n\nContact us at [email protected]."
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"Q:\n\nASP.net weird grid view behavior\n\nI am working in visual studio 2010 creating a ASP web application. ",
"I am trying to implement a search function with a grid view, where I will be passing in an ADO select command into a dataset and filling up the datagrid with my desired SQL. ",
"I know this is possible for winforms and datagridviews but for some reason, it is acting strangely on my ASP application. ",
"Here is some code...\n protected void btn_search_Click(object sender, EventArgs e)\n {\n SqlConnection cs = new SqlConnection(\"Data Source=WILSON-PC; Initial Catalog=KamManOnline; Integrated Security=TRUE\");\n SqlDataAdapter da = new SqlDataAdapter();\n DataSet ds = new DataSet();\n\n da.",
"SelectCommand = new SqlCommand(\"SELECT * FROM vw_orderView WHERE Supplier = @Supplier\", cs);\n\n da.",
"SelectCommand.",
"Parameters.",
"Add(\"@Supplier\", SqlDbType.",
"VarChar).Value = ddl_SupplierView.",
"Text.",
"ToString();\n ds.",
"Clear();\n\n da.",
"Fill(ds);\n gv_search.",
"DataSource = ds.",
"Tables[0];\n gv_search.",
"DataBind();\n\n }\n\nWhat happens is it picks out the right amount of data but does not show it on the grid view. ",
"For example, say if I had 3 fields as Wilson for the supplier. ",
"When I click my search button, it would bring out 3 rows but they are empty. ",
"Any ideas or another way to walk around this? ",
"Thanks!",
"\nP.S. I tried using the databind wizard but eventrually I want more flexability in my search, for example\nSELECT * FROM vw_orderView WHERE (Supplier = @Supplier OR @Supplier IS NULL). ",
"\n\nI tried writing this in the query builder but I need to add some if condition to say whether supplier will have a value or be null (check box). ",
"If this is the right approach, then please say so. ",
"Thanks\n\nA:\n\nI would do the following to troubleshoot.",
"\n\nRun the query directly from SSMS to verify that you get back the results you expect.",
"\nMake sure the GridView has AutoGenerateColumns=true if you are not manually defining Columns.",
"\nRun in debug mode with a breakpoint set on ds.",
"Clear() and inspect the freshly added Parameter to see that it contains the value you expect.",
"\n\n"
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"Alabama House committee kills LGBT civil rights bill\n\nA House committee Wednesday killed a bill that would have banned discrimination against individuals based on their sexual orientation or gender identity.",
"\n\nThe legislation, sponsored by Rep. Christopher England, D-Tuscaloosa, would have added the classes to state protections against discrimination in employment, housing, accommodations, financial transactions and voting.",
"\n\n\"I believe in order to protect those classifications, they need to be enumerated,\" England told the House Judiciary Committee Wednesday afternoon. \"",
"There is some case history that if it's not enumerated, it's not protected.\"",
"\n\nThe committee voted to carry it over, killing it for the remainder of the session. ",
"Rep. David Faulkner, R-Mountain Brook, who moved to have it carried over, said he \"did not want anyone discriminated against,\" but said that he had concerns about how the legislation would interact with existing statutes in Alabama.",
"\n\n\"It's creating a new protected class that our nation does not recognize, much less Alabama,\" he said. \"",
"When you are talking about those types of issues, this is much larger than marriage. ",
"This is far broader than that.\"",
"\n\nEngland and other supporters were upbeat about the result following the vote.",
"\n\n\"This is a process,\" said Rep. Patricia Todd, D-Birmingham, the director of the Human Rights Campaign Alabama and the only openly gay member of the Legislature. \"",
"I guess I've been here nine years now. ",
"We haven't passed any bad legislation, and that's great. ",
"Alabama is further ahead than Arkansas, Texas and other states. ",
"But now it's time to move forward with some positive legislation that protects people in the workplace, and that's what this bill would do.\"",
"\n\nThe HRC last year announced a campaign throughout the Deep South to put discrimination protections in place for gay, lesbian, bisexual and transgender people. ",
"The campaign got a boost in December when Apple CEO Tim Cook, a Robertsdale native and Auburn graduate, criticized Alabama's slow progress on LGBT rights in a speech at the State Capitol.",
"\n\nSenate President Pro Tem Del Marsh, R-Anniston and Rep. Mike Ball, R-Huntsville, have both introduced pieces of legislation that would ban discrimination against LGBT state workers. ",
"Ball's bill – which bans discrimination based on a \"trait or characteristic, immutable or otherwise\" unrelated to work performance – was approved by the House Judiciary Committee Tuesday. ",
"Unlike those bills, England's legislation would have covered the private sector as well.",
"\n\nAll the bills were introduced late in the session and face long odds of passage. ",
"Todd said she \"appreciated the sentiment\" of Ball's bill, but said it would be problematic.",
"\n\n\"It is so broad I can imagine courts having no way to rule whether anything was discrimination or not,\" she said. \"",
"What if you don't shower often and you come to work? ",
"You can't be fired for that?",
"\n\nEngland said he would be happy to work with other lawmakers on the bill. ",
"The representative said he thought an expected U.S. Supreme Court decision on same-sex marriage in late June could change people's minds.",
"\n\n\"I think there's inevitability behind this particular piece of legislation,\" he said. \"",
"As days go by, months go by the Supreme Court decision this summer, I think you'll see a wide perspective change in Alabama.\""
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"Q:\n\nSimple Oracle query hangs depending on WHERE clause\n\nNot used to using Oracle, but we have a large database where a non-unique query like\nSELECT * FROM employees where department = 'HR' \n\nis working, results list up no problem.",
"\nBut when I do \nSELECT * FROM employees where employeeID = '3HVtxO-F3004728F87EF61E' \n\nthe oracle database query is hanging (I am expecting one record to come back, and I am certain it exists because I copy pasted the employeeID from another query).",
"\nFor the columns, only difference between the two is:\ndepartment is VARCHAR2(25) NULL\nemployeeID is VARCHAR2(50) NULL\n\nAlso department would have many matches while employee ID would most likely have 1 (I can't see that it is particularly defined to be unique in the table definition).",
"\nOther table characteristics: \n\nnot actually an employee table, it has work related data so I renamed it here...\ncontains more than a million rows and a few dozen columns\na bit of an old database, not sure who designed it at work ages ago, could have database integrity / indexing issues? ",
" \na regular select * from employees with no where clause would not work either because it freezes up around the half a million rows found mark.",
"\n\nAny idea why this could be happening? ",
"Should I design my query better? ",
" How would you recommend diagnosing some issue related to problems with the database itself? ",
" Trying to get a hang of this oracle database but a bit awkward to get used to since a simple query which should return one item is hanging. ",
" Thank you.",
"\nUpdate 1:\nResponding to comments, there is no indexing for this column. ",
" Fortunately this is an outdated table which will not be in use at all, with a new version being made which will have indexed columns, so I think this was one issue.",
"\nRegarding the plan for the second query, it looks like:\nPlan hash value: 123724717\n\n------------------------------------------------------------------------------------------------\n| Id | Operation | Name | Rows | Bytes | Cost (%CPU)| Time | Pstart| Pstop |\n------------------------------------------------------------------------------------------------\n| 0 | SELECT STATEMENT | | 12 | 4416 | 2376K (1)| 07:55:19 | | |\n| 1 | PARTITION RANGE ALL| | 12 | 4416 | 2376K (1)| 07:55:19 | 1 | 14 |\n|* 2 | TABLE ACCESS FULL | [Employee| 12 | 4416 | 2376K (1)| 07:55:19 | 1 | 14 |\n------------------------------------------------------------------------------------------------\n\nQuery Block Name / Object Alias (identified by operation id):\n-------------------------------------------------------------\n\n 1 - SEL$1\n 2 - SEL$1 / Employees@SEL$1\n\nPredicate Information (identified by operation id):\n---------------------------------------------------\n\n 2 - filter(\"EmployeeID\"='3R5MMN-0F9345L9IK8A349A043')\n\nColumn Projection Information (identified by operation id):\n-----------------------------------------------------------\n-- The list of all the columns follows.",
"\n\nMy guess is that this is just a really awefully designed table and not designed to have gotten so big, or for someone to actually use a lot :) For practical purposes, I will move on to more recent incarnations of this table which will have indexing and hopefully that will fix it.",
"\n\nA:\n\nfollowing the advice of a_horse_with_no_name,\n\nPlease show us the execution plan for the second query –\n a_horse_with_no_name 4 hours ago\n\nI have posted the relevenat parts of the execution plan... however I can't make heads or tails of what is wrong with it from that.... \nI followed Mat's advice and guess that lack of indexing is the issue. ",
" Because there is no indexing, it must be as Matt says, that this simple query is doing a full table scan, which could take longer than the few minutes I have been waiting for the query to complete...\nUseful link about the concept of indexing: http://www.orafaq.com/node/1403\n\nIs that column indexed? ",
"Otherwise you'll get a full table scan, which\n can take a while if the table is big. – ",
"Mat 7 hours ago\nselect index_name, column_name from dba_ind_columns where index_owner\n = 'THE_SCHEMA' and table_name = 'YOUR_TAB' order by index_name will get you all the indexed columns. ",
"Look at the explain plan to see what\n it is doing (look into set autotrace or use a GUI that has that\n feature, like sqldeveloper) – Mat 7 hours ago\n\nThanks for your help guys. ",
" Let me know if I might be wrong in that assumption, or if you might have additional insight a_horse_with_no_name.... \n\n"
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"We'll fight for you in court: That is what the Texas attorney general is telling San Jacinto County after county leaders voted to maintain crosses at their courthouse over the threats of an atheist group.",
"\n\nThe Wisconsin-based Freedom from Religion Foundation contacted San Jacinto County Judge Fritz Faulker last month, telling him that a local resident complained about the crosses on the courthouse located in Coldspring, Texas.",
"\n\nThe crosses, four in total, are located on upper windows and are lit during the Christmas season.",
"\n\nAn attorney with FFRF told TV news station KPRC-TV that the crosses represent “a constitutional violation of the Establishment Clause.\"",
"\n\nPaxton\n\nEarlier this week, county commissioners voted unanimously to keep the crosses despite the threats from FFRF.",
"\n\nSan Jacinto County, located north of Houston, has a population of approximately 28,000. ",
"The county seat of Coldspring is home approximately to 900 people.",
"\n\nIn its letter to San Jacinto County, the Office of Attorney General Ken Paxton told their fellow Texans that FFRF seeks to impose its anti-religion agenda through intimidation tactics, and while the organization threatens more than it sues, if often loses when it does go through with a lawsuit.",
"\n\n\"We want to make it clear that your county may display historical religious symbols, like crosses, without violating the Establishment Clause of the First Amendment,” the letter assures the county officials.",
"\n\n“You should know,” the letter continues, “that you can reject FFRF's demand to impose its anti-religion bias against San Jacinto County.”"
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[
"At a budget update on Thursday, Finance Minister Karen Casey was vague about whether that decision will end up costing taxpayers\n\nAs the province declares a localized state of emergency in hopes of speeding up the removal of Halifax's infamous downed crane, it's still not clear how much of the cost will be footed by taxpayers.",
"\n\nGovernment announced Wednesday it was taking over liability of the crane, which will allow their officials to oversee its safe and timely removal.",
"\n\nBut at a budget update on Thursday, Finance Minister Karen Casey was vague about whether that decision will end up costing taxpayers.",
"\n\n\"Whenever there's anything affecting the safety and health of Nova Scotians, I would support that,\" said Casey. \"",
"If there are financial implications after that, that would be something we have to assume and we'll have to review as those come in.\"",
"\n\nCasey would not say if the province had done a financial analysis.",
"\n\n\"There's nothing in the (budget) update to respond to that because we don't have that, but it will be in the next update and I expect there will be other things that come in as a result of the damages from the hurricane,\" said Casey.",
"\n\nTwo days after the crane collapsed, several residents and businesses in the area were evacuated by Halifax Regional Municipality Fire and Emergency Services and haven't yet been allowed to return to their homes or stores.",
"\n\nThe crane is owned and operated by Lead Structural Formworks Ltd. The building it collapsed on is a site operated by WM Fares Group.",
"\n\nWith files from Matthew Moore"
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[
"If you want to share a pic of someone who looks like either a jam band fan or a member of the Taliban, please email me."
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"A systematic review and meta-analysis of the criterion validity of nutrition assessment tools for diagnosing protein-energy malnutrition in the older community setting (the MACRo study).",
"\nMalnutrition is a significant barrier to healthy and independent ageing in older adults who live in their own homes, and accurate diagnosis is a key step in managing the condition. ",
"However, there has not been sufficient systematic review or pooling of existing data regarding malnutrition diagnosis in the geriatric community setting. ",
"The current paper was conducted as part of the MACRo (Malnutrition in the Ageing Community Review) Study and seeks to determine the criterion (concurrent and predictive) validity and reliability of nutrition assessment tools in making a diagnosis of protein-energy malnutrition in the general older adult community. ",
"A systematic literature review was undertaken using six electronic databases in September 2016. ",
"Studies in any language were included which measured malnutrition via a nutrition assessment tool in adults ≥65 years living in their own homes. ",
"Data relating to the predictive validity of tools were analysed via meta-analyses. ",
"GRADE was used to evaluate the body of evidence. ",
"There were 6412 records identified, of which 104 potentially eligible records were screened via full text. ",
"Eight papers were included; two which evaluated the concurrent validity of the Mini Nutritional Assessment (MNA) and Subjective Global Assessment (SGA) and six which evaluated the predictive validity of the MNA. ",
"The quality of the body of evidence for the concurrent validity of both the MNA and SGA was very low. ",
"The quality of the body of evidence for the predictive validity of the MNA in detecting risk of death was moderate (RR: 1.92 [95% CI: 1.55-2.39]; P < 0.00001; n = 2013 participants; n = 4 studies; I2: 0%). ",
"The quality of the body of evidence for the predictive validity of the MNA in detecting risk of poor physical function was very low (SMD: 1.02 [95%CI: 0.24-1.80]; P = 0.01; n = 4046 participants; n = 3 studies; I2:89%). ",
"Due to the small number of studies identified and no evaluation of the predictive validity of tools other than the MNA, there is insufficient evidence to recommend a particular nutrition assessment tool for diagnosing PEM in older adults in the community. ",
"High quality diagnostic accuracy studies are needed for all nutrition assessment tools used in older community samples, including measuring of health outcomes subsequent to nutrition assessment by the SGA and PG-SGA."
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"Unsaturated fatty acids and cyclooxygenase inhibitors: effects on pial arterioles.",
"\nCerebral surface arterioles of the mouse were constricted in a dose-dependent manner by three different unsaturated fatty acids each with one of its double bonds in the n-6 position: arachidonate, linoleic, and 11,14,17-eicosatrienoic acid (ETA) in doses of 10-200 micrograms/ml. ",
"The constriction was transient, and its magnitude was significantly reduced by pretreatment of the mice with intraperitoneal injections of indomethacin (5 mg/kg), aspirin (100 mg/kg), or sodium 2-amino-3-(4 chlorobenzyl)-phenylacetate (AHR-6293, 100 mg/kg). ",
"The inhibitory effect of these cyclooxygenase inhibitors suggests that this enzyme is involved in the response to these fatty acids and is in keeping with suggestions in the literature stating that such unsaturated fatty acids may interact with cyclooxygenase even when they cannot form prostaglandin (PG) endoperoxides, The PG endoperoxide formed by arachidonate or the analogous hydroperoxy compounds formed by linoleic or 11,14,17 ETA, may then alter cerebrovascular tone by production of reactive, O2-containing species. ",
"Alternate explanations for the data are also proposed."
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"war game miniature are about 28mm~32mm ... that next on my sculpting list .......the chick with the flack cannon ... just that she will be in armor and the cannon will be smaller . ",
"if not i don't think she can stand if the miniature base is not metal."
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"High resolution UV roll-to-roll nanoimprinting of resin moulds and subsequent replication via thermal nanoimprint lithography.",
"\nUV roll-to-roll nanoimprinting at high resolution is still a relatively unexplored field of study with far-reaching application potential. ",
"One enabling technology that is particularly worthy of attention is mass production of high resolution resin moulds via UV roll-to-roll nanoimprinting at such high throughput and low cost that they can be used only once and disposed of or recycled economically. ",
"Low cost, high resolution resin moulds can greatly improve the production cost profile for a number of applications in biomedicine, nanofluidics, data storage and electronics with relatively low unit values but which require one or more nanoscale lithography steps. ",
"In this report, UV roll-to-roll nanoimprinting was employed to fabricate high fidelity resin moulds with nanoscale as well as mixed micro- and nanoscale features down to 50 nm feature diameter, at up to 120 cm(2) area and at 10 m min(-1) throughput. ",
"UV roll-to-roll nanoimprinted resin moulds were subsequently segmented out, employed in a batch mode thermal nanoimprinting process, and characterized to study performance and demonstrate viability. ",
"The results show that high resolution mixed nanostructures can be faithfully replicated in PMMA on silicon substrates with minimal volumetric shrinkage. ",
"Process details and challenges specific to roll-to-roll fabrication of resin moulds are discussed at length, particularly with respect to the curvature uniformity of the imprint roller."
] | {
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"Key elements of interventions for heart failure patients with mild cognitive impairment or dementia: A systematic review.",
"\nThe purpose of this systematic review was to (a) examine the effects of interventions delivered by a heart failure professional for mild cognitive impairment and dementia on cognitive function, memory, working memory, instrumental activities of daily living, heart failure knowledge, self-care, quality of life and depression; and (b) identify the successful elements of these strategies for heart failure patients with mild cognitive impairment or dementia. ",
"During March 2018, an electronic search of databases including CINAHL, MEDLINE, EMBASE and PsycINFO was conducted. ",
"All randomised controlled trials, which examined an intervention strategy to help heart failure patients with mild cognitive impairment or dementia cope with self-care, were included. ",
"An initial search yielded 1622 citations, six studies were included (N= 595 participants, mean age 68 years). ",
"There were no significant improvements in cognitive function and depression. ",
"However, significant improvements were seen in memory (p=0.015), working memory (p=0.029) and instrumental activities of daily living (p=0.006). ",
"Nurse led interventions improved the patient's heart failure knowledge (p=0.001), self-care (p<0.05) and quality of life (p=0.029). ",
"Key elements of these interventions include brain exercises, for example, syllable stacks, individualised assessment and customised education, personalised self-care schedule development, interactive problem-solving training on scenarios and association techniques to prompt self-care activities. ",
"Modest evidence for nurse led interventions among heart failure patients with mild cognitive impairment or dementia was identified. ",
"These results must be interpreted with caution in light of the limited number of available included studies."
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[
"Q:\n\nShow that $\\sum_{n=1}^{\\infty} \\frac{(-1)^{n}}{n^{2}}\\cos nx=\\frac{1}{12}(3x^{2}-\\pi^2)$ for $-\\pi \\leq x \\leq \\pi $\n\nHow do we show that for $-\\pi \\leq x \\leq \\pi $,\n$$\\sum_{n=1}^{\\infty} \\frac{(-1)^{n}}{n^{2}}\\cos nx=\\frac{1}{12}(3x^{2}-\\pi^2)$$\nI know that without $(-1)^{n}$ term, the series converges to $\\frac{x^{2}}{4}-\\frac{\\pi x }{2}+\\frac{\\pi^{2}}{6}$ for $x$ in $[0,2\\pi]$. But I'm not sure how to find the sum if there is a $(-1)^{n}$ term there.",
"\nThank you for your help!",
"\n\nA:\n\nYou could use the Fourier Series of $f(x)=\\frac1{12}(3x^2-\\pi^2)$ in $[-\\pi,\\pi].$\n$$f(x)=\\frac{a_0}2+\\sum_{n=1}^\\infty[a_n\\cos(nx)+b_n\\sin(nx)]$$where$$a_{n\\ge0}=\\frac1\\pi\\int_{-\\pi}^\\pi f(x)\\cos(nx)~dx=\\frac1{12\\pi}\\int_{-\\pi}^\\pi(3x^2-\\pi^2)\\cos(nx)~dx$$For $n=0$,$$a_0=\\frac1{6\\pi}[x^3-\\pi^2x]_0^\\pi=0$$For $n\\ge1$,\n$a_n=\\frac1{12\\pi}\\left\\{\\left[(3x^2-\\pi^2)\\int\\cos(nx)~dx\\right]_{-\\pi}^\\pi-6\\int_{-\\pi}^\\pi x\\int\\cos(nx)~dx~dx\\right\\}\\\\=-\\frac1{n\\pi}\\int_0^\\pi x\\sin(nx)~dx=-\\frac1{n\\pi}\\left\\{\\left[x\\int\\sin(nx)~dx\\right]^\\pi_0-\\int_0^\\pi\\int\\sin(nx)~dx\\right\\}\\\\=\\frac{\\cos(n\\pi)}{n^2}$\nand$$b_{n\\ge1}=\\frac1\\pi\\int_{-\\pi}^\\pi f(x)\\sin(nx)~dx=0~\\forall n.$$\nSince $f(x)$ is continuous in the given domain, the Fourier series$$\\sum_{n=1}^\\infty\\frac{(-1)^n}{n^2}\\cos(nx)$$will converge to $f(x)$ for each point due to Dirichlet conditions.",
"\n\nA:\n\nDenote $f(x)= \\sum_{n=1}^{\\infty} \\frac{(-1)^{n}}{n^{2}}\\cos nx$. Then,\n$$f(0)= \\sum_{n=1}^{\\infty} \\frac{(-1)^{n}}{n^{2}}=-\\frac{\\pi^2}{12} $$\n\\begin{align}\nf’(x) & = -\\sum_{n=1}^{\\infty} \\frac{(-1)^{n}}{n}\\sin nx\n=\\frac1{2i}\\sum_{n=1}^{\\infty}(-1)^{n+1}\\frac{e^{ixn }-e^{-ixn }}{n}\\\\\n&=\\frac1{2i}[\\ln(1+e^{ix })-\\ln (1+e^{-ix })]\\\\\n& =\\frac1{2i}\\ln \\frac{1+e^{ix}} {1+e^{-ix}}\n=\\frac1{2i}\\ln e^{ix}\n=\\frac{x}{2}\\\\\n\\end{align}\nThus\n$$\\sum_{n=1}^{\\infty} \\frac{(-1)^{n}}{n^{2}}\\cos nx\n= f(0) + \\int_0^x f’(t)dt = \\frac{1}{12}(3x^{2}-\\pi^2)$$\n\nA:\n\nLet $f(x;\\lambda)$ be given by the series\n$$f(x;\\lambda)=-\\sum_{n=1}^\\infty \\lambda^n e^{inx}\\tag1$$\nfor $|\\lambda|<1$.\n\nSumming the geometric series in $(1)$ we find that for $|\\lambda|<1$\n$$f(x;\\lambda)=\\frac{\\lambda e^{ix}}{\\lambda e^{ix}-1}\\tag2$$\n\nExploiting the uniform convergence of $\\sum_{n=1}^\\infty \\lambda^n e^{inx}$ for $\\lambda \\in [-1+\\delta, 1-\\delta]$, $\\delta>0$, integrating $f(x;\\lambda)$ in $(1)$, taking the real part reveals\n$$\\text{Re}\\left(\\int_0^x f(t;\\lambda)\\,dt\\right)=-\\sum_{n=1}^\\infty \\frac{\\lambda^n\\sin(nx)}{n}\\tag3$$\n\nThen, exploiting the uniform convergence of $\\sum_{n=1}^\\infty \\frac{\\lambda^n\\sin(nx)}{n}$ for $\\lambda \\in [-1,1]$ and for $x\\in [\\nu,2\\pi-\\nu]$, $\\nu>0$, we let $\\lambda \\to -1^+$ in $(3)$ to find\n$$\\begin{align}\n\\lim_{\\lambda\\to 1^-}\\text{Re}\\left(\\int_{0}^x f(t;\\lambda)\\,dt\\right)&=-\\sum_{n=1}^\\infty \\frac{(-1)^n\\sin(nx)}{n}\\tag4\n\\end{align}$$\n\nGoing back to $(2)$, we integrate $f(x;\\lambda)$, take the real part, and let $\\lambda\\to -1^+$ to find\n$$\\lim_{\\lambda\\to -1^-}\\text{Re}\\left(\\int_{0}^x f(t;\\lambda)\\,dt\\right)=\\frac x2\\tag5$$\n\nIntegrating $(4)$ and $(5)$ once more and using $\\sum_{n=1}^\\infty \\frac1{n^2}=\\frac{\\pi^2}{12}$ yields\n$$\\sum_{n=1}^\\infty \\frac{(-1)^n \\cos(nx)}{n^2}=\\frac{x^2}{4}-\\frac{\\pi^2}{12}$$\nas was to be shown!",
"\n\n"
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"Ubiquitin folds through a highly polarized transition state.",
"\nThe small alpha/beta protein ubiquitin has been used as a model system for experimental and computational studies on protein folding for many years. ",
"Here, we present a comprehensive phi-value analysis and characterize the structure and energetics of the transition state ensemble (TSE). ",
"Twenty-seven non-disruptive mutations are made throughout the structure and a range of phi-values from zero to one are observed. ",
"The values cluster such that medium and high values and found only in the N-terminal region of the protein, whilst the C-terminal region has consistently low phi-values. ",
"In the TSE, the main alpha-helix appears to be fully formed (two phi-values which specifically probe helical structure are one) and the helix is stabilized by packing against the first beta-turn, which is partially structured. ",
"In striking comparison, the phi-values in the C-terminal region are all very low, suggesting that this region of the protein is largely unstructured in the TSE. ",
"Data are consistent with a nucleation-condensation mechanism in which there is a highly polarized folding nucleus comprising the first beta-hairpin and the alpha-helix. ",
"Data presented from the protein engineering study and phi-value analysis are compared with results from other experimental studies and also computational studies."
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"Q:\n\nTimed Tasks (cron-like) in PHP\n\nIs there a full featured, job scheduling package available for PHP? ",
"I'm looking for the PHP equivalent to Java's Quartz. ",
"I'm fine having things triggered externally from cron to drive the system. ",
"The functionality I'd be looking for:\n\nAbility to register task (class/method) to be called at given intervals.",
"\nAbility to specify whether a given task can be run multiple times (potentially long running methods should not be run multiple times in certain cases).",
"\nAll registered entries/methods could be run in parallel (jobs are backgrounded so that they do not block other timed tasks).",
"\nAbility to set a timeout for a given task.",
"\nAbility to update job control dynamically, so for instance you could disable some tasks or change their frequency without code changes.",
"\n\nI know it is a lot to ask, but it seems like a useful batch of features and I thought someone might have put together some portion of them.",
"\nIf this or some portion of this does not already exist, any pointers to putting one together or an open source project that has a reasonably featureful implementation of some subset of these?",
"\n\nA:\n\nA quick google turns up a few decent results:\n\nhttp://www.bitfolge.de/pseudocron-en.htm\nhttp://www.phpclasses.org/browse/package/4140.html\nhttp://www.hotscripts.com/Detailed/61437.html\n\nReally, though, if you're on any decent shared hosting package you should have access to some sort of task scheduler be it Windows' Task Scheduler or cron under *nix. ",
"I know DreamHost allows user level crontabs, at least.",
"\n\n"
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"Steve Jobs was interviewed for \"An Immigrant's Gift\" on December 19, 1991, in Redwood City, California. ",
"Here is more of that interview from the files of the Dr. Juran \"An Immigrant's Gift\" Archival Project, research and dissemination of information from the interviews conducted about Joseph Juran for the PBS Special, An Immigrant's Gift.",
"\n\nSTEVE JOBS: . . ",
".I think Joe Juran has clearly had those experiences [being criticized and listening to own drummer] and become very internally driven. ",
"And I think he felt the bedrock of his -- of the truth of his pursuits. ",
"And that's what kept him going. . . ",
"I think that the great satisfaction that he got from Japan did not end in the '50's. ",
"I think he probably looks at Japan as something that he helped nurture along. ",
"And as every decade has passed, he sees his ideas blossoming even more. ",
"So I'm sure he gets tremendous satisfaction from having injected a very important ingredient into the early post-war culture of Japan, and he probably sees that in, you know, in every branch and leaf of a fairly large tree. ",
"And I think what he's trying to do now is to make sure that he -- he gets that into the -- into the future culture of American industry as it rebuilds itself. ",
"And I think if he is successful, which I think he is on the verge of being, that in his last breath, he will feel comfortable, knowing in the decades to come, that his work will get recognition.",
"\n\nMy Take-away: Steve Jobs is talking about Joseph Juran -- but it is easy to read into these sentiments and imagine Steve Jobs reflecting on his own \"fairly large tree\" -- make that an Apple tree -- and how he has shaped the world."
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[
" Let c(i) = 0 - i + 3 - 4. ",
"Calculate a*c(p) + b*n(p).",
"\n-p + 1\nLet m(q) = -4*q**2 - 4*q + 2. ",
"Let s(t) = t**2 - 3*t - 27. ",
"Let r be s(7). ",
"Let v be m(r). ",
"Let z(g) = 14*g - 11. ",
"Let a(d) = 5*d - 4. ",
"Determine v*z(h) + 17*a(h).",
"\nh - 2\nLet d(p) = 49*p**3 + 6*p**2 - 6*p + 6. ",
"Let w(u) = 50*u**3 + 8*u**2 - 7*u + 8. ",
"Determine 4*d(h) - 3*w(h).",
"\n46*h**3 - 3*h\nLet c(o) = 10*o**3 - 40*o**2 - 5*o + 11. ",
"Let w(f) = 2*f**3 - 8*f**2 - f + 2. ",
"Give -2*c(q) + 11*w(q).",
"\n2*q**3 - 8*q**2 - q\nLet b(s) = s + 14. ",
"Let o(g) = -3*g - 41. ",
"Determine -17*b(v) - 6*o(v).",
"\nv + 8\nLet z(t) = -8*t**2 + t - 7. ",
"Suppose -5*l = -4*d - 127, 3*l = 3*d + 41 + 37. ",
"Let n(u) = 2*u - 23 + u + 2 - l*u**2 + 1. ",
"Determine -6*n(x) + 17*z(x).",
"\n2*x**2 - x + 1\nLet t(i) = -i**3 + i - 1. ",
"Let f(h) = -h**2 + h + 1. ",
"Calculate -3*f(d) + t(d).",
"\n-d**3 + 3*d**2 - 2*d - 4\nLet c(q) = -2*q**2 - q + 1. ",
"Let v(b) = -b**2 + 1. ",
"Let x be 4/(-28)*-2 + 33/7. ",
"Calculate x*v(o) - 2*c(o).",
"\n-o**2 + 2*o + 3\nLet u(f) = -4*f - 31. ",
"Let v(q) = 4*q + 25. ",
"Calculate -5*u(k) - 6*v(k).",
"\n-4*k + 5\nLet f(t) = 9*t**2 + 15*t - 7. ",
"Let q(x) = 5*x**2 + 8*x - 4. ",
"Give -3*f(v) + 5*q(v).",
"\n-2*v**2 - 5*v + 1\nLet g(q) = 165*q**2 - 5*q + 4. ",
"Let i(v) = -2*v**2 + v - 2. ",
"Determine -g(n) - 2*i(n).",
"\n-161*n**2 + 3*n\nLet z(w) = 1. ",
"Let i(n) = 6*n + 274. ",
"Let y be i(-45). ",
"Let l(r) = r**2 + 4*r + 6. ",
"What is y*z(a) - l(a)?",
"\n-a**2 - 4*a - 2\nLet p(g) = -2*g**3 + 5*g**2. ",
"Let z(y) = -y**2 - y. Let m = 169 - 168. ",
"Calculate m*p(h) + 2*z(h).",
"\n-2*h**3 + 3*h**2 - 2*h\nLet d(a) = -18*a**3 + 4*a**2 - 6. ",
"Let m(n) be the third derivative of -19*n**6/120 + n**5/12 - 7*n**3/6 - 3*n**2 - 28*n. ",
"What is 5*d(k) - 4*m(k)?",
"\n-14*k**3 - 2\nLet c(m) = -m + 1. ",
"Let y = -51 - -85. ",
"Let d = y - 22. ",
"Let j(r) = -2*r + 4. ",
"Determine d*c(n) - 3*j(n).",
"\n-6*n\nLet v(w) be the third derivative of w**3/6 - w**2. ",
"Let u(a) be the third derivative of a**5/60 + 5*a**3/6 + 10*a**2. ",
"Calculate 4*u(s) - 20*v(s).",
"\n4*s**2\nLet f(n) = -16*n - 3. ",
"Let q be f(4). ",
"Let m = q + 73. ",
"Let a(w) = 8*w**2 - 4*w - 6. ",
"Let k(p) = p**2 - p - 1. ",
"Calculate m*k(t) - a(t).",
"\n-2*t**2 - 2*t\nSuppose 0*d - 3*d + 3*r = 0, r = -2. ",
"Let o(p) = -27 - 21 - 13 + 74 - 10 + p. Let j(u) = u + 2. ",
"What is d*o(h) + 3*j(h)?",
"\nh\nLet m(a) = -5*a**3 - 6*a**2 - 42*a - 6. ",
"Let i(s) = 4*s**3 + 5*s**2 + 42*s + 5. ",
"Determine 6*i(u) + 5*m(u).",
"\n-u**3 + 42*u\nLet f(u) = u**3 + 8*u**2 - 12*u + 1. ",
"Let h(a) = a**3 + 2*a**2 + a - 1. ",
"Give f(n) + h(n).",
"\n2*n**3 + 10*n**2 - 11*n\nLet u(v) = v**3 + 2*v**2 + 1. ",
"Let r(c) = -26*c**3 + 8*c**2 + 7. ",
"What is -r(p) + 4*u(p)?",
"\n30*p**3 - 3\nLet p be -3 + 2/11 + (-160)/(-88). ",
"Let i(h) = 6*h - 2. ",
"Suppose -7 - 9 = -2*q. ",
"Let g(f) = f. Give p*i(t) + q*g(t).",
"\n2*t + 2\nLet g(h) = -4*h + 5. ",
"Suppose -m + 2*c = -1 - 9, -2*m + c = -8. ",
"Let l(b) = -3*b + 4. ",
"Suppose -2*k + 3*k - 1 = 0. ",
"Let z be 2/k*(-6)/4. ",
"Give m*g(a) + z*l(a).",
"\na - 2\nLet r(c) be the first derivative of c**3/3 - c**2 - 6*c - 5. ",
"Let y = -3 - 3. ",
"Let n(w) = -2*w**2 + 4*w + 11. ",
"Give y*n(q) - 11*r(q).",
"\nq**2 - 2*q\nLet f(u) = -3 + 3*u - 2*u - 4*u + 5*u. ",
"Let m(y) = -y**2 - 3*y + 3. ",
"Let c(v) = 2*v**2 + 9*v + 6. ",
"Let j be c(-4). ",
"Give j*m(i) + 3*f(i).",
"\n-2*i**2 - 3\nLet q(j) = -j**2 + 2*j + 2. ",
"Let b = -151 + 153. ",
"Let v(l) = 14*l**b - 11*l**2 - 7 + l - 8*l. ",
"Calculate -7*q(z) - 2*v(z).",
"\nz**2\nLet t(g) = -6*g + 1. ",
"Let m(f) be the second derivative of f**4/24 + 3*f**2/2 - 9*f. ",
"Let v(y) be the first derivative of m(y). ",
"Determine -t(h) - 5*v(h).",
"\nh - 1\nLet m(o) = o - 1. ",
"Suppose 9*f = -6*f. ",
"Let g(d) be the second derivative of f - 1/2*d**2 + 1/3*d**3 - 3*d. ",
"Determine 2*g(p) - 3*m(p).",
"\np + 1\nLet w(s) = s + 1. ",
"Let j be w(4). ",
"Let u(b) = -15*b - 7. ",
"Let r(i) = 10*i + 5. ",
"What is j*u(n) + 7*r(n)?",
"\n-5*n\nLet m(b) be the third derivative of -b**4/24 + b**3/6 + 87*b**2. ",
"Let k(n) = 2*n - 2. ",
"What is k(t) + m(t)?",
"\nt - 1\nLet n(g) = -29259*g + 14631*g + 1 + 14629*g. ",
"Suppose 4*a + 4*k = -8, -3*a - 9 + 38 = -4*k. ",
"Let v(w) = 1. ",
"Determine a*v(f) + n(f).",
"\nf + 4\nLet f(r) = 11*r + 22. ",
"Let x(i) = -32*i - 65. ",
"Give 8*f(o) + 3*x(o).",
"\n-8*o - 19\nLet b(i) = 3*i**3 - 5*i**2 - 9*i. ",
"Let c be 10/3*(-3)/(-2). ",
"Let d(s) be the first derivative of 0*s + 5/2*s**2 + s**3 - 1/2*s**4 + 26. ",
"Calculate c*d(z) + 3*b(z).",
"\n-z**3 - 2*z\nLet u(b) = -b**2 - 4*b + 36. ",
"Let y(c) = -3*c**2 - 11*c + 108. ",
"Determine -11*u(p) + 4*y(p).",
"\n-p**2 + 36\nSuppose -9 = -22*g + 9 + 4. ",
"Let p(r) = -r - 1. ",
"Let q(x) be the second derivative of 1/2*x**3 + 0 + 3/2*x**2 + 2*x. ",
"What is g*q(n) + 2*p(n)?",
"\nn + 1\nLet t(u) = 3*u**2 + 5*u + 5. ",
"Let a(o) = -o. ",
"Let w be a(-11). ",
"Let s be (w/((-220)/24))/(2/5). ",
"Let h(q) = 2*q**2 + 3*q + 3. ",
"Give s*t(v) + 5*h(v).",
"\nv**2\nLet y(n) = 26*n**2 + 26*n - 6. ",
"Let c(r) = -1 + 9*r**2 + 9*r - 10 + 0 + 9. ",
"Determine -17*c(j) + 6*y(j).",
"\n3*j**2 + 3*j - 2\nLet g(d) = -25*d. ",
"Let h(o) be the first derivative of o**2/2 + 58. ",
"What is -g(c) - 30*h(c)?",
"\n-5*c\nLet w(t) = 9*t - 13. ",
"Let p(q) = q + 3. ",
"Give -2*p(y) + w(y).",
"\n7*y - 19\nLet h(p) = 3*p**2 - p + 2. ",
"Let y(o) = -47*o**2 + 2*o - 4. ",
"Calculate -6*h(m) - 3*y(m).",
"\n123*m**2\nLet j(k) = 16*k**3 + 15*k**2 - 14*k - 48. ",
"Let g(f) = -14*f**3 - 13*f**2 + 12*f + 48. ",
"Give -7*g(t) - 6*j(t).",
"\n2*t**3 + t**2 - 48\nLet x(s) = -3*s**3 + 3*s**2 - 8*s - 5. ",
"Let p be -4 - (-18 - -9) - 10. ",
"Let a(y) = -2*y**3 + 2*y**2 - 5*y - 3. ",
"What is p*x(n) + 8*a(n)?",
"\n-n**3 + n**2 + 1\nLet h(r) = 3*r - 1. ",
"Let p(s) = -11*s**3 + 2*s**2 + 14*s - 6. ",
"Give 5*h(u) - p(u).",
"\n11*u**3 - 2*u**2 + u + 1\nLet i(z) = z. Let d(n) = -6*n + 2*n + 12*n + 11 - 13. ",
"What is d(u) - 5*i(u)?",
"\n3*u - 2\nLet c(z) = -9*z**3 - 4 + 4*z**2 + 0 - z**2 + 0*z**2. ",
"Let k(u) = u**3 - u**2 + 1. ",
"Calculate c(n) + 4*k(n).",
"\n-5*n**3 - n**2\nLet q(l) = -l**3 + l**2 + l. Let b(u) = -111*u**3 + 2*u**2 + 2*u. ",
"What is 2*b(z) - 4*q(z)?",
"\n-218*z**3\nLet c(v) = 2*v - 3. ",
"Let s(i) be the first derivative of -9*i**2/2 + 12*i + 6. ",
"Give -26*c(d) - 6*s(d).",
"\n2*d + 6\nLet s(a) = -3*a**3 + 2*a**2 - 2*a. ",
"Let h = 67 - 66. ",
"Let g(r) = -r**2 + r + 1. ",
"What is h*s(u) + 2*g(u)?",
"\n-3*u**3 + 2\nLet c(b) = -89*b**2 - 15*b + 1. ",
"Let v(j) = -j**2 - 3*j. ",
"Give -c(y) + 5*v(y).",
"\n84*y**2 - 1\nLet r(w) = 3*w**3 + 23*w**2 - 14*w + 18. ",
"Let j(g) = -g**3 - 8*g**2 + 5*g - 6. ",
"Give -17*j(o) - 6*r(o).",
"\n-o**3 - 2*o**2 - o - 6\nLet o(d) = -d**2 - 1. ",
"Let y be o(2). ",
"Let s(k) = -k. ",
"Let r(t) = -t + 1. ",
"Let v(x) = x**2 + 4*x + 1. ",
"Let f(g) = r(g) - v(g). ",
"Calculate y*s(u) + f(u).",
"\n-u**2\nLet t(d) = -d - 19. ",
"Let n(y) = -11. ",
"Let b(s) = -5*n(s) + 3*t(s). ",
"Let r(a) = 7*a + 5. ",
"Give 5*b(z) + 2*r(z).",
"\n-z\nSuppose 0 = 4*d - 7 - 1. ",
"Let j(z) = -1. ",
"Let w(y) = 2*y - 2. ",
"Determine d*j(h) - w(h).",
"\n-2*h\nLet d(k) = -k. ",
"Let t(s) = 2*s. ",
"Let r(l) = l. Let p be ((-1)/(-2))/((9/3)/(-36)). ",
"Let i(q) = p*t(q) + 14*r(q). ",
"Give -7*d(n) - 3*i(n).",
"\nn\nLet c(m) = -m**2 + 2*m + 1. ",
"Let u(d) = 17*d**2 - 9*d + 2. ",
"Calculate 4*c(a) + u(a).",
"\n13*a**2 - a + 6\nLet g(y) = 2 - 85*y - 83*y + 167*y. ",
"Let d(u) = u - 1. ",
"Give 5*d(p) + 6*g(p).",
"\n-p + 7\nLet v(o) = 5*o**3 - 42*o**2 - 6*o - 6. ",
"Let i(n) = n**3 - n**2 - n - 1. ",
"Give 6*i(z) - v(z).",
"\nz**3 + 36*z**2\nLet k(t) = t**2 + 2*t + 1. ",
"Let v(l) = -2*l**2 - 3*l - 1. ",
"Let d be 1 + (8/56 - 6/(-7)). ",
"Calculate d*v(f) + 3*k(f).",
"\n-f**2 + 1\nLet b(m) = 15*m**3 + 5*m**2 - 5*m. ",
"Let y(a) = a**3 + a**2 - a. Let v be 45 + -59 - (-14 + 1). ",
"Determine v*b(n) + 5*y(n).",
"\n-10*n**3\nLet y(c) = 4*c + 93. ",
"Let n(u) = -2*u. ",
"Calculate 3*n(v) + y(v).",
"\n-2*v + 93\nLet t(w) = 150*w**2 - 13*w + 6. ",
"Let k(h) = -148*h**2 + 11*h - 5. ",
"Give -6*k(r) - 5*t(r).",
"\n138*r**2 - r\nLet r(l) = -l**2 + 22*l + 5. ",
"Let a be r(22). ",
"Let h(z) = 3*z**2 + 4*z - 8. ",
"Let s(v) = -3*v**2 - 3*v + 7. ",
"Calculate a*h(n) + 6*s(n).",
"\n-3*n**2 + 2*n + 2\nLet j(s) = -s**3 + s + 1. ",
"Suppose 4*v - 7 = 13. ",
"Let y(g) = 8*g**3 - 4*g**2 + g**2 - v*g - g**3 - 6. ",
"Give 5*j(u) + y(u).",
"\n2*u**3 - 3*u**2 - 1\nLet y(c) = c**3 - 9*c**2 - 16*c - 62. ",
"Let p be y(11). ",
"Let n(m) = 5. ",
"Let h(w) = w + 4. ",
"Calculate p*n(d) - 5*h(d).",
"\n-5*d\nSuppose 2*n + 1 = n. Suppose -55*m + 170 - 280 = 0. ",
"Let v(p) = p**2 - 3*p - 2. ",
"Let x(r) = r. What is m*x(s) + n*v(s)?",
"\n-s**2 + s + 2\nLet m(g) = -9*g**3 + 13*g**2 + 5*g. ",
"Let o(a) be the second derivative of 13*a**5/20 - 19*a**4/12 - 7*a**3/6 + 532*a. ",
"What is -7*m(v) - 5*o(v)?",
"\n-2*v**3 + 4*v**2\nLet k(z) = -893*z + 4 + 1 + 1794*z - 899*z. ",
"Let b(x) = 3*x + 4. ",
"Calculate -4*b(v) + 3*k(v).",
"\n-6*v - 1\nLet s(f) = -3 - 3 + 6 - f + 7. ",
"Let o(l) = -l + 4. ",
"Let v(j) = j**3 - 2*j**2 - j - 3. ",
"Let u be v(3). ",
"Let m be 3 - (-4)/6*u. ",
"Calculate m*o(q) - 3*s(q).",
"\n-2*q - 1\nLet l(z) = -7*z - 1. ",
"Let f(c) = 5*c + 5. ",
"Let v(t) = -28*t - 27"
] | {
"pile_set_name": "DM Mathematics"
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[
"You should be able to use this against your 2008 r2 instances. ",
"This project was originally built on that and has been gradually updated to support latest versions. ",
"If you run into issues with older versions please let us know."
] | {
"pile_set_name": "Pile-CC"
} | [
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[
"Prognostic significance of computed tomography criteria for pulmonary veno-occlusive disease in systemic sclerosis-pulmonary arterial hypertension.",
"\nSSc-pulmonary arterial hypertension (SSc-PAH) is associated with worse response to therapy and survival when compared with idiopathic PAH. ",
"It is suggested that the vasculopathy in SSc may involve postcapillary pulmonary venules resulting in pulmonary veno-occlusive disease (PVOD). ",
"This may underlie the lower gas transfer and worse outcome on therapy. ",
"We sought to test whether CT signs of PVOD (CTS-PVOD) were frequent in SSc-PAH and whether they were associated with pulmonary oedema on therapy and worse survival. ",
"CT thorax of 66 SSc patients with precapillary pulmonary hypertension (PH) were blindly scored by two radiologists for CTS-PVOD (⩽1 or ⩾ 2). ",
"Case note and radiograph review determined the presence of pulmonary oedema on therapy. ",
"Fifty-nine patients (89%) had ⩽1 CTS-PVOD and only 7 (11%) had ⩾2 CTS-PVOD. ",
"Pulmonary oedema on therapy was relatively common in those with ⩾2 CTS-PVOD. ",
"On univariate analysis ⩾2 CTS-PVOD were associated with a trend towards worse survival. ",
"CTS-PVOD were less frequent in this SSc-PAH cohort than in previous reports but the presence of at least two of these signs is associated with pulmonary oedema on therapy and a trend towards worse survival on univariate analysis."
] | {
"pile_set_name": "PubMed Abstracts"
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[
"Microsoft is also marketing on the perceived hate of Internet Explorer.",
"\n\nInternet Explorer 10, was part of the company's launch of Windows 8 and Windows RT in late October. ",
"In mid-November, a \"preview version\" of IE10 was released for Windows 7 users to download. ",
"Now, data from Net Applications shows that IE10 is being used by 0.51 percent of users worldwide.",
"\n\nThe November results were posted earlier this morning, and are pretty much as expected. ",
"Windows 8 itself is only being used by a small fraction of PC users at the moment, and the \"preview\" release of IE10 on Windows 7 will keep many people from trying it out until Microsoft releases the final version.",
"\n\nMicrosoft has been pushing to get more PC users to try IE and recently launched yet another new marketing campaign that actually takes on the haters of the web browser head on.",
"\n\nNet Applications shows IE8 in the number one spot in November with 24.49 percent of the market share, followed by IE9 with 20.80 percent. ",
"Firefox 16 from Mozilla is in third place on the list with 12.93 percent, and Chrome 23 is next with 10.52 percent.",
"\n\nAs usual, StatCounter, with its different methodology, has new data that is much different than Net Applications' numbers. ",
"StatCounter has Chrome 23 in the number one spot with 22.45 percent, followed by IE9 at 17.65 percent. ",
"Firefox 16 is in third at 15.29 percent and IE8 is fourth at 12 percent. ",
"IE10 is not listed at all in StatCounter's chart.",
"\n\nSource: Net Applications | Image via Net Applications"
] | {
"pile_set_name": "OpenWebText2"
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[
"1. ",
"Field of the Invention\nThe present invention is directed to stabilized cable filler compositions for cable and wire.",
"\n2. ",
"Description of Related Art\nFor certain uses, cable and wire are surrounded by an insulation layer, which, in turn, is surrounded by filler compositions that, in turn, are surrounded by jacket compositions. ",
"Such filler compositions, when employed, should possess physical properties that are desirable for the given use.",
"\nA typical telephone cable is constructed of twisted pairs of metal conductors for signal transmission. ",
"Each conductor is insulated with a polymeric material. ",
"The desired number of transmission pairs is assembled into a circular cable core, which is protected by a cable sheath incorporating metal foil and/or armor in combination with a polymeric jacketing material. ",
"The sheathing protects the transmission core against mechanical and, to some extent, environmental damage.",
"\nTelecommunication cable, whether of the metallic or fiber optic variety, is frequently employed where water, as a result of jacket deterioration, can pass through openings in the jacket and thereafter migrate through the filler component to the insulation layer of the cable system.",
"\nHowever, water entry into either metal conductor or fiber optic cables may be undesirable for several reasons. ",
"For example, such water entry may lead to deterioration of cable transmission properties owing to corrosion, particularly where cable end portions are spliced together. ",
"In order to protect such cables, it has become common practice to encase certain of their segments in an enclosure that acts as an extension of the cable sheath or cover. ",
"It has also become common practice to encapsulate the enclosed cable segment with a curable encapsulant in order to prevent water immigration. ",
"Sealants for this purpose are disclosed in U.S. Pat. ",
"No. ",
"4,221,696.",
"\nGrease-filled telephone cables were developed in order to minimize the risk of water penetration, which can severely upset electrical signal transmission quality. ",
"Here, a hydrocarbon filler grease is used to provide a watertight cable by filling the air spaces in the cable interstices. ",
"Although the cable filler grease will extract a portion of the antioxidants from the insulation and/or jacket layers, the watertight cable will not exhibit premature oxidative failure as long as the cable maintains its integrity.",
"\nIn the cable transmission network, however, junctions of two or more watertight cables are required and this joining is often accomplished in an outdoor enclosure known as a pedestal (an interconnection box). ",
"Inside the pedestal, the cable sheathing is removed, the cable filler grease is wiped off, and the transmission wires are interconnected. ",
"At this point, the pedestal now has exposed insulated wires that are often subjected to high temperatures, air, and/or moisture. ",
"This environment, combined with the reduction in antioxidant levels in the insulation and jacket layers brought about by extraction into the filler layer, can cause the insulation in the pedestal to exhibit premature oxidative failure. ",
"This failure can then cause embrittlement of the insulation and jacket layers, making them prone to cracking and flaking, which can cause a loss of electrical transmission performance.",
"\nHigh levels of antioxidants could be used in the polymeric insulation and jacket layers, but this would alter the performance characteristics of the insulation and would be undesirable economically owing to the cost of the antioxidants. ",
"Thus, there is a need for antioxidants capable of resisting extraction by the filler layer to the extent necessary to prevent oxidative failure and help ensure a 30 to 40 year service life.",
"\nU.S. Pat. ",
"No. ",
"3,255,136 discloses stabilizer compositions said to be useful in the stabilization of polypropylene against degradative deterioration in physical properties as a result of exposure to light and air, particularly at elevated temperatures, and over long periods of time. ",
"The stabilizer system comprises three stabilizers, namely, an organic mono- or polyhydric phenol, an organic phosphite, and a thiodipropionic acid ester. ",
"According to the patent, this stabilizer system not only improves the resistance of the polymer to discoloration and embrittlement upon exposure to air and light at normal atmospheric and elevated temperatures, particularly over long periods of time, but also improves the resistance of the polymer to reduction in melt viscosity when worked at elevated temperatures in the presence of oxygen.",
"\nU.S. Pat. ",
"No. ",
"4,190,570 discloses a waterproof filling and flooding composition for communication cables that comprises 90 percent or more by weight of petrolatum, about 5 to 7 percent polybutene-1, 0.5 to 2.0 percent polyethylene, and the remainder an amorphous saturated rubber, such as ethylenepropylene rubber (EPR), which is said to exhibit flow resistance at temperatures of 160.degree. ",
"to 170.degree. ",
"F. and even higher.",
"\nEP 0 675 508 B1 discloses a grease-filled cable construction that contains an antioxidant that is said to resist extraction so that it can be maintained in cable insulation at a satisfactory stabilizing level. ",
"The disclosure of this publication is hereby incorporated herein by reference.",
"\nIn the wire and cable industry, extended thermoplastic rubber (ETPR) and petroleum jelly/polyethylene are often incorporated into the filler component to effect water protection of the insulation layer. ",
"Examples of cable segments that are often placed in enclosures and thereafter encapsulated include:\n(1) the regions where two or more cables are spliced together; PA1 (2) the ends, or end block portions, of the cable; and PA1 (3) the junctions between air-pressurized cable and hydrocarbon grease-filled cable, or pressure block. ",
"PA1 is (a) metal dithiocarbamate salts, PA1 (b) amine antioxidants, and PA1 (c) sterically hindered phenolic antioxidants, PA1 R.sub.2 and R.sub.3 are independently selected from the group consisting of methyl, phenyl, and p-tolyl radicals; PA1 R.sub.4 is selected from the group consisting of methyl, phenyl, p-tolyl, and neopentyl radicals; PA1 R.sub.5 is selected from the group consisting of methyl, phenyl, p-tolyl, and 2-phenylisobutyl radicals; and, PA1 R.sub.6 is a methyl radical. ##",
"STR4## wherein R.sub.1 through R.sub.5 are independently selected from the radicals shown in Formula I and R.sub.7 is selected from the group consisting of methyl, phenyl, and p-tolyl radicals; PA1 X is a radical selected from the group consisting of methyl, ethyl, C.sub.3 -C.sub.10 sec-alkyl, .alpha.",
",.alpha.-dimethylbenzyl, .alpha.-methylbenzyl, chlorine, bromine, carboxyl, and metal salts of the carboxylic acids where the metal is selected from the group consisting of zinc, cadmium, nickel, lead, tin, magnesium, and copper; and, PA1 Y is a radical selected from the group consisting of hydrogen, methyl, ethyl, C.sub.3 -C.sub.10 sec-alkyl, chlorine, and bromine. ##",
"STR5## wherein R.sub.1 is selected from the group consisting of phenyl or p-tolyl radicals; PA1 R.sub.2 and R.sub.3 are independently selected from the group consisting of methyl, phenyl, and p-tolyl radicals; PA1 R.sub.4 is a radical selected from the group consisting of hydrogen, C.sub.3 -C.sub.10 primary, secondary, and tertiary alkyl, and C.sub.3 -C.sub.10 alkoxyl, which may be straight chain or branched; and PA1 X and Y are radicals selected from the group consisting hydrogen, methyl, ethyl, C.sub.3 -C.sub.10 sec-alkyl, chlorine, and bromine. ##",
"STR6## wherein R.sub.9 is a radical selected from the group consisting of methyl, phenyl, and p-tolyl; PA1 R.sub.10 is a radical selected from the group consisting of methyl, phenyl, p-tolyl and 2-phenyl isobutyl; and PA1 R.sub.13 is a radical selected from the group consisting of methyl, phenyl, and p-tolyl; PA1 R.sub.14 is a radical selected from the group consisting of methyl, phenyl, p-tolyl, and 2-phenylisobutyl; and PA1 R.sub.15 is a radical selected from the group consisting of hydrogen, .alpha.",
",.alpha.-dimethylbenzyl, .alpha.-methylbenzhydryl, triphenylmethyl, and .alpha.",
",.alpha.-p-trimethylbenzyl.",
"\nOne problem that arises, occurring when an antioxidant ingredient of the insulation or jacket layers is extracted from the insulation or jacket layers and incorporated into the filler, is that the wire and cable product is left unsuitable for its intended purpose, principally because of deterioration of the jacket and/or insulation layers.",
"\nIn general, to stabilize the filler component of cable and wire, at least one antioxidant ingredient is conventionally incorporated into the filler composition. ",
"Similarly, to stabilize the insulation and jacket components, at least one other antioxidant, usually different from the filler antioxidant, is incorporated into the jacket composition.",
"\nIn this regard, conventional stabilizers for polyolefin-based filler components of commercial cable and wire systems include organic phosphites, which may be combined with such polyhydric phenols as BHT and BHA, as are disclosed in U.S. Patent 4,190,570, supra.",
"\nOne aspect or feature of the present invention involves waterproof, high-performance, cost-efficient stabilizer systems for filler components of conventional wire and cable systems, a result of this invention.",
"\nSuch waterproof compositions may, indeed, be deemed indispensable in protecting those communication cables that are manufactured mainly from hydrocarbon materials."
] | {
"pile_set_name": "USPTO Backgrounds"
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[
"/*\n * Non-physical true random number generator based on timing jitter --\n * Jitter RNG standalone code.",
"\n *\n * Copyright Stephan Mueller <[email protected]>, 2015\n *\n * Design\n * ======\n *\n * See http://www.chronox.de/jent.html\n *\n * License\n * =======\n *\n * Redistribution and use in source and binary forms, with or without\n * modification, are permitted provided that the following conditions\n * are met:\n * 1. ",
"Redistributions of source code must retain the above copyright\n * notice, and the entire permission notice in its entirety,\n * including the disclaimer of warranties.",
"\n * 2. ",
"Redistributions in binary form must reproduce the above copyright\n * notice, this list of conditions and the following disclaimer in the\n * documentation and/or other materials provided with the distribution.",
"\n * 3. ",
"The name of the author may not be used to endorse or promote\n * products derived from this software without specific prior\n * written permission.",
"\n *\n * ALTERNATIVELY, this product may be distributed under the terms of\n * the GNU General Public License, in which case the provisions of the GPL2 are\n * required INSTEAD OF the above restrictions. ",
" (This clause is\n * necessary due to a potential bad interaction between the GPL and\n * the restrictions contained in a BSD-style copyright.)",
"\n *\n * THIS SOFTWARE IS PROVIDED ``AS IS'' AND ANY EXPRESS OR IMPLIED\n * WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES\n * OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE, ALL OF\n * WHICH ARE HEREBY DISCLAIMED. ",
" IN NO EVENT SHALL THE AUTHOR BE\n * LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR\n * CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT\n * OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR\n * BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY THEORY OF\n * LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT\n * (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE\n * USE OF THIS SOFTWARE, EVEN IF NOT ADVISED OF THE POSSIBILITY OF SUCH\n * DAMAGE.",
"\n */\n\n/*\n * This Jitterentropy RNG is based on the jitterentropy library\n * version 1.1.0 provided at http://www.chronox.de/jent.html\n */\n\n#ifdef __OPTIMIZE__\n #error \"The CPU Jitter random number generator must not be compiled with optimizations. ",
"See documentation. ",
"Use the compiler switch -O0 for compiling jitterentropy.c.\"",
"\n#endif\n\ntypedef\tunsigned long long\t__u64;\ntypedef\tlong long\t\t__s64;\ntypedef\tunsigned int\t\t__u32;\n#define NULL ((void *) 0)\n\n/* The entropy pool */\nstruct rand_data {\n\t/* all data values that are vital to maintain the security\n\t * of the RNG are marked as SENSITIVE. ",
"A user must not\n\t * access that information while the RNG executes its loops to\n\t * calculate the next random value. */",
"\n\t__u64 data;\t\t/* SENSITIVE Actual random number */\n\t__u64 old_data;\t\t/* SENSITIVE Previous random number */\n\t__u64 prev_time;\t/* SENSITIVE Previous time stamp */\n#define DATA_SIZE_BITS ((sizeof(__u64)) * 8)\n\t__u64 last_delta;\t/* SENSITIVE stuck test */\n\t__s64 last_delta2;\t/* SENSITIVE stuck test */\n\tunsigned int stuck:1;\t/* Time measurement stuck */\n\tunsigned int osr;\t/* Oversample rate */\n\tunsigned int stir:1;\t\t/* Post-processing stirring */\n\tunsigned int disable_unbias:1;\t/* Deactivate Von-Neuman unbias */\n#define JENT_MEMORY_BLOCKS 64\n#define JENT_MEMORY_BLOCKSIZE 32\n#define JENT_MEMORY_ACCESSLOOPS 128\n#define JENT_MEMORY_SIZE (JENT_MEMORY_BLOCKS*JENT_MEMORY_BLOCKSIZE)\n\tunsigned char *mem;\t/* Memory access location with size of\n\t\t\t\t * memblocks * memblocksize */\n\tunsigned int memlocation; /* Pointer to byte in *mem */\n\tunsigned int memblocks;\t/* Number of memory blocks in *mem */\n\tunsigned int memblocksize; /* Size of one memory block in bytes */\n\tunsigned int memaccessloops; /* Number of memory accesses per random\n\t\t\t\t * bit generation */\n};\n\n/* Flags that can be used to initialize the RNG */\n#define JENT_DISABLE_STIR (1<<0) /* Disable stirring the entropy pool */\n#define JENT_DISABLE_UNBIAS (1<<1) /* Disable the Von-Neuman Unbiaser */\n#define JENT_DISABLE_MEMORY_ACCESS (1<<2) /* Disable memory access for more\n\t\t\t\t\t * entropy, saves MEMORY_SIZE RAM for\n\t\t\t\t\t * entropy collector */\n\n/* -- error codes for init function -- */\n#define JENT_ENOTIME\t\t1 /* Timer service not available */\n#define JENT_ECOARSETIME\t2 /* Timer too coarse for RNG */\n#define JENT_ENOMONOTONIC\t3 /* Timer is not monotonic increasing */\n#define JENT_EMINVARIATION\t4 /* Timer variations too small for RNG */\n#define JENT_EVARVAR\t\t5 /* Timer does not produce variations of\n\t\t\t\t * variations (2nd derivation of time is\n\t\t\t\t * zero). */",
"\n#define JENT_EMINVARVAR\t\t6 /* Timer variations of variations is tooi\n\t\t\t\t * small. */",
"\n\n/***************************************************************************\n * Helper functions\n ***************************************************************************/\n\nvoid jent_get_nstime(__u64 *out);\n__u64 jent_rol64(__u64 word, unsigned int shift);\nvoid *jent_zalloc(unsigned int len);\nvoid jent_zfree(void *ptr);\nint jent_fips_enabled(void);\nvoid jent_panic(char *s);\nvoid jent_memcpy(void *dest, const void *src, unsigned int n);\n\n/**\n * Update of the loop count used for the next round of\n * an entropy collection.",
"\n *\n * Input:\n * @ec entropy collector struct -- may be NULL\n * @bits is the number of low bits of the timer to consider\n * @min is the number of bits we shift the timer value to the right at\n *\tthe end to make sure we have a guaranteed minimum value\n *\n * @return Newly calculated loop counter\n */\nstatic __u64 jent_loop_shuffle(struct rand_data *ec,\n\t\t\t unsigned int bits, unsigned int min)\n{\n\t__u64 time = 0;\n\t__u64 shuffle = 0;\n\tunsigned int i = 0;\n\tunsigned int mask = (1<<bits) - 1;\n\n\tjent_get_nstime(&time);\n\t/*\n\t * mix the current state of the random number into the shuffle\n\t * calculation to balance that shuffle a bit more\n\t */\n\tif (ec)\n\t\ttime ^= ec->data;\n\t/*\n\t * we fold the time value as much as possible to ensure that as many\n\t * bits of the time stamp are included as possible\n\t */\n\tfor (i = 0; (DATA_SIZE_BITS / bits) > i; i++) {\n\t\tshuffle ^= time & mask;\n\t\ttime = time >> bits;\n\t}\n\n\t/*\n\t * We add a lower boundary value to ensure we have a minimum\n\t * RNG loop count.",
"\n\t */\n\treturn (shuffle + (1<<min));\n}\n\n/***************************************************************************\n * Noise sources\n ***************************************************************************/\n\n/**\n * CPU Jitter noise source -- this is the noise source based on the CPU\n *\t\t\t execution time jitter\n *\n * This function folds the time into one bit units by iterating\n * through the DATA_SIZE_BITS bit time value as follows: assume our time value\n * is 0xabcd\n * 1st loop, 1st shift generates 0xd000\n * 1st loop, 2nd shift generates 0x000d\n * 2nd loop, 1st shift generates 0xcd00\n * 2nd loop, 2nd shift generates 0x000c\n * 3rd loop, 1st shift generates 0xbcd0\n * 3rd loop, 2nd shift generates 0x000b\n * 4th loop, 1st shift generates 0xabcd\n * 4th loop, 2nd shift generates 0x000a\n * Now, the values at the end of the 2nd shifts are XORed together.",
"\n *\n * The code is deliberately inefficient and shall stay that way. ",
"This function\n * is the root cause why the code shall be compiled without optimization. ",
"This\n * function not only acts as folding operation, but this function's execution\n * is used to measure the CPU execution time jitter. ",
"Any change to the loop in\n * this function implies that careful retesting must be done.",
"\n *\n * Input:\n * @ec entropy collector struct -- may be NULL\n * @time time stamp to be folded\n * @loop_cnt if a value not equal to 0 is set, use the given value as number of\n *\t loops to perform the folding\n *\n * Output:\n * @folded result of folding operation\n *\n * @return Number of loops the folding operation is performed\n */\nstatic __u64 jent_fold_time(struct rand_data *ec, __u64 time,\n\t\t\t __u64 *folded, __u64 loop_cnt)\n{\n\tunsigned int i;\n\t__u64 j = 0;\n\t__u64 new = 0;\n#define MAX_FOLD_LOOP_BIT 4\n#define MIN_FOLD_LOOP_BIT 0\n\t__u64 fold_loop_cnt =\n\t\tjent_loop_shuffle(ec, MAX_FOLD_LOOP_BIT, MIN_FOLD_LOOP_BIT);\n\n\t/*\n\t * testing purposes -- allow test app to set the counter, not\n\t * needed during runtime\n\t */\n\tif (loop_cnt)\n\t\tfold_loop_cnt = loop_cnt;\n\tfor (j = 0; j < fold_loop_cnt; j++) {\n\t\tnew = 0;\n\t\tfor (i = 1; (DATA_SIZE_BITS) >= i; i++) {\n\t\t\t__u64 tmp = time << (DATA_SIZE_BITS - i);\n\n\t\t\ttmp = tmp >> (DATA_SIZE_BITS - 1);\n\t\t\tnew ^= tmp;\n\t\t}\n\t}\n\t*folded = new;\n\treturn fold_loop_cnt;\n}\n\n/**\n * Memory Access noise source -- this is a noise source based on variations in\n *\t\t\t\t memory access times\n *\n * This function performs memory accesses which will add to the timing\n * variations due to an unknown amount of CPU wait states that need to be\n * added when accessing memory. ",
"The memory size should be larger than the L1\n * caches as outlined in the documentation and the associated testing.",
"\n *\n * The L1 cache has a very high bandwidth, albeit its access rate is usually\n * slower than accessing CPU registers. ",
"Therefore, L1 accesses only add minimal\n * variations as the CPU has hardly to wait. ",
"Starting with L2, significant\n * variations are added because L2 typically does not belong to the CPU any more\n * and therefore a wider range of CPU wait states is necessary for accesses.",
"\n * L3 and real memory accesses have even a wider range of wait states. ",
"However,\n * to reliably access either L3 or memory, the ec->mem memory must be quite\n * large which is usually not desirable.",
"\n *\n * Input:\n * @ec Reference to the entropy collector with the memory access data -- if\n * the reference to the memory block to be accessed is NULL, this noise\n * source is disabled\n * @loop_cnt if a value not equal to 0 is set, use the given value as number of\n *\t loops to perform the folding\n *\n * @return Number of memory access operations\n */\nstatic unsigned int jent_memaccess(struct rand_data *ec, __u64 loop_cnt)\n{\n\tunsigned char *tmpval = NULL;\n\tunsigned int wrap = 0;\n\t__u64 i = 0;\n#define MAX_ACC_LOOP_BIT 7\n#define MIN_ACC_LOOP_BIT 0\n\t__u64 acc_loop_cnt =\n\t\tjent_loop_shuffle(ec, MAX_ACC_LOOP_BIT, MIN_ACC_LOOP_BIT);\n\n\tif (NULL == ec || NULL == ec->mem)\n\t\treturn 0;\n\twrap = ec->memblocksize * ec->memblocks;\n\n\t/*\n\t * testing purposes -- allow test app to set the counter, not\n\t * needed during runtime\n\t */\n\tif (loop_cnt)\n\t\tacc_loop_cnt = loop_cnt;\n\n\tfor (i = 0; i < (ec->memaccessloops + acc_loop_cnt); i++) {\n\t\ttmpval = ec->mem + ec->memlocation;\n\t\t/*\n\t\t * memory access: just add 1 to one byte,\n\t\t * wrap at 255 -- memory access implies read\n\t\t * from and write to memory location\n\t\t */\n\t\t*tmpval = (*tmpval + 1) & 0xff;\n\t\t/*\n\t\t * Addition of memblocksize - 1 to pointer\n\t\t * with wrap around logic to ensure that every\n\t\t * memory location is hit evenly\n\t\t */\n\t\tec->memlocation = ec->memlocation + ec->memblocksize - 1;\n\t\tec->memlocation = ec->memlocation % wrap;\n\t}\n\treturn i;\n}\n\n/***************************************************************************\n * Start of entropy processing logic\n ***************************************************************************/\n\n/**\n * Stuck test by checking the:\n *\t1st derivation of the jitter measurement (time delta)\n *\t2nd derivation of the jitter measurement (delta of time deltas)\n *\t3rd derivation of the jitter measurement (delta of delta of time deltas)\n *\n * All values must always be non-zero.",
"\n *\n * Input:\n * @ec Reference to entropy collector\n * @current_delta Jitter time delta\n *\n * @return\n *\t0 jitter measurement not stuck (good bit)\n *\t1 jitter measurement stuck (reject bit)\n */\nstatic void jent_stuck(struct rand_data *ec, __u64 current_delta)\n{\n\t__s64 delta2 = ec->last_delta - current_delta;\n\t__s64 delta3 = delta2 - ec->last_delta2;\n\n\tec->last_delta = current_delta;\n\tec->last_delta2 = delta2;\n\n\tif (!",
"current_delta || !",
"delta2 || !",
"delta3)\n\t\tec->stuck = 1;\n}\n\n/**\n * This is the heart of the entropy generation: calculate time deltas and\n * use the CPU jitter in the time deltas. ",
"The jitter is folded into one\n * bit. ",
"You can call this function the \"random bit generator\" as it\n * produces one random bit per invocation.",
"\n *\n * WARNING: ensure that ->prev_time is primed before using the output\n *\t of this function! ",
"This can be done by calling this function\n *\t and not using its result.",
"\n *\n * Input:\n * @entropy_collector Reference to entropy collector\n *\n * @return One random bit\n */\nstatic __u64 jent_measure_jitter(struct rand_data *ec)\n{\n\t__u64 time = 0;\n\t__u64 data = 0;\n\t__u64 current_delta = 0;\n\n\t/* Invoke one noise source before time measurement to add variations */\n\tjent_memaccess(ec, 0);\n\n\t/*\n\t * Get time stamp and calculate time delta to previous\n\t * invocation to measure the timing variations\n\t */\n\tjent_get_nstime(&time);\n\tcurrent_delta = time - ec->prev_time;\n\tec->prev_time = time;\n\n\t/* Now call the next noise sources which also folds the data */\n\tjent_fold_time(ec, current_delta, &data, 0);\n\n\t/*\n\t * Check whether we have a stuck measurement. ",
"The enforcement\n\t * is performed after the stuck value has been mixed into the\n\t * entropy pool.",
"\n\t */\n\tjent_stuck(ec, current_delta);\n\n\treturn data;\n}\n\n/**\n * Von Neuman unbias as explained in RFC 4086 section 4.2. ",
"As shown in the\n * documentation of that RNG, the bits from jent_measure_jitter are considered\n * independent which implies that the Von Neuman unbias operation is applicable.",
"\n * A proof of the Von-Neumann unbias operation to remove skews is given in the\n * document \"A proposal for: Functionality classes for random number\n * generators\", version 2.0 by Werner Schindler, section 5.4.1.",
"\n *\n * Input:\n * @entropy_collector Reference to entropy collector\n *\n * @return One random bit\n */\nstatic __u64 jent_unbiased_bit(struct rand_data *entropy_collector)\n{\n\tdo {\n\t\t__u64 a = jent_measure_jitter(entropy_collector);\n\t\t__u64 b = jent_measure_jitter(entropy_collector);\n\n\t\tif (a == b)\n\t\t\tcontinue;\n\t\tif (1 == a)\n\t\t\treturn 1;\n\t\telse\n\t\t\treturn 0;\n\t} while (1);\n}\n\n/**\n * Shuffle the pool a bit by mixing some value with a bijective function (XOR)\n * into the pool.",
"\n *\n * The function generates a mixer value that depends on the bits set and the\n * location of the set bits in the random number generated by the entropy\n * source. ",
"Therefore, based on the generated random number, this mixer value\n * can have 2**64 different values. ",
"That mixer value is initialized with the\n * first two SHA-1 constants. ",
"After obtaining the mixer value, it is XORed into\n * the random number.",
"\n *\n * The mixer value is not assumed to contain any entropy. ",
"But due to the XOR\n * operation, it can also not destroy any entropy present in the entropy pool.",
"\n *\n * Input:\n * @entropy_collector Reference to entropy collector\n */\nstatic void jent_stir_pool(struct rand_data *entropy_collector)\n{\n\t/*\n\t * to shut up GCC on 32 bit, we have to initialize the 64 variable\n\t * with two 32 bit variables\n\t */\n\tunion c {\n\t\t__u64 u64;\n\t\t__u32 u32[2];\n\t};\n\t/*\n\t * This constant is derived from the first two 32 bit initialization\n\t * vectors of SHA-1 as defined in FIPS 180-4 section 5.3.1\n\t */\n\tunion c constant;\n\t/*\n\t * The start value of the mixer variable is derived from the third\n\t * and fourth 32 bit initialization vector of SHA-1 as defined in\n\t * FIPS 180-4 section 5.3.1\n\t */\n\tunion c mixer;\n\tunsigned int i = 0;\n\n\t/*\n\t * Store the SHA-1 constants in reverse order to make up the 64 bit\n\t * value -- this applies to a little endian system, on a big endian\n\t * system, it reverses as expected. ",
"But this really does not matter\n\t * as we do not rely on the specific numbers. ",
"We just pick the SHA-1\n\t * constants as they have a good mix of bit set and unset.",
"\n\t */\n\tconstant.u32[1] = 0x67452301;\n\tconstant.u32[0] = 0xefcdab89;\n\tmixer.u32[1] = 0x98badcfe;\n\tmixer.u32[0] = 0x10325476;\n\n\tfor (i = 0; i < DATA_SIZE_BITS; i++) {\n\t\t/*\n\t\t * get the i-th bit of the input random number and only XOR\n\t\t * the constant into the mixer value when that bit is set\n\t\t */\n\t\tif ((entropy_collector->data >> i) & 1)\n\t\t\tmixer.u64 ^= constant.u64;\n\t\tmixer.u64 = jent_rol64(mixer.u64, 1);\n\t}\n\tentropy_collector->data ^= mixer.u64;\n}\n\n/**\n * Generator of one 64 bit random number\n * Function fills rand_data->data\n *\n * Input:\n * @ec Reference to entropy collector\n */\nstatic void jent_gen_entropy(struct rand_data *ec)\n{\n\tunsigned int k = 0;\n\n\t/* priming of the ->prev_time value */\n\tjent_measure_jitter(ec);\n\n\twhile (1) {\n\t\t__u64 data = 0;\n\n\t\tif (ec->disable_unbias == 1)\n\t\t\tdata = jent_measure_jitter(ec);\n\t\telse\n\t\t\tdata = jent_unbiased_bit(ec);\n\n\t\t/* enforcement of the jent_stuck test */\n\t\tif (ec->stuck) {\n\t\t\t/*\n\t\t\t * We only mix in the bit considered not appropriate\n\t\t\t * without the LSFR. ",
"The reason is that if we apply\n\t\t\t * the LSFR and we do not rotate, the 2nd bit with LSFR\n\t\t\t * will cancel out the first LSFR application on the\n\t\t\t * bad bit.",
"\n\t\t\t *\n\t\t\t * And we do not rotate as we apply the next bit to the\n\t\t\t * current bit location again.",
"\n\t\t\t */\n\t\t\tec->data ^= data;\n\t\t\tec->stuck = 0;\n\t\t\tcontinue;\n\t\t}\n\n\t\t/*\n\t\t * Fibonacci LSFR with polynom of\n\t\t * x^64 + x^61 + x^56 + x^31 + x^28 + x^23 + 1 which is\n\t\t * primitive according to\n\t\t * http://poincare.matf.bg.ac.rs/~ezivkovm/publications/primpol1.pdf\n\t\t * (the shift values are the polynom values minus one\n\t\t * due to counting bits from 0 to 63). ",
"As the current\n\t\t * position is always the LSB, the polynom only needs\n\t\t * to shift data in from the left without wrap.",
"\n\t\t */\n\t\tec->data ^= data;\n\t\tec->data ^= ((ec->data >> 63) & 1);\n\t\tec->data ^= ((ec->data >> 60) & 1);\n\t\tec->data ^= ((ec->data >> 55) & 1);\n\t\tec->data ^= ((ec->data >> 30) & 1);\n\t\tec->data ^= ((ec->data >> 27) & 1);\n\t\tec->data ^= ((ec->data >> 22) & 1);\n\t\tec->data = jent_rol64(ec->data, 1);\n\n\t\t/*\n\t\t * We multiply the loop value with ->osr to obtain the\n\t\t * oversampling rate requested by the caller\n\t\t */\n\t\tif (++k >= (DATA_SIZE_BITS * ec->osr))\n\t\t\tbreak;\n\t}\n\tif (ec->stir)\n\t\tjent_stir_pool(ec);\n}\n\n/**\n * The continuous test required by FIPS 140-2 -- the function automatically\n * primes the test if needed.",
"\n *\n * Return:\n * 0 if FIPS test passed\n * < 0 if FIPS test failed\n */\nstatic void jent_fips_test(struct rand_data *ec)\n{\n\tif (!",
"jent_fips_enabled())\n\t\treturn;\n\n\t/* prime the FIPS test */\n\tif (!",
"ec->old_data) {\n\t\tec->old_data = ec->data;\n\t\tjent_gen_entropy(ec);\n\t}\n\n\tif (ec->data == ec->old_data)\n\t\tjent_panic(\"jitterentropy: Duplicate output detected\\n\");\n\n\tec->old_data = ec->data;\n}\n\n/**\n * Entry function: Obtain entropy for the caller.",
"\n *\n * This function invokes the entropy gathering logic as often to generate\n * as many bytes as requested by the caller. ",
"The entropy gathering logic\n * creates 64 bit per invocation.",
"\n *\n * This function truncates the last 64 bit entropy value output to the exact\n * size specified by the caller.",
"\n *\n * Input:\n * @ec Reference to entropy collector\n * @data pointer to buffer for storing random data -- buffer must already\n *\t exist\n * @len size of the buffer, specifying also the requested number of random\n *\tin bytes\n *\n * @return 0 when request is fulfilled or an error\n *\n * The following error codes can occur:\n *\t-1\tentropy_collector is NULL\n */\nint jent_read_entropy(struct rand_data *ec, unsigned char *data,\n\t\t unsigned int len)\n{\n\tunsigned char *p = data;\n\n\tif (!",
"ec)\n\t\treturn -1;\n\n\twhile (0 < len) {\n\t\tunsigned int tocopy;\n\n\t\tjent_gen_entropy(ec);\n\t\tjent_fips_test(ec);\n\t\tif ((DATA_SIZE_BITS / 8) < len)\n\t\t\ttocopy = (DATA_SIZE_BITS / 8);\n\t\telse\n\t\t\ttocopy = len;\n\t\tjent_memcpy(p, &ec->data, tocopy);\n\n\t\tlen -= tocopy;\n\t\tp += tocopy;\n\t}\n\n\treturn 0;\n}\n\n/***************************************************************************\n * Initialization logic\n ***************************************************************************/\n\nstruct rand_data *jent_entropy_collector_alloc(unsigned int osr,\n\t\t\t\t\t unsigned int flags)\n{\n\tstruct rand_data *entropy_collector;\n\n\tentropy_collector = jent_zalloc(sizeof(struct rand_data));\n\tif (!",
"entropy_collector)\n\t\treturn NULL;\n\n\tif (!(",
"flags & JENT_DISABLE_MEMORY_ACCESS)) {\n\t\t/* Allocate memory for adding variations based on memory\n\t\t * access\n\t\t */\n\t\tentropy_collector->mem = jent_zalloc(JENT_MEMORY_SIZE);\n\t\tif (!",
"entropy_collector->mem) {\n\t\t\tjent_zfree(entropy_collector);\n\t\t\treturn NULL;\n\t\t}\n\t\tentropy_collector->memblocksize = JENT_MEMORY_BLOCKSIZE;\n\t\tentropy_collector->memblocks = JENT_MEMORY_BLOCKS;\n\t\tentropy_collector->memaccessloops = JENT_MEMORY_ACCESSLOOPS;\n\t}\n\n\t/* verify and set the oversampling rate */\n\tif (0 == osr)\n\t\tosr = 1; /* minimum sampling rate is 1 */\n\tentropy_collector->osr = osr;\n\n\tentropy_collector->stir = 1;\n\tif (flags & JENT_DISABLE_STIR)\n\t\tentropy_collector->stir = 0;\n\tif (flags & JENT_DISABLE_UNBIAS)\n\t\tentropy_collector->disable_unbias = 1;\n\n\t/* fill the data pad with non-zero values */\n\tjent_gen_entropy(entropy_collector);\n\n\treturn entropy_collector;\n}\n\nvoid jent_entropy_collector_free(struct rand_data *entropy_collector)\n{\n\tjent_zfree(entropy_collector->mem);\n\tentropy_collector->mem = NULL;\n\tjent_zfree(entropy_collector);\n\tentropy_collector = NULL;\n}\n\nint jent_entropy_init(void)\n{\n\tint i;\n\t__u64 delta_sum = 0;\n\t__u64 old_delta = 0;\n\tint time_backwards = 0;\n\tint count_var = 0;\n\tint count_mod = 0;\n\n\t/* We could perform statistical tests here, but the problem is\n\t * that we only have a few loop counts to do testing. ",
"These\n\t * loop counts may show some slight skew and we produce\n\t * false positives.",
"\n\t *\n\t * Moreover, only old systems show potentially problematic\n\t * jitter entropy that could potentially be caught here. ",
"But\n\t * the RNG is intended for hardware that is available or widely\n\t * used, but not old systems that are long out of favor. ",
"Thus,\n\t * no statistical tests.",
"\n\t */\n\n\t/*\n\t * We could add a check for system capabilities such as clock_getres or\n\t * check for CONFIG_X86_TSC, but it does not make much sense as the\n\t * following sanity checks verify that we have a high-resolution\n\t * timer.",
"\n\t */\n\t/*\n\t * TESTLOOPCOUNT needs some loops to identify edge systems. ",
"100 is\n\t * definitely too little.",
"\n\t */\n#define TESTLOOPCOUNT 300\n#define CLEARCACHE 100\n\tfor (i = 0; (TESTLOOPCOUNT + CLEARCACHE) > i; i++) {\n\t\t__u64 time = 0;\n\t\t__u64 time2 = 0;\n\t\t__u64 folded = 0;\n\t\t__u64 delta = 0;\n\t\tunsigned int lowdelta = 0;\n\n\t\tjent_get_nstime(&time);\n\t\tjent_fold_time(NULL, time, &folded, 1<<MIN_FOLD_LOOP_BIT);\n\t\tjent_get_nstime(&time2);\n\n\t\t/* test whether timer works */\n\t\tif (!",
"time || !",
"time2)\n\t\t\treturn JENT_ENOTIME;\n\t\tdelta = time2 - time;\n\t\t/*\n\t\t * test whether timer is fine grained enough to provide\n\t\t * delta even when called shortly after each other -- this\n\t\t * implies that we also have a high resolution timer\n\t\t */\n\t\tif (!",
"delta)\n\t\t\treturn JENT_ECOARSETIME;\n\n\t\t/*\n\t\t * up to here we did not modify any variable that will be\n\t\t * evaluated later, but we already performed some work. ",
"Thus we\n\t\t * already have had an impact on the caches, branch prediction,\n\t\t * etc. ",
"with the goal to clear it to get the worst case\n\t\t * measurements.",
"\n\t\t */\n\t\tif (CLEARCACHE > i)\n\t\t\tcontinue;\n\n\t\t/* test whether we have an increasing timer */\n\t\tif (!(",
"time2 > time))\n\t\t\ttime_backwards++;\n\n\t\t/*\n\t\t * Avoid modulo of 64 bit integer to allow code to compile\n\t\t * on 32 bit architectures.",
"\n\t\t */\n\t\tlowdelta = time2 - time;\n\t\tif (!(",
"lowdelta % 100))\n\t\t\tcount_mod++;\n\n\t\t/*\n\t\t * ensure that we have a varying delta timer which is necessary\n\t\t * for the calculation of entropy -- perform this check\n\t\t * only after the first loop is executed as we need to prime\n\t\t * the old_data value\n\t\t */\n\t\tif (i) {\n\t\t\tif (delta !",
"= old_delta)\n\t\t\t\tcount_var++;\n\t\t\tif (delta > old_delta)\n\t\t\t\tdelta_sum += (delta - old_delta);\n\t\t\telse\n\t\t\t\tdelta_sum += (old_delta - delta);\n\t\t}\n\t\told_delta = delta;\n\t}\n\n\t/*\n\t * we allow up to three times the time running backwards.",
"\n\t * CLOCK_REALTIME is affected by adjtime and NTP operations. ",
"Thus,\n\t * if such an operation just happens to interfere with our test, it\n\t * should not fail. ",
"The value of 3 should cover the NTP case being\n\t * performed during our test run.",
"\n\t */\n\tif (3 < time_backwards)\n\t\treturn JENT_ENOMONOTONIC;\n\t/* Error if the time variances are always identical */\n\tif (!",
"delta_sum)\n\t\treturn JENT_EVARVAR;\n\n\t/*\n\t * Variations of deltas of time must on average be larger\n\t * than 1 to ensure the entropy estimation\n\t * implied with 1 is preserved\n\t */\n\tif (delta_sum <= 1)\n\t\treturn JENT_EMINVARVAR;\n\n\t/*\n\t * Ensure that we have variations in the time stamp below 10 for at\n\t * least 10% of all checks -- on some platforms, the counter\n\t * increments in multiples of 100, but not always\n\t */\n\tif ((TESTLOOPCOUNT/10 * 9) < count_mod)\n\t\treturn JENT_ECOARSETIME;\n\n\treturn 0;\n}\n"
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[
"Leonard Pelham Lee\n\nLeonard Pelham Lee (1903–1980) was an executive in the English internal combustion engine industry.",
"\n\nBiography\nLeonard Pelham Lee was born as the son of Horace Pelham Lee on 31 May 1903. ",
" He joined Coventry Climax Engines in 1919 and became a Director in 1927.",
"\n\nHe married Ivy D. Jones in 1933, and had a son, Charles Pelham Lee.",
"\n\nIn 1953, he was appointed Chairman and Managing Director of Coventry Climax Engines on the death of his father, who was the founder/owner.",
"\n\nHe was appointed Chairman (formerly Joint MD) of Godiva Fire Pumps in 1957.",
"\n\nHe lived at Park House, Warwick Road, Coventry, and was appointed the Chairman of British Internal Combustion Engine Manufacturers Association in 1960 at age 57.",
"\n\nHe died in 1980 in Warwickshire, England.",
"\n\nFormula One\nIn 1961, Coventry Climax was dominating the British Formula One field with the successful FPF and FWMV engines, but FWMV's initial selling price (3,000 Pounds), though considerably higher than the selling price of FPF (2,250 Pounds), did not cover the development cost and the mounting maintenance cost as more and more teams wanted to run it. ",
" He announced that the situation is the equivalent of his company subsidising the teams, so that the company will withdraw from Formula One racing at the end of the year.",
"\n\nAs the customer teams did not have alternative engine suppliers, and thus being totally dependent on the supply of the FWMV engine, the teams got together and negotiated with Lee so that Oil company sponsorship funds would be funneled through the teams to Coventry Climax to cover the mounting costs, and Lee agreed to continue the development and support of these engines.",
"\n\nThis incident became the seed for the formation of Formula One Constructors Association later in the 1970s.",
"\n\nDewar Trophy\nIn May 1964, the Royal Automobile Club presented the Dewar Trophy, which is given at the recommendation of RAC's Technical and Engineering Committee for the most outstanding British achievement in the automotive field, to Leonard Pelham Lee. ",
" The citation reads: \"Awarded to Coventry Climax Engines Ltd. for the design, development and production of engines which have brought British cars to the forefront in the field of Grand Prix racing.\"",
"\n\nHistory of this trophy dates back to 1906. ",
" The last time Dewar Trophy was awarded before 1964, the recipient was Alec Issigonis for British Motor Corporation in 1959, who once was a Junior Engineer at Coventry Climax, on the design and production of ADO15 Mini.",
"\n\nSee also\nHenry Pelham Lee\n\nCoventry Climax Engines\n\nGodiva Fire Pumps\n\nReferences\n\nCategory:1903 births\nCategory:1980 deaths\nCategory:English businesspeople"
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"Introduction {#sec1}\n============\n\nProtein interactions (protein--protein, protein--nucleotide (DNA, RNA), and protein--small-molecule interactions) underlie most biological functions.^[@ref1]^ However, we know far more about protein sequences than protein functions, owing largely to the rapid advances of next-generation DNA/RNA sequencing technologies. ",
"It is therefore highly desirable to develop next-generation protein technologies that allow rapid characterization of protein functions, especially protein interactions. ",
"Current approaches for protein interactions, for example, isothermal titration calorimetry^[@ref2]^ and fluorescence polarization,^[@ref3]^ often require costly instruments and extensive protein purification and labeling and therefore are time-consuming and limited to a few protein targets at one time. ",
"The cell-based genetic two-hybrid systems,^[@ref4]^ on the other hand, have the advantages of carrying out a large number of protein interactions in each cell for selection or screening. ",
"In a typical genetic two-hybrid system, two target proteins are expressed inside the cell as hybrid proteins fused to an activation domain (AD) and a DNA(promoter)-binding domain (DB), respectively. ",
"The interaction between the target proteins recruits AD to the promoter region in the nucleus and activates the promoter-bound RNA polymerase. ",
"The issues with the genetic systems, however, are potential interferences from endogenous cellular proteins, which can lead to false negative or false positive results,^[@ref4],[@ref5]^ toxicity of some expressed protein interactions, and accessibility to targets due to cellular membranes and efflux pumps.^[@ref6]^\n\nCell-free systems in general have advantages over cell-based systems for protein function studies.^[@ref7]^ Without the need to grow and genetically manipulate cells, proteins (including toxic proteins) can be made and tested in a few hours in cell-free systems. ",
"Without the barrier of a cell wall or membrane, a variety of conditions, such as addition of labeled or unnatural amino acids and small-molecule inhibitors, can be applied to cell-free systems.^[@ref8]^ Cell-free split-protein systems (or protein fragment complementation assays^[@ref4],[@ref9]^) have been developed for *in vitro* protein interaction studies and have additional advantages of simultaneously expressing the target proteins and detecting their interactions via simple reporter assays.^[@ref10]−[@ref12]^ In the absence of the protein--protein interaction, the split fragments of the reporter by themselves cannot reassemble into the active form. ",
"The interaction between two target proteins, each of which is fused to a reporter fragment, results in the reconstitution of the activity of the reporter.",
"\n\nIn this work, we intend to create a synthetic *in vitro* two-hybrid system (IVT2H) from a reconstituted cell-free system. ",
"We chose the two-hybrid approach because the protein interaction in a two-hybrid system only has to bring the activation domain to the vicinity of the RNA polymerase, which can result in activation of the expression of an intact reporter. ",
"In comparison, the detection of the protein interaction in a split-reporter system requires the precise alignment of the active site residues of the split reporter, and the reconstitution of its native structure while it is fused to two interacting proteins. ",
"Even under a strong protein--protein interaction, the reconstituted split reporter can have a significantly lower activity than the intact (nonfragmented) reporter,^[@ref13]^ suggesting that a majority of split fragments do not form the native structure. ",
"We reason that the two-hybrid system is potentially less affected by protein conformation than the split-reporter approach. ",
"We chose the reconstituted cell-free system because it has additional advantages of lacking most cellular proteins and activities, allowing *in vitro* reconstruction of the process of bacterial transcription initiation in the absence of other regulatory factors.^[@ref14],[@ref15]^ Building on our previous work, we here report the creation of the first cell-free equivalent of the genetic two-hybrid systems.",
"\n\nResults and Discussion {#sec2}\n======================\n\nEngineering Bacterial Transcription Regulation in the Reconstituted Cell-Free System {#sec2.1}\n------------------------------------------------------------------------------------\n\nThe design principle of IVT2H (Figure [1](#fig1){ref-type=\"fig\"}) was based on the process of transcriptional activation of σ^54^-RNAP in *Escherichia coli*, due to the similarity to the eukaryotic mode of gene activation.^[@ref16]^ σ^54^-RNAP forms an inactive transcriptional initiation complex on a σ^54^ promoter (*pspA*), which can be activated in *E. coli* by the bacterial enhancer binding protein PspF.^[@ref16],[@ref17]^ PspF functions by binding to the upstream activation sequences (UAS) near the promoter and contacting the promoter-bound σ^54^-RNAP via DNA looping stabilized by the binding of integration host factor (IHF).^[@ref17],[@ref18]^ As a transcriptional activator, PspF is a modular protein, consisting of an N-terminal activation domain (AD), which forms a hexamer in order to activate transcription, and a C-terminal DNA binding domain (BD), which binds UAS (I and II) to facilitate the oligomerization of AD.^[@ref19]^ Like the transcription factors in the genetic two-hybrid systems,^[@ref4]^ PspF was the basis for constructing the hybrid fusion proteins in IVT2H (Figure [1](#fig1){ref-type=\"fig\"} and Figure S1B, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"The components of IVT2H were derived from a reconstituted bacterial transcription and translation system.^[@ref14]^ In addition to the purified *E. coli* translation components and T7 RNA polymerase,^[@ref15]^ the protein components of IVT2H included purified *E. coli* RNA polymerase core enzyme (RNAP), recombinant *E. coli* IHF, and RNase inhibitor. *",
"E. coli* σ^54^ was added as a purified protein or expressed during the IVT2H reaction from a DNA construct (Figure S1A, [Supporting Information](#notes-3){ref-type=\"notes\"}, P~T7~-σ^54^).",
"\n\n{#fig1}\n\nTo demonstrate PspF-dependent, enhancer-specific transcription activation (Figure [1](#fig1){ref-type=\"fig\"}A), we expressed the full-length PspF (AD-BD) or its activation domain (AD) under T7 promoter in an IVT2H reaction containing a reporter DNA *pspA*-Fluc expressing firefly luciferase (Fluc) under the *pspA* promoter^[@ref17]^ with UAS I and II (Figure [1](#fig1){ref-type=\"fig\"}A and Figure S1B,C, [Supporting Information](#notes-3){ref-type=\"notes\"}) and measured the luciferase activities of aliquots after incubation at 37 °C. ",
"The expression of PspF resulted in a significant luciferase activity, whereas in the absence of the DNA binding domain, no significant luciferase activity was observed (Figure [2](#fig2){ref-type=\"fig\"}A, PspF and AD, gray columns). ",
"The data suggest that the binding of the expressed full-length PspF to the reporter DNA *pspA*-Fluc was necessary to activate the expression of Fluc in IVT2H, consistent with previous *in vivo* studies or *in vitro* experiments using purified PspF and AD.^[@ref16],[@ref17]^ Next, we used the lambda repressor protein Cro to replace the DNA binding domain (BD) of PspF, generating a hybrid fusion protein AD-Cro. ",
"Cro binds to its consensus operator sequence (*consensus*) as a homodimer.^[@ref20],[@ref21]^ Accordingly, we replaced the PspF BD-specific UAS I and II in *pspA*-Fluc with 2 copies of the Cro consensus operator sequence to generate another reporter DNA *2xcons*-Fluc (Figure S1C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"The expression of AD-Cro resulted in a significantly higher luciferase activity from *2xcons*-Fluc than that from *pspA*-Fluc (Figure [2](#fig2){ref-type=\"fig\"}A, AD-Cro, white vs gray columns), whereas the expression of PspF generated higher luciferase from the wild-type promoter in *pspA*-Fluc than that from *2xcons*-Fluc (Figure [2](#fig2){ref-type=\"fig\"}A, PspF, gray vs white columns). ",
"The data suggest that we could fuse a different DNA binding domains to the activation domain of PspF and activate transcription simply by inserting a corresponding DNA recognition sequence upstream of the promoter. ",
"Two copies of the Cro consensus sequence in *2xcons*-Fluc seemed to be sufficient to induce the hexamer formation of AD to activate transcription, presumably by recruiting AD-Cro near the promoter and increasing the local concentration of AD. ",
"Use of one copy of the Cro consensus sequence decreased the reporter expression, whereas more copies of the Cro consensus sequences did not further increase the reporter expression (Figure S2A, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"Taken together, these results not only demonstrate that we have recapitulated the PspF-mediated transcription activation *in vitro* but also suggest that IVT2H could potentially be used to study protein--DNA interaction (Figure [1](#fig1){ref-type=\"fig\"}A), a concept well-known as the yeast and bacterial one-hybrid systems.^[@ref22],[@ref23]^\n\n![",
"Transcription activation and detection of protein--DNA interaction in IVT2H. (A) PspF-dependent, enhancer-specific transcription activation in IVT2H. The full-length PspF protein (PspF), the PspF activation domain (AD), or a hybrid fusion protein (AD-Cro) was expressed in IVT2H containing a reporter DNA with an upstream activation sequence specific to either PspF (*pspA*-Fluc, gray columns) or Cro (*2xcons*-Fluc, white columns). (",
"B) Protein--DNA interactions. ",
"For AD-Cro and AD-Cro K56\\[DGEVK\\], *2xcons*-GFP was the reporter DNA; for AD-Zif and AD-ZifAA4, *4xzif*-GFP was the reporter DNA. ",
"Data in panels A and B are means from at least two independent IVT2H reactions; error bars show sd.](ja-2014-02512g_0002){#fig2}\n\nProtein--DNA Interaction {#sec2.2}\n------------------------\n\nTo further demonstrate the above application, we replaced Cro with the DNA binding domain of zinc-finger protein Zif268 (Zif).^[@ref24]^ Zif binds to its consensus operator sequence (*zif*) as a monomer with *K*~d~ = 0.5--5 nM.^[@ref25],[@ref26]^ In comparison, Cro binds to its consensus operator sequence with a much higher affinity (*K*~d~ = 1.2 pM).^[@ref20]^ We used four copies of Zif consensus operator sequence as UAS to construct a reporter DNA *4xzif*-GFP, expressing a green fluorescent protein for the hybrid fusion protein AD-Zif (Figure S1C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"To facilitate the comparison, we constructed *2xcons*-GFP for AD-Cro. ",
"The expression of AD-Cro resulted in a significantly higher GFP fluorescence from *2xcons*-GFP than AD-Zif from *4xzif*-GFP, suggesting that the higher DNA binding affinity led to stronger transcription activation (Figure [2](#fig2){ref-type=\"fig\"}B, first and third columns). ",
"However, it has been postulated that the high affinity of Cro is due to its dimerization coupled to DNA binding,^[@ref21],[@ref27]^ whereas Zif binds DNA as a monomer without the cooperativity.^[@ref25]^ We therefore suspected that the high fluorescence signal of AD-Cro could be the synergistic effect of Cro dimerization and DNA binding on enhancing the hexamer formation of AD and transcription activation. ",
"To address this question, we fused AD to a Cro monomeric mutant Cro K56\\[DGEVK\\]. ",
"The expression of the hybrid fusion protein AD-Cro K56\\[DGEVK\\] resulted in a drastic decrease in the fluorescent signal from *2xcons*-GFP (Figure [2](#fig2){ref-type=\"fig\"}B, second column) compared with AD-Cro and to a similar level as that of AD-Zif from *4xzif*-GFP (Figure [2](#fig2){ref-type=\"fig\"}B, third column). ",
"The data are consistent with previous studies suggesting that the K56\\[DGEVK\\] mutation reduced Cro DNA binding affinity by \\>2000-fold.^[@ref27]^ Taking a step further, we added a synthetic leucine zipper (AA4)^[@ref28]^ to the C-terminus of Zif to artificially homodimerize Zif. ",
"The expression of the resulting hybrid fusion protein AD-ZifAA4 indeed increased GFP fluorescence significantly compared with AD-Zif from the same reporter DNA (*4xzif*-GFP) (Figure [2](#fig2){ref-type=\"fig\"}B, fourth and third columns). ",
"As control experiments, AD-Cro K56\\[DGEVK\\] or AD-Zif was expressed in IVT2H with a reporter DNA containing a nonspecific UAS (*4xAT*-GFP, Figure S1C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"Both hybrid fusion proteins generated significantly higher GFP fluorescence from the specific UAS (*2xcons* and *4xzif*, respectively) than from the nonspecific UAS (Figure S2B, [Supporting Information](#notes-3){ref-type=\"notes\"}, white vs gray columns).",
"\n\nProtein--Protein Interaction {#sec2.3}\n----------------------------\n\nTo demonstrate real-time detection of protein--protein interaction in IVT2H (Figure [1](#fig1){ref-type=\"fig\"}B), we first chose FK506 binding protein (FKBP) and FKBP-rapamycin binding domain of mTOR (FRB), known to form a heterodimer in the presence of rapamycin.^[@ref29]^ The hybrid fusion proteins, AD-FKBP and FRB-Cro were coexpressed in the IVT2H reactions containing the reporter DNA *2xcons*-GFP in the presence or absence of rapamycin. ",
"The fluorescent signal of each reaction was monitored in real-time during incubation at 37 °C. ",
"In the presence of rapamycin, GFP fluorescence increased significantly after ∼60 min and reached a saturation after ∼6 h (Figure [3](#fig3){ref-type=\"fig\"}A, left panel, +rapamycin). ",
"In the absence of rapamycin, only a small increase in the GFP fluorescence was observed over a period of 8 h (Figure [3](#fig3){ref-type=\"fig\"}A, left panel, −rapamycin). ",
"Here we successfully demonstrated the concept of the genetic two-hybrid system^[@ref4]^ in IVT2H, whereby the specific interaction between FKBP and FRB from expressed hybrid fusion proteins resulted in transcription activation and GFP expression. ",
"Using FKBP and FRB, we further demonstrate the use of IVT2H as a reverse two-hybrid system^[@ref30]^ in which the protein--protein interaction represses the reporter expression (Figure [1](#fig1){ref-type=\"fig\"}C). ",
"In the reverse IVT2H, the FKBP and FRB interaction was designed to activate the expression of an *E. coli* transcription repressor anti-σ^28^, which inhibits the GFP expression under a σ^28^ promoter *fliC* by binding to a coexpressed σ^28^ (Figure [1](#fig1){ref-type=\"fig\"}C). ",
"In addition to the DNA constructs for AD-FKBP and FRB-Cro, the reverse IVT2H reaction contained a repressor DNA (*2xcons*-anti-σ^28^), a σ^28^-expressing DNA (P~T7~-σ^28^), and a reporter DNA (*flicC*-GFP) (Figure S1A,B, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"In contrast to the IVT2H reaction (Figure [3](#fig3){ref-type=\"fig\"}A, left panel), the presence of rapamycin in the reverse IVT2H reaction resulted in a low GFP signal (Figure [3](#fig3){ref-type=\"fig\"}A, right panel, +rapamycin), whereas the absence of rapamycin led to a significant increase in the GFP signal (Figure [3](#fig3){ref-type=\"fig\"}A, right panel, −rapamycin).",
"\n\n{ref-type=\"notes\"}). ",
"The dashed line indicates the level of fluorescence (background) of an IVT2H reaction in which the protein interaction pair has no known affinity. ",
"The data are means from at least two independent IVT2H reactions; error bars show sd.](ja-2014-02512g_0003){#fig3}\n\nTo further establish IVT2H for detecting binary protein--protein interactions, we tested a number of other protein pairs with a wide range of known affinities (Table S1, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"We observed a remarkable correlation of the intensity of GFP fluorescence with the reported *K*~d~ of the protein--protein interaction (Figure [3](#fig3){ref-type=\"fig\"}B, between 10 and 1000 nM). ",
"However, no obvious correlation was observed when *K*~d~ is below 10 nM (Figure [3](#fig3){ref-type=\"fig\"}B, between 0.1 and 10 nM). ",
"The data suggest that the affinity of the binary protein--protein interaction, if between 10 nM and 1.0 μM, primarily determined the amount of the synthesized reporter protein under the IVT2H conditions. ",
"Despite the dynamic nature of the IVT2H reaction in which the concentrations of the synthesized proteins change over time and are limited by the overall protein synthesis capacity,^[@ref14]^ the correlation of the protein interaction affinity with the signal output in IVT2H can potentially be described by a mathematical model for three-component binding equilibria.^[@ref31]^ The formation of a ternary complex of AD-X, Y-Cro, and the reporter DNA in IVT2H is a critical step for transcription activation (Figure [1](#fig1){ref-type=\"fig\"}B) and therefore is directly correlated to the GFP expression. ",
"In the equilibria of three components, AD-X, Y-Cro, and the reporter DNA, the concentration of the ternary complex is determined by the concentration of each component, the affinity between X and Y (*K*~X·Y~) and the affinity between Cro and its specific UAS (*K*~Cro·DNA~) (Figure S2C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"Cro binds its UAS with a *K*~d~ of 1.2 pM, making the affinity of X and Y a limiting factor for the ternary complex formation. ",
"Using simulations provided by the mathematical model,^[@ref31]^ we plotted the dose--response curves of the ternary complex at different affinities of X and Y (Figure S2D, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"The results (see the legend in Figure S2D, [Supporting Information](#notes-3){ref-type=\"notes\"}) are consistent with not only the observed correlation between the GFP expression and the affinity of the protein--protein interaction (between 10 and 1000 nM, Figure [3](#fig3){ref-type=\"fig\"}B) but also with the observed noncorrelation at affinities below 10 nM (between 0.1 and 10 nM, Figure [3](#fig3){ref-type=\"fig\"}B).",
"\n\nProtein--RNA Interaction {#sec2.4}\n------------------------\n\nWe further demonstrated the use of IVT2H as a three-hybrid system^[@ref32]^ for the detection of protein--RNA interactions (Figure [1](#fig1){ref-type=\"fig\"}D). ",
"As the hybrid fusion proteins, we chose the first 22 residues of the N-protein of the bacteriophage lambda (λN22)^[@ref33]^ and the coat protein of the *Pseudomonas* phage PP7 (PP7CP),^[@ref34]^ generating AD-λN22 and PP7CP-Cro, respectively. ",
"Since λN22 and PP7CP bind to their hairpin RNA substrates, λboxB and PP7, respectively, we created a substrate RNA construct (P~T7~ λboxB-PP7), which can produce a hybrid RNA substrate (λboxB-PP7) from T7 promoter during the IVT2H reaction. ",
"As a control, PP7 was replaced by TAR, a hairpin RNA from HIV,^[@ref35]^ to generate a nonsubstrate construct (P~T7~ λboxB-TAR). ",
"In the IVT2H reactions expressing both AD-λN22 and PP7CP-Cro, addition of P~T7~ λboxB-PP7 resulted in significant luciferase activity (Figure [4](#fig4){ref-type=\"fig\"}, third column), whereas in the absence of P~T7~ λboxB-PP7 or the presence of the nonsubstrate RNA (P~T7~ λboxB-TAR), no significant luciferase activity was observed (Figure [4](#fig4){ref-type=\"fig\"}, first and second columns, respectively). ",
"Expression of only one hybrid protein (AD-λN22) also failed to generate significant luciferase activity (Figure [4](#fig4){ref-type=\"fig\"}, fourth column). ",
"The data suggest that the specific binding of the hybrid fusion proteins to both RNA substrates activated the expression of the luciferase reporter.",
"\n\n{#fig4}\n\nScreening Small-Molecule Inhibitors of Protein--Protein Interaction {#sec2.5}\n-------------------------------------------------------------------\n\n*In vitro* biochemical assays and genetic two-hybrid systems have been widely used for high-throughput screening (HTS) of small molecule inhibitors of protein--protein interactions.^[@ref36],[@ref37]^ To demonstrate the use of IVT2H as a homogeneous mix-and-read biochemical assay for HTS, we chose the protein--protein interaction between the ligand binding domain of human estrogen receptor α (ERα LBD) and the receptor interaction domain of human nuclear receptor coactivator 1 (NCOA1 RID), due to commercial availability of small-molecule modulators and the fact that the steroid hormone 17β-estradiol (E2) can induce the interaction by binding to ERα LBD.^[@ref38]^ We first showed that addition of E2 resulted in a dose-dependent increase in the luciferase activity (Figure S3A, [Supporting Information](#notes-3){ref-type=\"notes\"}), thus establishing IVT2H as an *in vitro* assay for the ERα/NCOA1 interaction. ",
"Using such IVT2H assay with E2, we set up to screen a library of 67 steroid and steroidal mimetic compounds (Table S2, [Supporting Information](#notes-3){ref-type=\"notes\"}) for inhibitors of the ERα/NCOA1 interaction in a 1536-well plate quantitative high-throughput screen (qHTS) format.^[@ref39]^ The activity of each compound was determined over an 11-point titration range from nanomolar to 100 μM (Figure [5](#fig5){ref-type=\"fig\"}A). ",
"A known antagonist, 4-hydroxytamoxifene, was used as a positive control for the inhibitor screen. ",
"From our screen, we identified raloxifene and fulvestrant (ICI 182 780) as inhibitors with higher potency than 4-hydroxytamoxifene (Figure [5](#fig5){ref-type=\"fig\"}B). ",
"The data are consistent with the activities of these compounds as the only known antagonists of the ERα/NCOA1 interaction in the 67-compound library.^[@ref40],[@ref41]^ Since the hybrid fusion proteins were synthesized during the IVT2H assay, the concentrations of ERα LBD and NCOA1 RID started at zero and increased to an estimated micromolar range at the end of the IVT2H reactions (Figure S5, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"This could explain that higher IC~50~ values were obtained in the IVT2H assays than those of biochemical inhibition assays in which the protein concentrations are often fixed at a low nanomolar range.^[@ref42]^ Nevertheless, the rank order of inhibition observed in the IVT2H assay for these compounds seemed to be consistent with other assays (Figure [5](#fig5){ref-type=\"fig\"}B).^[@ref40],[@ref41]^\n\n{ref-type=\"notes\"}) against E2-mediated interaction of ERα LBD/NCOA1 RID as measured by the luciferase activity. ",
"Lines connect data points (black dots) from 11-point compound titrations. ",
"Color lines: four parameter fit to compounds yielding a concentration--response (cyan, inhibitory; red, stimulatory; green, positive control (4-hydroxytamoxifene). ",
"Gray lines: data not fit into a concentration--response curve. (",
"B) Concentration--response curves of three active compounds (raloxifene, IC~50~ = 33.9 nM; fulvestrant, IC~50~ = 141 nM; lithocholic acid, IC~50~ = 15.2 μM) and the control compound (4-hydroxytamoxifene, IC~50~ = 5.2 μM). ",
"See Supplemental Table 3, [Supporting Information](#notes-3){ref-type=\"notes\"} and online methods for additional protocol information.](ja-2014-02512g_0005){#fig5}\n\nIn summary, we recreated the process of bacterial enhancer-specific gene activation in a reconstituted cell-free system using a bottom-up synthetic biology approach. ",
"We further engineered such synthetic system to create IVT2H and demonstrated its broad utility as a universal assay format for protein interactions. ",
"Unlike cell-based genetic systems that require manipulating cellular genetic backgrounds for detecting different types of protein interactions, IVT2H can be formulated into one-hybrid, two-hybrid, reverse two-hybrid, or three-hybrid assay simply by changing DNA constructs, while the protein components of IVT2H remain unchanged. ",
"Such flexibility of IVT2H can be harnessed for more applications. ",
"For instance, IVT2H can be constructed as a reverse two-hybrid assay for screening small-molecule inhibitors, allowing inhibition to generate a positive signal (Figure S3B, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"As a three-hybrid system, IVT2H can potentially be used to detect not just RNA but any molecule in solution (Figure [1](#fig1){ref-type=\"fig\"}D).",
"\n\nDetection of protein interactions in IVT2H requires the same reconstituted protein translation machinery to synthesize multiple proteins (interacting proteins, σ^54^, and reporter protein) in coupled steps. ",
"In *in vitro* reactions, IVT2H has a defined capacity for protein synthesis; therefore, the amounts of DNA in IVT2H affect the optimal signal-to-noise ratio. ",
"Since the interacting proteins and σ^54^ are expressed under the strong T7 promoter and the reporter under the relatively weak σ^54^ promoter, the DNA concentrations in IVT2H are adjusted to the picomolar range for the interacting proteins and σ^54^ and the nanomolar range for the reporter. ",
"By varying the DNA concentrations, we determined that the optimal DNA concentration for the DNA-interacting protein is ∼10 pM and that for protein--protein interacting pairs is ∼50 pM (Figure S4A,B, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"Higher DNA concentrations resulted in higher amounts of the interacting proteins (Figure S5A,B, [Supporting Information](#notes-3){ref-type=\"notes\"}) but lower GFP reporter signals (Figure S4A,B, [Supporting Information](#notes-3){ref-type=\"notes\"}), likely due to the limited synthesis capacity of IVT2H. The optimal DNA concentrations and the correlations of the DNA concentrations with the protein amounts in IVT2H have been carefully characterized for only a few proteins (Figure S5, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"It is possible that some interacting proteins are not expressed or are expressed at unusually high levels, which could lead to false negative or false positive signals in IVT2H. At least 4.4--10 nM of the reporter DNA is needed in IVT2H to generate sufficient GFP signal (Figure S4C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"Further increasing the reporter DNA concentrations can result in a stronger GFP signal but also a higher signal from the nonspecific interaction (Figure S4C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"In addition, using higher reporter DNA concentrations increases the cost of making DNA. ",
"The protein components of IVT2H can be readily purified^[@ref43]^ or obtained from commercial sources (Table S4, [Supporting Information](#notes-3){ref-type=\"notes\"}).",
"\n\nCell-free split-protein systems represent a similar approach to IVT2H for *in vitro* detection of a variety of protein interactions.^[@ref10],[@ref11]^ Like IVT2H, split-protein systems can also be applied for screening small-molecule inhibitors of protein--protein interaction.^[@ref44]^ The signal from the cell-free split-protein assay is dependent on the reconstitution of the activity of the reporter protein, potentially can be monitored in real-time, but is not coupled to a gene activation event (at least *in vitro*). ",
"In IVT2H, protein interaction is coupled to the activation of a reporter gene via domain recruitment. ",
"Consequently the signal is amplified by the transcription and translation of the nonfragmented reporter protein. ",
"In addition, we show that the signal from IVT2H is correlated to the relative strength of the protein interaction.",
"\n\nConclusions {#sec3}\n===========\n\nThough a variety of genetic systems and *in vitro* systems for detecting protein interactions have been developed,^[@ref4]^ direct comparison of these methods against the same reference sets reveals that each method has inherent limitations and often detects a subset of interactions.^[@ref45]^ In this work, we develop IVT2H as a unique cell-free system for detection of protein interactions, which is clearly distinct from cell-based methods and cell-free split-protein systems. ",
"IVT2H may serve as an alternative and independent tool for validating existing protein interaction data and providing new ones. ",
"Without using cells, IVT2H may detect \"elusive\" protein interactions, such as those of difficult-to-express proteins or those toxic to cells. ",
"The next step for IVT2H is its integration with high-throughput platforms to allow selection or screening of protein interactions, a current advantage of cell-based genetic systems. ",
"Cell-free systems are compatible with liposomes^[@ref46]^ and microdroplets;^[@ref47]^ thus use of IVT2H for high throughput protein interaction studies is highly possible.",
"\n\nAs a reconstituted synthetic biological system, IVT2H contains a defined number of components with known initial concentrations, thus representing a unique experimental model for computational simulations of synthetic gene circuits or chemical biology of gene regulation.",
"\n\nMaterials and Methods {#sec4}\n=====================\n\nReconstitution of IVT2H {#sec4.1}\n-----------------------\n\nIVT2H was based on previous work that coupled *E. coli* transcriptional machinery to the reconstituted protein synthesis system.^[@ref14],[@ref15]^ IVT2H typically contained the reconstituted protein synthesis system (with T7 RNA polymerase),^[@ref14],[@ref15]^ purified *E. coli* RNA polymerase core enzyme (New England Biolabs), purified recombinant *E. coli* IHF,^[@ref43]^ murine RNase inhibitor (New England Biolabs), and DNA constructs (plasmids and linear DNA) expressing sigma factors, hybrid fusion proteins, RNA substrates, and reporters (see below).",
"\n\nDNA Constructions for IVT2H {#sec4.2}\n---------------------------\n\nThe gene for *E. coli* sigma 54 (σ^54^) was amplified by PCR from *E. coli* genomic DNA and cloned into an expression vector pCOAT containing a T7 promoter^[@ref48]^ to generate the plasmid DNA P~T7~-σ^54^ (Figure S1A, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"The σ^54^ protein was expressed in *E. coli* from P~T7~-σ^54^ as a recombinant protein with a N-terminal 6xhis tag and purified according a previous protocol.^[@ref48]^ The gene for *E. coli* phage-shock protein F (PspF) was amplified from *E. coli* genomic DNA and cloned into pCOAT to give P~T7~-PspF (Figure S1B, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"Similarly, the activation domain (AD, residues 1--296) of PspF was cloned into pCOAT to give P~T7~-AD. ",
"The gene for the lambda repressor protein Cro^[@ref49]^ was amplified from lambda phage DNA, whereas the genes for Cro K56\\[DGEVK\\],^[@ref50]^ the zinc finger DNA binding domain of Zif268 (Zif),^[@ref51]^ and the fusion protein ZifAA4^[@ref28]^ were synthesized commercially (Integrated DNA Technologies) (Figure S1B, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"The genes for interacting protein pairs (X and Y), including FK506 binding protein (FKBP) and a 100-amino acid domain (E2015 to Q2114) of the mammalian target of rapamycin (mTOR) known as the FKBP-rapamycin binding domain (FRB),^[@ref52]^ the first 22 residues of the N-protein of the bacteriophage lambda (λN22)^[@ref33]^ and the coat protein of the *Pseudomonas* phage PP7 (PP7CP),^[@ref34]^ and the protein pairs listed in Supplementary Table 1, [Supporting Information](#notes-3){ref-type=\"notes\"}, were synthesized commercially (Integrated DNA Technologies) and typically cloned to the C-terminus of AD in pCOAT to generate P~T7~-AD-X, or the N-terminus of Cro in pCOAT to generate P~T7~-Y-Cro (Figure S1B, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"To generate the RNA substrate for the three-hybrid IVT2H, the gene for the hybrid hairpin RNA λboxB-PP7 was synthesized and cloned into pUCA105T7^[@ref14]^ to generate the substrate DNA construct (P~T7~ λboxB-PP7). ",
"As a control, PP7 was replaced by TAR, a hairpin RNA from HIV,^[@ref35]^ to generate a nonsubstrate DNA (P~T7~ λboxB-TAR).",
"\n\nTo construct a reporter DNA for σ^54^-mediated transcription activation, the −130 to +20 region of the *E. coli pspA* promoter was amplified from *E. coli* genomic DNA to replace the T7 promoter in pUCA108T7.^[@ref14]^ The gene for firefly luciferase (*fluc*) was then cloned into such vector to generate *pspA*-Fluc (Figure S1C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"The *pspA* promoter region contains a binding site for IHF and two upstream activation sequences (UAS I and II, between position −80 and −126 relative to the transcription start site) for PspF.^[@ref18],[@ref53]^ To facilitate the replacement of UAS I and II with other DNA recognition sequences, we introduced a unique restriction enzyme site (*Bam*HI) at 3′ end of UAS II such that UAS I and II were flanked by *Btm*I and *Bam*HI sites. ",
"By simple linker insertion, we replaced UAS I and II with the consensus operator sequence for Cro (*consensus*)^[@ref20]^ or Zif (*zif*)^[@ref51]^ (Figure S1E, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"As a nonspecific DNA binding control (nonspecific UAS), we also replaced UAS I and II with an arbitrary AT-rich sequence (*AT*) (Figure S1E, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"To allow real-time monitoring of transcription activation, we also cloned the gene for green fluorescence protein (GFP) in the reporter DNA constructs, replacing Fluc as the reporter (Figure S1C, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"In all IVT2H reactions, the reporter DNA constructs were used as linear PCR fragments generated by direct amplification from the corresponding plasmids using the primer pUCAfw (5′-CAGGGTTATTGTCTCATGAGCGG-3′) and pUCArv (5′-GAGCTGATACCGCTCGCCGCAGC-3′).",
"\n\nFor the reverse IVT2H, the gene for *E. coli* sigma 28 (σ^28^)^[@ref54]^ was amplified by PCR from *E. coli* genomic DNA and cloned into pCOAT to generate P~T7~-σ^28^ (Figure S1A, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"The gene for *E. coli* anti-sigma 28 (anti-σ^28^ or FlgM^[@ref54]^) was amplified by PCR from *E. coli* genomic DNA to replace the GFP gene in *2xcons*-GFP, generating the repressor DNA *2xcons*-anti-σ^28^ (Figure S1D, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"To construct the reporter DNA for σ^28^-mediated transcription activation, −120 to +20 region of the *E. coli fliC* promoter^[@ref55]^ was amplified from *E. coli* genomic DNA to replace the T7 promoter in pUCA108T7.^[@ref14]^ The gene for Fluc or GFP was then cloned into such vector to generate *fliC*-Fluc or *fliC*-GFP (Figure S1C, [Supporting Information](#notes-3){ref-type=\"notes\"}).",
"\n\nSetting up IVT2H Reactions {#sec4.3}\n--------------------------\n\nUnless specified otherwise, all IVT2H reactions contained 144 nM RNAP core enzyme, 1.2 μM IHF, 0.8 units μL^--1^ RNAase inhibitor, 0.2 ng μL^--1^ (45 pM) plasmid DNA expressing σ^54^, 0.2 ng μL^--1^ (∼40--60 pM) DNA constructs expressing hybrid fusion proteins, 4.4 nM linear reporter DNA expressing Fluc or GFP, and the reconstituted protein synthesis system^[@ref14],[@ref15]^ (Table S4, [Supporting Information](#notes-3){ref-type=\"notes\"}). ",
"For binary protein--protein interactions in Figure [3](#fig3){ref-type=\"fig\"}B, purified recombinant σ^54^ protein (80 nM) was used instead of the plasmid DNA (although no major difference was observed between protein and DNA). ",
"For the reverse IVT2H (Figure [3](#fig3){ref-type=\"fig\"}A, right panel, and Figure S3B, [Supporting Information](#notes-3){ref-type=\"notes\"}), the plasmid DNA P~T7~-σ^28^ (40 pM), the plasmid reporter DNA *fliC*-GFP or *fliC*-Fluc (1.5 nM) and the linear repressor DNA *2xcons*-anti-σ^28^ (4.4 nM) were additionally used. ",
"For the three-hybrid IVT2H (Figure [4](#fig4){ref-type=\"fig\"}), the plasmid DNA P~T7~ λboxB-PP7 (80 pM) was additionally used. ",
"For the IVTH reactions involving small molecules (except those for qHTS), small molecules (in H~2~O or DMSO (\\<25%)) were added (typically 1 μL in a 25 μL reaction) in the indicated final concentrations before the IVT2H reactions. ",
"For the IVT2H involving the interaction between phosphorylated YEEI peptide (pYEEI) and SH~2~ domain (Figure [3](#fig3){ref-type=\"fig\"}B, Table S1, [Supporting Information](#notes-3){ref-type=\"notes\"}), purified recombinant Src kinase (GST-tagged human Src kinase from Sigma; 1.5 μL in a 25 μL reaction) was added before the reaction.",
"\n\nIVT2H reactions were typically set up by mixing the DNA constructs with the protein components in a 25 μL reaction volume and then incubating at 37 °C in 500 μL Epppendorf tubes for the luciferase reporter or in a 383-well microplate (Corning, Lowell, MA) for the GFP reporter. ",
"IVT2H for qHTS is described separately below.",
"\n\nActivity Assays of the Reporter Proteins {#sec4.4}\n----------------------------------------\n\nThe activity of the luciferase reporter (Fluc) was assayed using the Luciferase Assay System (Promega, Madison, WI) in a microplate luminometer (Centro LB 640, Berthold Technologies, Oak Ridge, TN) according to manufacturers' instructions. ",
"Aliquots (5 μL) from the IVT2H reactions incubated at 37 °C for 2--4 h were diluted 10-fold in 1× cell culture lysis reagent (Promega, Madison, WI) containing 1 mg/mL BSA. ",
"Aliquots (5 μL) of the dilutions were then added in triplicate to a microplate for the luciferase assay in the luminometer. ",
"The GFP fluorescence (ex. ",
"513 nm, em. ",
"532 nm) was measured directly from a 384-well microplate (Corning, Lowell, MA) every 5 min for up to 8 h in a Spectramax M5 microplate reader (Molecular Devices, Sunnyvale, CA) in which the chamber temperature was maintained at 37 °C.",
"\n\nUsing IVT2H for qHTS Assay {#sec4.5}\n--------------------------\n\nqHTS is the simultaneous testing of compound arrays across a dilution series covering 4--5 orders of magnitude in concentration. ",
"The approach, most efficient in low-volume assay formats, enables the pharmacological characterization of chemical libraries. ",
"To adapt the IVT2H assay to a qHTS format, a 1536-well white/solid bottom plate (Cat. ",
"no. ",
"789175-F, Greiner Bio-One North America) was pretreated with 5 μL of 0.1% tween-20 using the BioRAPTR flying reagent dispenser (FRD; Beckman Coulter Inc., Indianapolis, IN), covered, and allowed to stand overnight at ambient temperature. ",
"Next day, the plate was inverted and centrifuged for 3 min at 1000 rpm to remove detergent and allowed to air-dry. ",
"Two microliters/well of IVT2H solution (final concentrations 60% ER-NR-CoA1 solution A, 40% PIA solution B) with or without 20 nM β-estradiol (E2) were dispensed into respective wells of the pretreated plate with a BioRAPTR FRD where the dispense tubing had been precoated with 0.1% tween-20 to prevent adsorption of protein components. ",
"A 1536-well compound library plate (Cat. ",
"no. ",
"789270-C, Greiner Bio-One North America) containing 11-point titrations of 67 steroids and steroid-mimetics from the Prestwick collection (Prestwick Chemical, Washington, DC) was prepared in DMSO starting at concentration between 4.5 and 10 mM and ending with a concentration of between 75.7 and 169 nM, depending on the specific compound (see Figure [3](#fig3){ref-type=\"fig\"}). ",
"From this plate, 23 nL of each sample was transferred using a 1536-well pin tool (Wako Hornet-KL uHTS system, DJK Scientific, Inc., San Diego, CA), which allows for delivery of each compound to the assay plate at final compound concentrations ranging from approximately 51--115 μM to 87 pM to 2 nM. Controls were as follows: 23 nL/well of high concentration (final concentration 115 μM) 4-hydroxytamoxifene positive antagonist control, a 16-point 1:2 titration (115 μM to 3.5 nM final concentration range) of 4-hydroxytamoxifene in duplicate/plate control titration, or DMSO vehicle control were dispensed into columns 1, 2, 3, and 4 respectively, with the Wako pin tool as above. ",
"The assay plate was manually covered with an aluminum foil plate seal (Cat. ",
"no. ",
"6569, VWR, Bridgeport CT), centrifuged for 30 s at 1000 rpm, and incubated at 37 °C for 4 h. One microliter/well of One-Glo FLuc reagent (Promega Corporation, Madison, WI) was added to each well of the assay plate with a BioRAPTR FRD. ",
"The plate was incubated for 10 min at room temperature, protected from light, and luminescence was measured with a ViewLux uHTS Microplate Imager (PerkinElmer, Waltham, MA) with a clear emission filter, 1 s exposure, medium gain, slow speed, and 2 × 2 binning.",
"\n\nConcentration--Response Curve Fitting {#sec4.6}\n-------------------------------------\n\nqHTS data was displayed after correction for plate-based aberrations and normalization using Origin software (OriginLab Corp., Northampton, MA) for the three-axis plot of activity for the 67 compounds (Figure [5](#fig5){ref-type=\"fig\"}A) or in Prism (GraphPad Software, San Diego, CA) for the four inhibitors (Figure [5](#fig5){ref-type=\"fig\"}B).",
"\n\nSupporting data and figures, details of DNA constructs, protocols, and lists of protein interaction pairs, HTS compounds, and components of IVT2H. This material is available free of charge via the Internet at <http://pubs.acs.org>.",
"\n\nSupplementary Material\n======================\n\n###### \n\nja502512g_si_001.pdf\n\n^∥^ N.S.: Microfluidic and Biological Engineering, IMTEK - Department of Microsystems Engineering, University of Freiburg, Georges-Koehler-Allee 103, 79110 Freiburg, Germany\n\n^⊥^ Y.Z. and H. A. contributed equally to this work.",
"\n\nThe authors declare no competing financial interest.",
"\n\nWe thank Drs. ",
"Chris Noren, Chris Taron, and Bill Jack for suggestions and comments on the manuscript, Dr. Dongxian Yue for supplying RNA polymerase core enzyme, G. B. Robb for suggestions of RNA binding proteins, Dr. Ryan MacArthur for informatics support, and Drs. ",
"Richard Roberts and Donald Comb for encouragement. ",
"This study was supported by NIH GM086930 and New England Biolabs to S.C. and by Divisions of Intramural Research at the National Human Genome Institute and the National Center for Advancing Translational Sciences at the National Institutes of Health to J.I. and P.D.\n"
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[
"Q:\n\nCustom short citations (Biblatex Verbose)\n\nI'm trying to suppress the comma in the postnotes but just in the short citations. ",
"In my MWE I get\n\nStratoydaki-White, «Patriarch Photios - A Christian Humanist», cit., ",
"p.\n 196.",
"\n\ninstead of\n\nStratoydaki-White, «Patriarch Photios - A Christian Humanist», cit. ",
"p.\n 196.",
"\n\nI tried with the redefinition:\n\\renewcommand*{\\postnotedelim}{\\addspace}\n\nBut it obviously it affects every citation, not just the short ones.",
"\nHow could I fix the problem?",
"\nMWE:\n% !",
"TEX TS-program = XeLaTeX\n% !",
"TEX encoding = UTF-8 Unicode\n\n\\begin{filecontents}{archivio.bib}\n\n@article{Stu:Pat,\n Author = {Despina Stratoydaki-White},\n Date-Added = {2015-11-18 12:39:01 +0000},\n Date-Modified = {2015-11-18 12:40:01 +0000},\n Journal = {The Greek Orthodox Theological Review},\n Number = {2},\n Pages = {195-205},\n Title = {Patriarch Photios - A Christian Humanist},\n Volume = {25},\n Year = {1980}}\n\n@article{Szi:Usu,\n Author = {Szidat, Joachim},\n Date-Added = {2017-09-25 13:16:22 +0000},\n Date-Modified = {2017-09-25 13:17:10 +0000},\n Journal = {Historia. ",
"Zeitschrift für Alte Geschichte},\n Pages = {487-508},\n Title = {Die Usurpation des Eugenius},\n Volume = {28},\n Year = {1979}}\n\n\\end{filecontents}\n\n\\documentclass[11pt, twoside]{book} %openany\n\\usepackage{polyglossia}\n\\setmainlanguage[babelshorthands=true]{italian}\n\\setotherlanguages{latin, english, french}\n\n%%% bibliografia\n\\usepackage[babel,italian=guillemets]{csquotes}\n\n\\usepackage[ style=verbose-trad2, \n language=italian,\n useprefix=true, \n firstinits=true, \n citepages=omit, \n backend=biber, \n ]{biblatex} \n\n% \\renewcommand*{\\postnotedelim}{\\addspace}\n\n\\addbibresource{archivio.bib}\n%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%\n\n\\begin{document}\n\na\\footcite[197-198]{Stu:Pat} \\\\\n\nb\\footcite[488]{Szi:Usu} \\\\\n\nc\\footcite[196]{Stu:Pat}\n\n\\end{document}\n\nMany thanks!",
"\n\nA:\n\n\\DefineBibliographyStrings{italian}{opcit = {cit\\adddot\\nopunct}}\n\nworks for the issue at hand and seems to be the least bad of several bad options.",
"\n\nA safer, but more tedious version, introduces a new check if we had an 'op. ",
"cit.' ",
"citation. ",
"That check needs to be done with a toggle, since at the time \\postnotedelim is printed, the native checks to find out if a citation is 'op. ",
"cit.' ",
"are not available any more.",
"\n\\documentclass[11pt, twoside]{book}\n\\usepackage{polyglossia}\n\\setmainlanguage[babelshorthands=true]{italian}\n\\usepackage{csquotes}\n\\usepackage[style=verbose-trad2, useprefix=true, giveninits=true, citepages=omit, backend=biber]{biblatex}\n\n\\addbibresource{biblatex-examples.bib}\n\n\\makeatletter\n\\newtoggle{cbx:opcit}\n\n\\renewbibmacro*{cite}{%\n \\usebibmacro{cite:citepages}%\n \\global\\togglefalse{cbx:fullcite}%\n \\global\\togglefalse{cbx:loccit}%\n \\global\\togglefalse{cbx:opcit}%\n \\bibhypertarget{cite\\the\\value{instcount}}{%\n \\ifciteseen\n {\\iffieldundef{shorthand}\n {\\ifciteibid\n {\\usebibmacro{cite:ibid}}\n {\\ifthenelse{\\ifciteidem\\AND\\NOT\\boolean{cbx:noidem}}\n {\\usebibmacro{cite:idem}}\n {\\usebibmacro{cite:name}}%\n \\usebibmacro{cite:title}}%\n \\usebibmacro{cite:save}}\n {\\usebibmacro{cite:shorthand}}}\n {\\usebibmacro{cite:full}%\n \\usebibmacro{cite:save}}}}\n\n\\renewbibmacro*{cite:title}{%\n \\printtext[bibhyperlink]{%\n \\printfield[citetitle]{labeltitle}%\n \\setunit{\\printdelim{nametitledelim}}%\n \\bibstring[\\mkibid]{opcit}}%\n \\global\\toggletrue{cbx:opcit}}\n\n\\renewcommand*{\\postnotedelim}{\\iftoggle{cbx:opcit}{\\addspace}{\\addcomma\\space}}\n\\makeatother\n\n\\begin{document}\na\\footcite[197-198]{sigfridsson}\n\nb\\footcite[488]{vizedom:related}\n\nc\\footcite[196]{sigfridsson}\n\\end{document}\n\n"
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[
"Okay, say what you will, but I am a devoted Mac user/lover. ",
"They may kick me, cajole me, break my piggy bank all they want, but I still come back for more. ",
"I started on my dad’s Macintosh Plus (though I did do some initial tinkering on an older Apple with the big floppy drives) and got my first computer, a Mac SE, in 1988. ",
"Those were exciting times. ",
"Having just returned from an extended trip to Europe, I quit school, moved away from my friends and family to the city and found myself with no social life to speak of (you don’t mind if I end my sentences with a preposition, do you?…thanks). ",
"So what would any self-respecting, slightly bored Graphic Design drop-out do? (",
"And note, there weren’t even computer courses for designers at that time; we were spending hours doing freehand typography, cut-and-paste, and a typewriter and Xerox machine were still the most technological elements of our creations). ",
"Without any experience, anything to base myself off of really, I decided to start a magazine, designed on my new-fangled 40 megabyte computer. ",
"It is said that “The power of the press only goes to those who can afford to own one.” ",
"Before 1985, it took hundreds of thousands of dollars for equipment to set up a small publishing company. ",
"By then that price dropped to around $10,000. ",
"The Desktop Publishing evolution was upon us, but it was so early on, I didn’t even comprehend what I was about to become a part of.",
"\n\nEven with the idea in one’s mind that people had more patience with slow computers because they had nothing to compare it to, I could have gnawed through my leg waiting for that SE to refresh its screen after making a simple change in Pagemaker (yes kids, we’re talking Pagemaker 1.0 and there were no options). ",
"I would make a change, go to the kitchen and prepare a sandwich, check the computer to see if it was finished, and on most occasions could actually eat the sandwich before the thing was done processing. ",
"Aldus and Adobe were changing the landscape, and pretty much saving Apple from near doom, by introducing post-script fonts and the publishing software to run them. ",
"It was such a headache: from the buggy nature to access of fonts that would print properly (most low-budgeters had to do some serious maneuvering to scam print-quality type faces). ",
"I made friendly with my local computer store, hung out there for days on end listening to Apple customers with questions and Apple geeks with solutions, and they’d let me print originals on their snazzy Laser Printer. (",
"I won’t go into detail about how, before I could afford printing on a real printing press, we did covert nighttime missions into the Los Angeles Times offices [with the help of a dutiful employee – all in the name of freedom of the press…mixed with a dash of Abbie Hoffman] and copied thousands of issues on their copy machines – but I’ll simply give a shout out for their support! ",
"Mahalo!)",
"\n\nOnce I had enough money (after making a bunch by stumbling across work as an Art Director for a top-10 ad agency [they were just getting their first Mac’s in the late ’80s so I had an “in” as a self-taught “expert”]), I bought a Mac IIcx, a gynormous monitor, and a LaserWriter II NT. ",
"This set up cost me a bit more than that approximate $10,000. ",
"Ouch. ",
"It was still slow, precarious, and seemed as if we were paying to be the test dummies for the new (personal) computer age. ",
"And yes, I was only happy to participate. ",
"It so happens, I would end up paying this amount many times over off the course of my long-term love affair with Apple (IIci, Quadra 950, Power Macintosh G3 Tower, Powerbooks, endless printers and monitors and mice and keyboards…).",
"\n\nAll to say that from the early beginnings I’ve been there; I’ve stood by Apple. ",
"When Steve got the boot, when Steve made the great return. ",
"When quality lacked and before the revolution resumed with full-force. ",
"I felt the twinge, when in it’s slow decline and with people jumping ship, that I should make a serious investment in Apple stock, show my commitment and make a few bucks off the comeback I felt sure to come (unfortunately all my monies were eaten up by publishing debt [access to publish didn’t seem to increase the profit margin for small press].) ",
"IBM and Microsoft were tech-geeks who weren’t social enough to relate to human beings. ",
"Windows was trying to be Mac OS, and didn’t do it all that well. ",
"Microsoft jealously grasping at creativity, could only mimic the visionary user-ability of Apple (as it does to this day [those are some pretty bad reviews of Vista, eh, and whoosh, we’re already moving on to Leopard!]). ",
"Even when Apple capitalized on the ideas and technologies of others, ehem, it always repackaged with an innovative, friendly functionality and smart design that brought people and their machines closer together.",
"\n\nSo sure, nothing’s perfect. ",
"Perhaps us fanatics put too much of our hopes and dreams on one company and one man. ",
"But it was like we were a team. ",
"So when Mac seemingly became too big for their britches, when they left the illusion of personal relationship to post-iPod monstrosity, how were the old-school devotees supposed to feel?",
"\n\nTimes have been hard. ",
"I admittedly strayed, regrettably purchasing a Sony Vaio Picturebook (only for the convenience of it’s compact size for travel writing…no, really), which ended up wiping out all of my writing –and much inspiration– due to some faulty hard drive issues. ",
"And I essentially had my quirky G3 stolen by an incompetent computer repair man here in Hawaii and it was years before I could even presume to afford another machine (the only thing I could count on was my eMate and though I love that thing it’s not the same as a real laptop – plus I can’t get it to download onto my MacBook [any tips?]). ",
"Even the borrowed clamshell iBook went belly up suddenly, one fine day. ",
"As a Licensed Massage Therapist I worked overtime massaging many rich so-and-so’s, who come here to buy land, increase housing costs and traffic congestion, and build their water-consuming, ocean-polluting golf courses. ",
"Hell, I even massaged Michael Dell and wife in order to afford a new Mac! ",
"I waited patiently, getting an inside tip on the upcoming release of the new MacBook Pro, got in on the first early 2006 shipment, and voilá, I was back in the world of computers. ",
"My old passion returning with zest. ",
"Might I actually write again? ",
"Design a new web site? ",
"Podcasting and blogs as the new ‘zine revolution. ",
"There was a lot of catching up to do!",
"\n\nI spent what in my current debt-lovin’ situation is a lot of money, and admittedly expected perfection (or at least some caring assistance with any problems). ",
"And there were problems. ",
"What were those weird annoying sounds buzzing from my new MacBook? ",
"And the laptop seemed so hot; sometimes the area around the keyboard felt almost electrified when I touched it. ",
"When the metal seemed to be peeling off the back of the machine I emailed Apple. ",
"There was only a computer generated response. ",
"Then my battery was barely holding a charge. ",
"I contacted Apple and they said there was nothing wrong with the battery. ",
"When after another few months I realized it wasn’t just metal peeling off the back, but that it was the battery expanding and that it was holding no charge, I called again. “",
"Oh, we have a recall for that battery.” ",
"Huh? ",
"And no one bothered to tell me because…. “",
"And you better take the battery out of the machine. ",
"You should only use it plugged in.” ",
"What? ",
"With a (nice as it is) magnetic power cord, how awful is that when it accidentally -easily- unplugs while you’re working? (",
"I can tell you!",
"🙂 )\n\nSo it only takes a few days for the new battery to arrive. ",
"And wow, I can actually type for more than 15 minutes before it shuts itself down – nice change. ",
"The peeling metal isn’t cutting me anymore. ",
"Sure, there are operating quirks, which upgrades seem to repair, but despite ignoring the heat/noise/electric issues the machine is an absolute blast. ",
"And all is well, that is until two new problems arise. ",
"Not big problems, but problems none-the-less. ",
"One is my power cord, the other is sleep mode. ",
"I put off doing anything about these because I have major events in my life, and soon will be making a trip to the mainland, where (instead of mailing my machine, which I’m disinclined to do) I can enjoy the ability to walk into a Mac store and meet geniuses at the Genius Bar who will immediately comprehend everything that is wrong with me, my life, and my computer and make it all better. ",
"That’s the kind of faith I have….",
"\n\nI go to the SimiValley store which is crowded (though much less so than others in Los Angeles) and ask for help. ",
"Well actually, it’s not made perfectly clear upon entering that one must type a reservation onto a computer so that you’re actually in line but after a while I stop one of the buzzing employees long enough to ask and am informed (as are others wistfully waiting) of the rules – seems you gotta be in the know. ",
"They ask what I need help with and I pull out the power cord. ",
"The end where the cord connects with the actual MagSafe power adapter is separating and fraying. ",
"I tell the young woman that I read a number of comments, some posted on forums on the Apple site actually, of people who this has happened to with some saying their computer started smoking because of it. (",
"Upon looking right now, even the Wikipedia entry includes “…complaints about the MagSafe adapter focus on its tendency to fray at the connector head, and in some cases melt or catch fire in this area…”). ",
"I ask if there has been any recall similar to the battery that perhaps I’m unaware of. ",
"She glares at me as if I’m an idiot. ",
"Takes my power cord, looks it over, then with a ’tisk’ declares, “We haven’t had any problems with this. ",
"We use tons of adapters here. ",
"This only happens when people don’t handle it properly.” ",
"Oh!, ",
"I’m thinkin’, no shedi’nt!!! “",
"How do you take out your plug?” ",
"she then asks. ",
"I’m trying to restrain myself. “",
"How do you wrap it?” ",
"like I need a lesson. ",
"I actually have to show her how I wrap the power cord properly. “",
"I assure you,” I insist, “I haven’t abused my power cord, it started separating and there was no way to stop it. ",
"I’ve been very careful.” “",
"How often do you leave the computer plugged in? ",
"How often do you take it somewhere to work on it?…” ",
"She continues with a laundry list of idiotic questions as if trying to break me down ’til I would admit, You’re right, it was me! ",
"I did it! ",
"As if somehow it was my fault that a power cord which seemingly should last more than a year was now disintegrating. ",
"It was exactly how I felt when I inquired about the battery before they were forced to fess-up that there was a problem. ",
"To keep a long story from getting too much longer,🙂 I waited over half an hour while she first went through the rigamarole of deciding whether or not I was even covered, and then (at my request) while she called stores in the surrounding area to see if there were any power cords available (apparently no store in or around Los Angeles had any in stock – huh?!). ",
"Despite all that time I spent with her I would have to do it all over again over the phone with Apple Customer Service and hope they could ship one out next week (Monday was a holiday). ",
"Then, to add insult to injury, she coldly informed me that she was going to have to “confiscate” my power cord because “it’s too dangerous for you to have this…the metal is showing”. ",
"Okay, so I was not going to be able to use my computer for almost a week? ",
"I don’t think so! ",
"I told her I wanted my power cord. ",
"She said she was going to have to put it in the database that I insisted on taking it, and that if anything happened it would not be covered. ",
"Could it get any worse? ",
"Suffice to say, I was not feeling the love portion of this love/hate thing.",
"\n\nSwallowing my pride I now had to tell her my problem with sleep mode. ",
"I explain that when I shut the lid (and hoping to avoid her banal inquiries I inform her that indeed I make certain it is shut all the way) half the time it doesn’t automatically go into sleep mode as it is supposed to (another common post on the Mac Forums). ",
"I explained that I would close it, put it in its case, only to find the computer burning hot with no battery power left when I took it out to work on. ",
"She takes the machine, does the P-Ram reset, and tells me it’s all fixed. ",
"Well, at least something good to come out of this little visit. ",
"I thank her and am happy to go. ",
"I run across the way to Brooks Brothers and sit in their massage chair ’til the store closes. ",
"That feels better. ",
"Unfortunately the feeling doesn’t last too long, as I will soon discover that her P-Ram reset did not resolve my problem, except to leave me without time to leave my computer in the store for repair, since my trip is almost over. ",
"And now I will have to spend $250 to renew my AppleCare which is to end that month, just so I can deal with that repair (and whatever new dilemma may arise) the next time I travel to a place with an Apple Store.",
"\n\nI’m not even going to get into my refurbished iPod Nano, purchased 23 days before the new more inexpensively priced and increased battery life Nanos were released (it’s 21 days to be able to return the product). ",
"The fact they didn’t discount the old Nanos before the release, so we didn’t feel so duped….I’ll just leave it at that.",
"\n\nI don’t know what the solution is? ",
"Perhaps, like AAA or Costco, we should have cards that show how many years we’ve been a member. ",
"And then add discounts the longer we’ve participated, the more we’ve purchased. ",
"My g-d, my card will show over 20 years of devotion. ",
"Surely I should have some priority? ",
"At least a hint of respect from the newbie “Geniuses” – especially snooty girls who don’t have battle scars from living through the days of one megabyte of RAM! ",
"Or didn’t pay their whole college tuition to essentially be beta testers of these early personal computers and, in a sense, help create the awesome computers we see today. ",
"And just because I can’t currently afford ProCare, why not offer me something even better, like Family Member perks? ",
"Because that’s what you do for family, Steve. ",
"And you’re always looking for new customers but maybe it’s time to reward the old ones. ",
"How many people have us first generation Mac geeks personally converted? ",
"How many conversations about why Macs are better than PCs have we had over the past 20 years?! ",
"We have been your street level ad campaign managers; your tireless cheerleaders. ",
"We have supported you during the worst of times and the best of times and gave you a foundation to improve and grow (as yes, you have done with us). ",
"But we have never faltered. ",
"We have been your rock. ",
"Steve, I still love you, but I need some real Apple Support right now. ",
"Don’tcha think it’s time to give back? ",
"That personal, clandestine relationship we’ve had all these years…I want it again…Steve…I miss you…I’ll be waiting for your call.",
"\n\nShare this:\n\nLike this:\n\nFor those wondering wha’happend…this post will eventually include some story. ",
"And I hope to include links to all the past Ben Is Dead Magazine contributors. ",
"So check back with us again later. ",
"xo\n\nAll posts written under the name “coconut girl” are written by ex-Ben Is Dead editress Darby Romeo.",
"\n\nAll contributors who happen to have found me long lost…will be visiting from Hawai’i end of June ’07 Kern river-rafting reunion for all former BID writers out on bond🙂 Please bring life-vests – can’t take any chances with you guys. ",
"Brian Doherty (currently big-wig Libertarian at Reason Magazine) is co-ordinating so get ahold of him! ",
"Check MySpace for bulletins."
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"The present invention relates to a folded casing for products to be filled individually. ",
"In particular, the present invention relates to a casing, folded to form what is known as a \"stick\" or concertina, for packaging an individual product, wherein a front end of the casing is tied up."
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"Dopo l'ennesimo episodio che ha visto la violazione dell'area archeologica del Colosseo, arrivano le soluzioni possibili della Soprintendenza per i Beni archeologici di Roma. \"",
"Stiamo valutando la possibilità di creare un'area per così dire di non libero accesso, una zona rossa\" ha spiegato il soprintendente, Francesco Prosperetti. \"",
"Un'area separata non da sistemi fisici o recinzioni, ma da dissuasori come catenelle sul perimetro di questa zona, all'interno della quale sarà installato un sistema di videocontrollo. ",
"La zona rossa avrà la dimensione originaria dell'area del Colosseo in epoca romana, in un raggio di una quindicina di metri. ",
"Ovviamente è un'ipotesi da verificare con il comune di Roma con cui abbiamo aperto da tempo un tavolo di lavoro anche su numerosi altri temi, come i Fori Imperiali\".",
"Accesissima infatti la polemica dopo che stanotte due brasiliani hanno scavalcato la cancellata del Colosseo precipitando all'interno. ",
"E dopo che, nel pomeriggio, sono state ritrovate due scritte sui pilastri in marmo: \"Morte\" e \"Balto\".",
"\n\nI due brasiliani, stanotte intorno alle 2.30, hanno scavalcato la cancellata del Colosseo convinti, ubriachi com’erano, di vivere chissà quale avventura entrando dentro il tempio della romanità antica. ",
"E invece hanno perso l’equilibrio e sono precipitati giù, quattro metri di caduta libera. ",
"Uno dei due non si è fatto nulla. ",
"L’altro dovrà essere operato e ha riportato una brutta frattura al bacino.",
"Quello rimasto illeso e che ha la cittadinanza italiana, appena si è reso conto della gravità dello stato del suo amico, ha chiamato il 118 che, con qualche difficoltà, ha recuperato i due e ha poi allertato il commissariato Celio, diretto dalla dottoressa Stefania D’Andrea. ",
"Gli agenti si sono presentati in ospedale e hanno portato in commissariato il 32enne per interrogarlo.",
"Le due scritte con vernice nera, \"Balto\" e \"Morte\", sono state invece trovate nel pomeriggio su un pilastro, dal lato dell'ingresso della metropolitana. ",
"Anche su questa vicenda indaga il commissariato Celio, che anche in questo caso sta visionando le telecamere di videosorveglianza per risalire al responsabile dell'atto vandalico.",
"Negli intenti della soprintendenza con il progetto di cui si sta discutendo ormai da diversi giorni, episodi come quelli di oggi non si dovrebbero più verificare. ",
"L'anello che gira tutto intorno al Colosseo sarebbe infatti dotato di un sistema di allarme proprio per impedire intrusioni all'interno del monumento. ",
"Ci sarebbe anche l'idea di impiegare un servizio di guardia notturno. ",
"Il progetto, spiega Prosperetti, lo \"abbiamo allo studio da mesi, ma non è di facile attuazione\".",
"Sulle scritte Prosperetti spiega che \"il dilemma su chi sia stato, se i due giovani brasiliani o addirittura altri, sarà presto risolto perchè le forze dell'ordine stanno visionando i filmati. ",
"In ogni caso, i restauratori sono già all'opera per rimuovere le scritte\".",
"Ma il punto per il soprintendente resta la sicurezza del monumento è la necessità di \"evitare questo tipo di incidenti.",
"Ci preoccupa che questi eventi diventino una specie di gioco, che si scateni una gara\". ",
"Ecco perchè \"ho preso contatti con la prefettura, chiedendo un incontro con il coordinamento interforze, esercito, polizia e carabinieri, per capire quali misure adottare. ",
"Da qualche mese, da quando cioè il cantiere che circondava il Colosseo è stato rimosso, ci domandiamo come impedire questi episodi\".",
"La soluzione, però, \"non è facile\", ammette Prosperetti: \"La nostra idea è istituire una zona ad anello nelle ore di chiusura del monumento che sia presidiata da un sistema di allarme antintrusione, ma il problema è distinguere l'intrusione umana da quella di un animale, perchè altrimenti basterebbe un gatto a far scattare l'allarme\".",
"Al momento, \"all'interno del Colosseo non c'è un servizio di sicurezza notturno, non abbiamo abbastanza personale per farlo\", ricorda il soprintendente. \"",
"Abbiamo un presidio che ha sede al palatino, ma si tratta di una sala regia che interviene quando accade qualcosa, cosí come è successo questa notte\".",
"Sulla vicenda è intervenuto anche il ministro dei beni e delle attività culturali e del turismo, Dario Franceschini, che ha voluto ricordare i contenuti del provvedimento del governo che introduce un sistema sanzionatorio improntato a una maggiore severità per chi commette delitti contro il patrimonio culturale. ",
"Per chi deturpa o imbratta i beni culturali le norme, ora all'esame del parlamento, raddoppiano le pene da un minimo di un anno a un massimo di 5 anni di reclusione.",
"\"Il gesto vandalico di oggi al Colosseo è un autentico sfregio a un monumento simbolo del patrimonio culturale mondiale\" ha detto Franceschini. \"",
"Alla prevenzione sempre necessaria per impedire ogni danno ai beni storici, artistici e archeologici si devono affiancare pene più severe per chi compie simili gesti, così come previsto dal disegno di legge delega approvato lo scorso 23 dicembre dal Governo che introduce, tra l'altro, specifiche fattispecie di reato per il deturpamento, il danneggiamento e l'imbrattamento di beni culturali e paesaggistici. ",
"Auspico che il Parlamento concluda quanto prima l'esame del provvedimento per arrivare in tempi brevi alla sua definitiva approvazione\"."
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"Authorities in Florida said a large monkey, estimated to be 4 feet tall when on all fours, has been spotted at least four times in the St. Cloud region.",
"\nOsceola County Animal Control and the St. Cloud Police Department said the primate has been spotted in the area on at least four occasions, once behind a Home Depot store in Dakota Avenue and three times in the Wisconsin Avenue area, WKMG-TV, Orlando, reported Wednesday.",
"\n\nAuthorities said they do not know where the animal came from and they are encouraging anyone who spots the monkey to call police or Animal Control.",
"\n\nLes Platt, who lives in the Wisconsin Avenue area, said the monkey was spotted by some houseguests.",
"\n\n“He just walked across, and then he stood upright on his two hind legs. ",
"Up to that point, they thought they were looking at a wildcat,” Plett said. “",
"I lived in the Philippines, I had a number of pet monkeys — and they can be very mean and can bite — so maybe someone just got tired of taking care of the monkey.”"
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"Q:\n\nWhy do Chinese writers have three different names?",
"\n\nI've been reading about Chinese writers and apparently they have too many names! ",
"For example, in the article of Wikipedia about 黃遠庸 (Huang Yuanyong) there's first this name as the title of the article. ",
"Then appear the pen name 黃遠生, and after that it says that his given name is 黃為基, why is that? ",
"I understand the pen name but if there's a pen name and a given name, what's the other one? ",
"Thanks.",
"\n\nA:\n\nYou probably know something about the intricacies of Chinese names prior to the downfall of the last dynasty, picking names at different stages of life was common among intellectuals. ",
"\nIn the case of Huang Yuanyong, check the Chinese language version of the Wiki article. ",
" \nIt reads:\n\n原名黄为基，字远庸，笔名远生\n\nThus, his original name was 为基, his 字 name was 远庸 and his pen name was 远生. ",
"In the pre-Republican era, it was common to pick a 字 name (or courtesy name in English). ",
"This name was most likely chosen by a teacher, and henceforth an educated person was to be referred to by his courtesy name, the given name was only used within the family. ",
"Since Huang Yuanyong was socialized in the late 19th century, there is nothing uncommon with him having three different names. ",
"\nBut having alternate names is not something restricted to China or Chinese writers. ",
"Many Western intellectuals, writers or revolutionaries are in the need of an alternate name at some point, some even used multiples (Lenin e.g. was known as Ulyanov, Ilyin, Karpov, Mueller or Frei, just to name a few.)",
"\nAlthough it is true that the Chinese name system is more elaborate, but until the modern ages it was common for Western scholars to Latinize (Linné used Linnæus in Latin) their names or pick a Latin name, this is somewhat similar to the Chinese courtesy name. ",
"\n\n"
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"Serum lipoprotein(a) levels are greater in female than male patients with type-2 diabetes.",
"\nWomen with diabetes are faced with a higher risk of dyslipidemia and cardiovascular disorders than men with diabetes. ",
"We aimed to study the role of gender and menopausal status in serum Lp(a) levels in patients with type 2 diabetes. ",
"We quantified serum Lp(a) levels in a group of 477 patients with type 2 diabetes (men, premenopausal and postmenopausal women with diabetes), as well as in 105 controls. ",
"We stratified the patients into two groups of low Lp(a) levels (Lp(a) <35 mg/dl) and elevated Lp(a) levels (Lp(a) >35 mg/dl). ",
"Patients with diabetes had higher serum Lp(a) levels than the controls. ",
"Serum Lp(a) levels was significantly higher in women with diabetes than men with diabetes. ",
"Lp(a) levels did not differ between male and females in the control group. ",
"Premenopausal and postmenopausal women with diabetes did not differ significantly in serum Lp(a) levels. ",
"The odds ratio of having a serum Lp(a) level higher than 35 was 5.85 in premenopausal women with diabetes, 5.08 in postmenopausal women with diabetes, 2.41 in men with diabetes and 1.9 in the women in the control group compared to the men in the control group, after adjustment for age and BMI. ",
"This observational study clearly indicated that serum Lp(a) levels were significantly higher in women and men with diabetes. ",
"The increase in women was independent of menopause. ",
"The level of serum Lp(a) had no correlation with lipid parameters in men or women."
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"Q:\n\nMagento - Random text on 'Shopping cart' page\n\nIm having a magento online shop in Australia. ",
"Im try to add a text line right before the \"proceed to checkout\" button. ",
"I have tried to look for the phtml that controls this page, but couldn't find one.",
"\nThe main reason that im doing that is becouse i want to let customer know that they are paying with AU$ and not US$.",
"\nAnyone idea how to do this? ",
"or even a better way for solving that?",
"\nwill be much appritiated!",
"\n\nA:\n\ngoto app/design/frontend/yourpackage/YourTemplate/templat/Checkout/Onepage/link.phtml\nThere you can the code .it will resolved your issue\n\n"
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"Q:\n\nDeveloping new version of iOS app. ",
"Need new bundle ID?",
"\n\nI'm working on a new version of an app that is currently on the App Store. ",
" I'd like to keep the current version on my testing device while developing the new version alongside it. ",
"That way, I can easily access the public version (e.g., during customer support) while developing the new version. ",
"\nDoes that mean I change the bundle ID from com.company.myapp to com.company.myappV1_1? ",
" \nIf so, should I change it back to com.company.myapp when uploading to the App Store?",
"\nIs there a better way to accomplish my goal?",
"\nThanks for reading!",
"\n\nA:\n\nYou need to have a unique bundle ID on your device or else that'll overwrite the old version. ",
"When you submit to the AppStore you can change the bundle ID back to the initial one and overwrite. ",
"You basically answered your own question, since it's imperative bundle ID's are unique.",
"\n\n"
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"[Interactions between drugs and food in pediatric age].",
"\nInteractions between food and drugs represent a very interesting chapter even in paediatric field, although this subject has not been very treated so far. ",
"We have tried to locate common points between pharmacology and elementary metabolism, in order to divide drug-food interactions into five great categories, according to the scheme suggested by Vannucci and Capriati. ",
"This scheme is based on the phases in which the interactions take place: 1) before gastroenteric absorption; 2) during gastroenteric absorption; 3) during distribution and storage in tissues; 4) during process of bio-transformation; 5) during excretion. ",
"If we want rationally to give a drug, we must exactly know its pharmacokinetic, particularly in paediatrics. ",
"In fact, we can avoid detrimental interactions drug-food merely adjusting the pharmacologic dosage to the particular diet of the considered child and vice versa."
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"The common vampire bat Desmodus rotundus (Chiroptera: Phyllostomidae) and the transmission of the rabies virus to livestock: A contact network approach and recommendations for surveillance and control.",
"\nThe importance of the common vampire bat Desmodus rotundus for the transmission of the rabies virus does not lie solely in its ability to transmit this disease to other mammals, but also in its capacity to adapt to environmental and climatic changes, granting them a wide geographical distribution. ",
"Control of this disease is currently based on culling of the vampire bat and vaccination of the livestock. ",
"A transmission model incorporating geographic and behavioral determinants of the vampire bat was proposed to direct and optimize the epidemiological surveillance and control of livestock rabies. ",
"This model was built using a bimodal network connecting 260 vampire bat roosts among themselves (roost-roost-network) and with 1557 farms (roost-farm network) in eastern Sao Paulo State, Brazil. ",
"These roosts were grouped in 9 communities, some very interconnected, and some not and the farms were grouped in 14 communities. ",
"From 2013 to 2017, 44 livestock rabies outbreaks occurred in the area, circulating among the farm communities during the entire period, with possible introductions from neighboring areas. ",
"Based on the network and environment parameters, it was possible to reasonably predict both the roosts' occupation type (harem, bachelor, overnight and empty) and livestock rabies outbreak occurrence. ",
"The network approach brings light to the importance of phylogenetic studies of bats and rabies virus. ",
"Finally, the understanding of the interactions between bats and their feeding sources, influenced by the environment, allows to establish more precise surveillance and control measures and, ultimately, with a lower cost-benefit ratio of these actions."
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"More people are having facelifts and breast implants in crisis-wracked Greece than in any other country in the world\n\nIn 2011, 142,394 cosmetic procedures were performed in the country\n\nOne in 79 Greeks had procedures such as liposuction and Botox injections\n\nSurgeons are charging an average of 40 percent less for their procedures\n\n\n\nThey are a bit down in the mouth about their desperate economy, which may be why people in Greece are having more facelifts than in any other country in Europe.",
"\n\nIn 2011, 142,394 cosmetic procedures were performed in the country of 11million people – meaning one in 79 Greeks has had procedures such as liposuction, eyelid corrections and Botox injections.",
"\n\n\n\nWorldwide, the Greeks ranked second only to the South Koreans in terms of the number of procedures performed. ",
"In the economic giant of Germany, only one in 200 had work done in 2011.",
"\n\n\n\nPlastic surgeon Athanasios Athanasiou, 42, said: ‘I believe that when people are not doing well, it is especially important to hear others say: “Wow, you look great”.",
"\n\n‘I always saw the economic crisis as an opportunity.’",
"\n\nRise: In 2011, 142,394 cosmetic procedures were performed in the country of 11 million people\n\nOne reason why so many are opting for the beauty treatments is a fall in costs.",
"\n\n\n\nSurgeons are charging an average of 40 percent less for their procedures while the cost of an operating theatre has fallen from £1,800 to £600.",
"\n\n\n\nBotox: Jennifer Aniston is half Greek and the actress has admitted using Botox in the past\n\nDr Athanasiou said 80 percent of his patients are Greeks.",
"\n\n'People are working,' he added. '",
"Maybe they’re earning less money, but they are working. ",
"We adjust ourselves to the market.'",
"\n\nGreece has cut costs drastically in other areas of medicine.",
"\n\nIn 2009, the Greek government spent £12 billion on its health care system, while in 2012 government health care spending declined to only £8 billion.",
"\n\n\n\nMany hospitals have reduced their emergency room hours to only four days a week, resulting in longer waits for patients.",
"\n\n\n\nOwing to wage payment cuts to doctors, many now expect patients to pay their bills in cash. ",
"Likewise, experts estimate that about 35 percent of Greeks have no health insurance.",
"\n\n\n\nThe grotesqueness of beauty treatments in a land where essential drugs are running short and hospital staff scavenge in waste bins for food scraps grates on many people.",
"\n\n\n\nDr. Giorgos Vichas, a cardiologist who devotes much of his time to a clinic where the poor come when they have been turned away by the state, said: 'I know cancer patients who were refused treatment because they were unable to pay for medication, and of pregnant women who don’t know how they’ll pay the costs of delivery.",
"\n\nContradiction: A woman walks past a shut down store in Athens. ",
"They might be down in the mouth about their desperate economy, but more people are having facelifts in Greece than in any other country in Europe\n\n'We Greeks were not always saints before the crisis. ",
"To a certain extent, many of us played a role in what has happened here. ",
"Those who can afford these cosmetic procedures now are among those who exploited the old system in the first place.'",
"\n\n\n\nPsychiatrist Matthew Josafat, 76, said he doesn’t find the boom in cosmetic surgery surprising and that people do feel better after a facelift.",
"\n\n\n\n'In England, the men on my couch usually talked about their jobs,' he said, but in Greece 'the patients on my couch are more likely to talk about romance, love and Eros.",
"\n\n\n\n'In antiquity, women were second-class citizens. ",
"Their appearance was their currency,' says Josafat.",
"\n\n\n\n'The notion of the emancipated companions that women have become in the modern age hasn’t taken hold in Greece as quickly as it has in northern Europe.",
"I fear the crisis and the lack of jobs could force women back into their old role: being attractive and getting married.”",
"\n\n\n\nWorldwide, the Greeks ranked second only to the South Koreans in terms of the number of procedures performed.",
"\n\n\n\nHowever, the International Society of Aesthetic Plastic Surgery (ISAPS) estimates that with the declining costs of procedures, the Greeks will overtake the rest of the world when 2012 figures are published later this year.",
"\n\n\n\nItaly is presently third and the U.S. second. ",
"Britain is not in the top ten."
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[
"1. ",
"Introduction {#sec1}\n===============\n\nPerilymph fistula (PLF) has been a contentious topic in otolaryngology for fifty years. ",
"The modern meaning of the term is a leak of perilymph at the round or oval window. ",
"It excludes other conditions with \"fistula\" tests such as a canal dehiscence from cholesteatoma and the superior canal dehiscence syndrome. ",
"PLF was first recognized as a complication in the early days of stapes mobilization and stapedectomy surgery and attributed mainly to the use of gelatine sponge as a seal around the prosthesis \\[[@B1]\\]. ",
"The symptoms were vertigo, tinnitus and hearing fluctuation, imbalance and aural fullness, and the similarity of these to those of endolymphatic hydrops was postulated. ",
"By 1982 Shea \\[[@B2]\\] was able to claim that with the use of a small prosthesis and natural tissue seal the problem had been solved. ",
"In 1968 Fee \\[[@B3]\\] reported on three patients with an oval window PLF following mild head injury or a series of head injuries without concussion. ",
"The predominant symptom was dizziness. ",
"In 1970 Stroud and Calceterra \\[[@B4]\\] introduced the term \"spontaneous perilymph fistula\" based on four adults whose onset of symptoms was apparently unrelated to a traumatic event.",
"\n\nThe recognition that a PLF could occur without stapes surgery or trauma aroused interest in the phenomenon and the publication of some large institutional series. ",
"The first was from the University of Iowa \\[[@B5]\\]. ",
"Ears in a hundred and seventy-seven patients were explored for tinnitus, hearing loss, and vestibular symptoms which were disequilibrium and motion intolerance. ",
"Other than stapedectomy the commonest cause was trauma (direct, barotrauma, acoustic) and straining, but in 24% there was no identifiable cause.",
"\n\n In the \"Stanford Experience\" over eleven years \\[[@B6]\\] seventy-eight ears were explored for PLF whose commonest symptom was postural unsteadiness but some were said to have vertigo. ",
"51% had no identifiable cause and were called spontaneous. ",
"In the Dartmouth-Hitchcock Medical Centre Experience \\[[@B7]\\] thirty-five fistulas were diagnosed in thirty-five patients. ",
"In 79% of the patients the symptoms began soon after an event involving physical or mechanical stress.",
"\n\nAt the House Ear Clinic over a twelve-year period the ears of eighty-six patients were explored \\[[@B8]\\]. ",
"The main symptoms were \"dizziness\" and hearing loss but not tinnitus. ",
"Where a fistula was found-one-third had a history of ear surgery or trauma. ",
"After fistula repair hearing improvement was unlikely, and the House Ear Clinic advised a very cautious approach to the diagnosis of PLF for hearing loss and particularly in children \\[[@B9]\\].",
"\n\nAt the University of Texas Southwestern Medical Centre Meyerhof \\[[@B10]\\] explored the ears and patched their windows in a hundred and twenty patients with a variety of symptoms, including tinnitus and sudden hearing loss. ",
"The greatest improvement was in those with a trauma history and imbalance and worst for those with only tinnitus or hearing loss. ",
"In the Portland Experience on PLF Black and colleagues \\[[@B11], [@B12]\\] found seventy-nine fistulas in ninety ears in patients who nearly all had a mild head injury or a series of head injuries without concussion. ",
"Their main symptom was \"disequilibrium\" (90%), subjective aural symptoms being half as common. \"",
"Cognitive dysfunction\" was also a feature.",
"\n\nThe possibility of PLF in children became a topic of interest \\[[@B13]\\], particularly in congenitally abnormal ears \\[[@B14]\\]. ",
"Supance and Bluestone \\[[@B15]\\] reported repairing twenty-nine fistulas in forty-four children\\'s ears. ",
"The vestibular symptoms resolved in all but the hearing was unchanged in 86%. ",
"The unlikelihood of improving hearing with a PLF repair has been emphasised by others \\[[@B9], [@B16]\\].",
"\n\nIn 1971 Goodhill \\[[@B17]\\] advanced a theory of labyrinthine ruptures as a possible cause of sudden deafness associated with exertion or trauma. ",
"The two proposed mechanisms were implosive and explosive. \"",
"Explosive\" would require an increase in cerebrospinal fluid (CSF) pressure transmitted from the internal auditory canal or by the cochlear aqueduct which could rupture the basilar membrane Reissner\\'s membrane, the semicircular canal system, the round window membrane or the annular ligament of the stapes. ",
"Conversely an \"implosive\" force from a valsalva manoeuvre causes sudden air pressure through the Eustachian tube, a sharp increase in intratympanic pressure and rupture of the round window membrane or annular ligament of the stapes. ",
"Tonkin and Fagan \\[[@B18]\\] reported on thirteen patients with a round window fistula where the initiating event appeared to be direct head trauma in four, but exertion, barotrauma from flying and diving, acoustic trauma, vomiting and postoperative in the remainder. ",
"In The Royal Ear Nose and Throat Hospital in London in a seven-year period thirty-two patients had a confirmed PLF \\[[@B19]\\]. ",
"When the cause was blunt, head trauma of the fistula was always at the oval window. ",
"When the cause was barotrauma, exertion or unknown, it was always at the round window. ",
"These findings give some credence for Goodhill\\'s theory to explain a round window PLF, but suggest that for an oval window PLF something else is required.",
"\n\nEarly temporal bone studies in the 1930s showed that a crack between the round window niche and the posterior canal ampulla was not uncommon but assumed to be artifact. ",
"Subsequently it has been shown to be developmental \\[[@B20]\\]. ",
"These findings were the impetus for Kohut\\'s temporal bone studies on patients who *might*have had a PLF \\[[@B21]\\]. ",
"On the *assumption* that PLF ears would have endolymphatic hydrops the paired temporal bones of patients with histological hydrops and from patients with normal hearing and no vestibular symptoms were examined in regard to oval and round window features. ",
"In all the normal bones the fissula ante fenestram was closed by cartilage and the round window fissure was sealed by collagen or bone. ",
"In the bones with hydrops one had a patent round window fissure and a history of vertigo attacks which had been diagnosed as Meniere\\'s disease. ",
"One had a \"patent\" fissula ante fenestram containing only fibrous tissue and a patent round window fissure and a history of \"waxing and waning disequilibrium\" that could have been a PLF.",
"\n\nEarly temporal bone studies had shown that a potential patency of the fissula can be present at birth. ",
"Kohut suggested that a \"patent\" fissula ante fenestram could be a preexisting congenital feature predisposing to a PLF. ",
"Unfortunately there is an almost total absence of detailed cases of post-mortem histology on ears with a premortem diagnosis of a treated PLF. ",
"The only one has been provided by Kohut et al. ",
"\\[[@B22]\\]. ",
"A sixty-eight-year-old male with \"constant disequilibrium\" had hearing loss in the right ear after a five inch gun fired beside it. ",
"Sound and sneezing would make him stagger. ",
"Exploration of his right ear revealed a PLF at the fissula ante fenestram and round window fissure which were repaired with connective tissue. ",
"His balance returned but not the hearing. ",
"Four years later his temporal bones were examined. ",
"In the unoperated ear the fissula ante fenestram and round window fissure were not potentially patent. ",
"In the operated ear both were \"patent\". ",
"Of particular note there was no evidence of endolympahtic hydrops in either ear.",
"\n\nThe most predominant symptoms of PLF are vestibular, and these have been assumed to be attributable to endolymphatic hydrops in the fistula ear \\[[@B1]\\]. ",
"In animal models of PLF caused by removing or breaching the round window membrane in guinea pigs and cats histology and auditory brainstem thresholds suggest that PLFs can heal, that there may be no long-term hearing loss, and sometimes cochlear hydrops is observed. ",
"Electrocochleography (EcochG) with a click stimulus has been used to diagnose hydrops in PLF patients and in guinea pigs, but it is now known that this is a very unreliable criterion. ",
"Also it has not been proved that even if hydrops is present that it is the cause of the vestibular symptoms of a PLF \\[[@B22]\\].",
"\n\nAs the vestibular symptoms of PLF are the most predominant, potentially correctable tests of balance and possible provocative stimuli are of interest. ",
"An early attempt on the use of ENG testing for eliciting nystagmus by canal pressure with a pneumatic otoscope (Hennebert\\'s sign) predicted a PLF in some patients \\[[@B23]\\]. ",
"This implies stimulation of the vestibuloocular reflex so the stimulus was transmitted to the horizontal canal receptor, presumably requiring a large defect. ",
"Black and colleagues used sinusoidal (300--500 mm H~2~O) ear canal pressure in patients with platform posturography to simulate postural reflexes, reflected by postural sway in PLF patients \\[[@B24]\\].",
"\n\nIn 1929 Tullio \\[[@B25]\\] showed that loud sounds could induce nystagmus in dogs with surgically fenestrated superior canals and head tilting and leg flexion in pigeons and rabbits with intact labyrinths. ",
"The possible relevance of the Tullio phenomenon to PLF diagnosis has been considered. ",
"Pyykko and colleagues \\[[@B26]\\] showed that a low frequency sound induced postural sway in seven patients with a suspected and confirmed PLF, but in none of control subjects with a sensorineural hearing loss. ",
"McNeill and colleagues \\[[@B27]\\] also used a 250 Hz tone in standing patients and found a 77% specificity with a confirmed PLF. ",
"Clearly it is not specific for a PLF but it appears to be a logical investigation. ",
"As the Tullio phenomenon is stimulating a purely vestibulospinal response it is initiated from the otolith organs.",
"\n\nThat PLF patients may have a *unique* balance problem was first suggested by Singleton \\[[@B28]\\]. ",
"For the \"eyes-closed turning test\" the patient is asked to walk forward with eyes closed and turn quickly one step and stop. ",
"A positive test is an inability to stay stable. ",
"Twenty-three of twenty-six subjects with a fistula had a positive test which appeared negative in patients with other causes of dizziness. ",
"A logical simplification was suggested to the author by Zee \\[[@B29]\\]. ",
"As the test is detecting a lateral instability, the patient (eyes closed or blindfolded) is asked to take two steps sideways.",
"\n\n2. ",
"Methods {#sec2}\n==========\n\nThe details of twenty patients (all female) with a confirmed PLF treated over twenty years are summarized in [Table 1](#tab1){ref-type=\"table\"}. ",
"The ages at the time of repair ranged from 19 years to 78 years. ",
"The range of times from onset of symptoms to exploration and repair was 3 months to 10 years (median 1 year). ",
"All had a full ear, nose and throat, and neurootological examination and pure tone audiogram. ",
"MRI scanning was done in some cases. ",
"In two symptoms began after acute otitis media, even though there was a prior traumatic event. ",
"The predominant symptoms were difficulty with balance, nausea, motion intolerance (and sometimes new onset motion sickness), and subtle difficulty with memory. ",
"All displayed a subtle unilateral balance instability on at least two components of the \"sideways stepping\" test. ",
"In thirteen there was a well-documented preceding traumatic event: head injury, whiplash, direct blow to the ear, and mastoid surgery. ",
"In seven the patient could not initially recall a relevant traumatic event or concealed it. ",
"Four other patients had negative explorations ([Table 2](#tab2){ref-type=\"table\"}).",
"\n\nAll ears were explored under a general anaesthetic, via an endaural incision. ",
"Two drops of optical fluorescein were added to the local anaesthetic \\[[@B30]\\]. ",
"A posterior tympanomeatal flap was elevated. ",
"Bone posterior to the chorda tympani nerve was curetted to give maximum exposure of the oval window. ",
"The round and oval windows were inspected, and when required the anaesthetist was asked to increase intrathoracic pressure. ",
"Mucosa adjacent to the fistula site was elevated and the fistula site packed with connective tissue from the endaural incision and (in most cases) covered with tissue glue. ",
"At six weeks the operated ear was inspected, a repeat pure tone audiogram performed, and the patient\\'s balance retested [Figure 1](#fig1){ref-type=\"fig\"}.",
"\n\n3. ",
"Results {#sec3}\n==========\n\nOf the twenty-one PLFs seven were in the right ear and fourteen in the left ear ([Table 1](#tab1){ref-type=\"table\"}). ",
"Patient 8 with a round window fistula from a direct blow to the left ear had a recurrence eight years (with symptoms for a year) later from a mild head injury. ",
"Six PLFs were at the round window. ",
"Twelve were at the fissula ante fenestram of the oval window, one with an extra crack in the footplate. ",
"Two were at a crack in the footplate. ",
"In one round window fistula (patient 10) an air bubble was seen on the other side.",
"\n\nPostoperatively none had hearing loss attributable to the operation. ",
"One required repair of a small eardrum perforation. ",
"All had complete recovery of balance, resolution of motion intolerance and nausea, and their subtle cognitive difficulties.",
"\n\n[Table 2](#tab2){ref-type=\"table\"} lists four patients with negative explorations. ",
"Patient 7 rerepresented two years later requesting reexploration, which was negative but remains free of disequilibrium after seventeen years. ",
"Twowith no PLF had no change in symptoms. ",
"It became apparent that patient 22 had functional imbalance and early dementia. ",
"Just prior to exploration she displayed a dramatic instability in all directions.",
"\n\nSeven confirmed PLF patients were requestioned about a possible traumatic cause ([Table 3](#tab3){ref-type=\"table\"}). ",
"In four none could be found. ",
"In three an event was found. ",
"Patient 1 remembered helping with building repairs and being struck on the head by a ladder and then hitting her head on a plank. ",
"Patient 6 was an air hostess. ",
"Her hospital records revealed that she had been admitted four years prior with a neck injury sustained when she hit her head on the galley roof as the aircraft plunged in an air pocket. ",
"Her symptoms began after acute otitis media. ",
"Patient 9 admitted that her husband had \"smacked\" her left ear and that she had always known that this was the cause.",
"\n\n4. ",
"Discussion {#sec4}\n=============\n\nIn this series the main presenting symptom was vestibular---a persisting subtle abnormality of their balance. ",
"Most could nominate a particular side. ",
"A particular feature was that they knew, unlike most vestibular disorders, that it was there immediately upon wakening and before moving. ",
"It fluctuated, with \"good\" and \"bad\" days. ",
"On a \"bad\" day many had mild nausea and an unpleasant aggravation by vehicle motion, without a prior history of motion sickness. ",
"Most had subtle cognitive problems, such as inability to remember simple familiar facts and a frustration of \"not coping.\"",
"\n\nTrauma from head injury, flying and diving barotrauma, sneezing, coughing, and labor as the most common cause of a PLF has been a feature in all the institutional series discussed. ",
"Three novel causes have been lightening strike \\[[@B31]\\], airbag trauma \\[[@B32]\\], and acoustic trauma from a fire engine siren \\[[@B33]\\].",
"\n\nGrimm and colleagues \\[[@B34]\\] performed detailed neurological studies on one hundred and two adults with mild defined craniocervical trauma who had a confirmed PLF. ",
"The predominant symptom was \"disequilibrium, dizziness\", motion intolerance, nausea, memory loss, stiff neck, and headache. ",
"Hearing loss was a less common feature. ",
"They emphasised that these symptoms could be or easily assumed to be postconcussional syndrome. ",
"Grimm \\[[@B35]\\] has suggested that these subtle symptoms of a PLF make it a neurological syndrome as well as otological. ",
"After an inner ear injury there is nearly always recovery or central adaption. ",
"However, a PLF is a rare example of an *unstable* peripheral organ \\[[@B36]\\]. ",
"The vestibular system is a very primitive aspect of brain function which preoccupied with calculating gravity and orientation to earth-vertical, so when it is perpetually confused, higher brain function may become subtly involved. ",
"There is increasing evidence from other human and animal studies that patients with acute vestibular disorders can also experience cognitive dysfunction \\[[@B37]\\].",
"\n\nThere are numerous descriptions of clinical balance testing on PLF patients, as variations on the Romberg test. ",
"The Fukuda/Unterberger test is well accepted as a clinical balance test of vestibular *hypofunction.* ",
"References to the fact that PLF patients have a unique imbalance from otolith dysfunction (rather than from hydrops) are rare \\[[@B38]\\], but it is a valid proposal.",
"\n\nThe terms often used for PLF vestibular symptoms have been \"dizziness,\" \"imbalance,\" \"disequilibrium,\" and often \"vertigo.\" ",
"In contrast to \"dizziness\" vertigo has always had at its simplest level a well-understood definition of an hallucination of motion, but in the PLF literature the term has been been used loosely and probably to mean any vestibular symptom. ",
"If the PLF patient is truly experiencing vertigo, it implies a discrete attack of rotational vertigo caused by Meniere\\'s disease or something resembling it and should be *personally witnessed* by the clinician. ",
"With the best of intentions one cannot diagnose a cause of a patient\\'s vestibular symptoms purely from their description of them. ",
"Similarly the claim that PLF patients have positionally induced nystagmus may be explained by coincidental benign positional vertigo.",
"\n\nThe Barany Society has sought to refine the definition of common vestibular symptoms \\[[@B39]\\]. ",
"Vertigo is \"the sensation of self-motion when no self-motion is occurring or the sensation of distorted self-motion during an otherwise normal head movement.\" ",
"Dizziness is \"the sensation of disturbed spatial orientation without false or distorted sense of motion.\"",
"\n\nPLF patients do not describe either of these. ",
"The most predominant symptom is of being \"off balance\" or disequilibrium (the new Barany Society term is \"lateral pulsion\"). ",
"This again raises question that PLF patients have a *unique*balance abnormality that is not explained by hydrops or by vestibular*hypofunction* in the affected ear. ",
"There are no VEMP studies on PLF patients, but an abnormal VEMP in a PLF ear may provide (other than possible hydrops) some evidence.",
"\n\nThere is as yet no vestibular condition in which a balance test is the only or the essential diagnostic feature. ",
"The accuracy of any balance test can be compromised by patient understanding, concentration, and motive (both intentional and unintentional). ",
"Clearly Singleton\\'s \"eyes-closed turning test\" and the simplified modification described here require objective verification on PLF subjects, normal subjects and in patients with conventional unilateral vestibular hypofunction \\[[@B40]\\].",
"\n\nIn summary a PLF is likely to occur in subjects with a potential congenital patency at the round or oval window. ",
"The main symptoms are vestibular with a subtle abnormality of balance, suggesting otolith disfunction. ",
"Nearly always there is an identifiable prior traumatic event. ",
"As other authors have noted it may have been forgotten by the patient and, in fact, even concealed. ",
"When there seems not to be, idiopathic PLF is a more appropriate term than spontaneous.",
"\n\nThe authors declare that they have no conflict of interests.",
"\n\nThe author thanks patients who gave permission for use of their video recordings and Slipstream Creative (<http://www.slipstreamcreative.co.nz/>) for illustrations. ",
"This paper is dedicated to the memory of Drs Brian F McCabe, Robert J Grimm and F Owen Black. ",
"And this paper was presented sequentially at Royal Australasian College of Surgeons Scientific Meeting, Wellington 1990; International Conference on Perilymph Fistula, Portland 1991; Neuro-otological Society of Australia, Sydney 2005; 27th Politzer Society Meeting, London 2009; Prosper Meniere Society Meeting, zell im Zillertal 2010.",
"\n\n{#fig1}\n\n###### \n\nTwenty patients with a surgically confirmed PLF.",
"\n\n -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n Patient Sex Age Symptoms For Ear Site Repair Preceding event Symptoms Followup\n --------- ----- ------ ------------------ ------- ------------------------- ------------------------- ------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------ -----------------------------------------------\n 1 F 51 4 yr Left OW (FA) CT Nil Disequilibrium to left; nausea; subtle memory difficulty; normal hearing 23 yr\n\n \n\n 2 F 51 5 mo Right RW CT Fainted→concussion Disequilibrium to right; motion intolerance, tinnitus right ear; normal hearing 22 yr\n\n \n\n 3 F 35 6 mo Left OW (FA) CT 2 whiplash injuries Acute otitis media→vertigo + vomiting→disequilibrium to left; nausea; motion intolerance; subtle memory difficulty; normal hearing 21 yr\n\n \n\n 4 F 59 8 mo Right OW (FA) CT Nil Disequilibrium to right; nausea; motion intolerance; subtle memory difficulty; normal hearing 20 yr\n\n \n\n 5 F 40 1 yr Left OW (FA) CT Face hit by cricket ball; knocked down by a sheep Vertigo after acute otitis media; disequilibrium to left; nausea; motion intolerance; subtle memory difficulty; normal hearing 20 yr\n\n \n\n 6 F 37 3 mo Left OW (central footplate) CT Nil Acute otitis media→disequilibrium to left; motion sickness; subtle memory difficulty; normal hearing 20 yr\n\n \n\n 7 F 63 15 yr Left OW (FA) CT MVA→whiplash Disequilibrium to left, nausea, motion intolerance, tinnitus and sensorineural hearing loss left ear. ",
"Positive Hennerbert\\'s test. ",
" 19 yr; see [Table 2](#tab2){ref-type=\"table\"}\n\n \n\n 8 F 19 6 mo Left RW CT + glue Struck over left ear by milking cups Disequilibrium to left; nausea; motion sickness; subtle memory difficulty; normal hearing 17 yr\n\n F 28 1 yr Right RW CT + glue Concussion and whiplash Same symptoms 9 yr \n\n \n\n 9 F 53 2 yr Right RW CT + glue Nil Disequilibrium to right; nausea; motion intolerance; tinnitus right ear; normal hearing 16 yr\n\n \n\n 10 F 45 1 yr Left RW (air bubble) CT + glue Nil Disequilibrium to left; nausea; subtle memory difficulty; normal hearing 16 yr\n\n \n\n 11 F 34 18 mo Right RW CT + glue Nil Disequilibrium to right; nausea; motion sickness; popping tinnitus right ear; normal hearing 15 yr\n\n \n\n 12 F 40 6 mo Left OW (FA) CT + glue Punched on left ear Disequilibrium to left; nausea; motion sickness; tinnitus left ear; normal hearing 13 yr\n\n \n\n 13 F 40 6 mo Right OW (FA) CT + glue Nurse. ",
"Hit head on bed frame Disequilibrium to right; nausea; motion sickness; subtle memory difficulty; normal hearing 12 yr\n\n \n\n 14 F 26 7 yr; worse 9 mo Left OW (FA) CT + glue Recent head injury; previous whiplash and prior fall from horse→ head injury Disequilibrium to left; nausea; motion intolerance; tinnitus left ear; normal hearing 11 yr\n\n \n\n 15 F 42 10 yr Left OW (FA) CT + glue Whiplash in train crash Disequilibrium to left; falls; nausea; motion intolerance; normal hearing 9 yr\n\n \n\n 16 F 78 3 yr Right OW (FA) CT + glue Fall from a horse; mastoidectomy at age 2 yr Disequilibrium to right; motion intolerance; mixed hearing loss right ear 7 yr\n\n \n\n 17 F 63 3 yr Left OW (FA)\\ CT + glue Nil Disequilibrium to left; nausea; motion sickness; normal hearing 6 yr\n (+crack in footplate) \n\n \n\n 18 F 61 6 mo Left RW CT + glue Mastoidectomy presenting as meningitis 13 yr prior Disequilibrium to left; nausea; motion intolerance; tinnitus; left mastoid cavity; no hearing left ear 6 yr\n\n \n\n 19 F 47 17 mo Left OW (FA) CT + glue MVA whiplash injury Disequilibrium to left; nausea; motion intolerance; Nausea from loud sounds; normal hearing 6 yr\n\n \n\n 20 F 32 8 mo Left OW (crack in footplate) CT + glue Head injury in fall from horse Disequilibrium to left; nausea; nausea from vestibular therapy; normal hearing 4 yr later repair small drum perforation.",
"\n -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\nRW: round window, OW: oval window, FA: fissula ante fenestram, CT: connective tissue.",
"\n\n###### \n\nFour patients with a negative exploration for PLF.",
"\n\n Patient Sex Age Ear Symptoms for Site Preceding event Symptoms Followup\n --------- ----- ------- ------- -------------- --------- ----------------- ----------------------------------------------------- ------------------------------------------------------------------------------------\n 7 F 65 yr Left 3 mo No leak Nil Disequilibrium to left, motion intolerance 17 yr. ",
"dysgeusia. ",
"Sensorineural loss increased. ",
"Later left BPPV. ",
"No disequilibrium\n \n 21 F 62 yr Right 1 yr No leak Blew nose Disequilibrium to right, nausea, sensorineural loss 15 yr. ",
"Unchanged\n \n 22 F 68 yr Left 5 yr No leak MVA→whiplash Disequilibrium to left, nausea, poor memory 1 yr. ",
"Dementia. ",
"Functional imbalance\n \n 23 F 28 yr Left 1 yr No leak Nil Disequilibrium to left, motion intolerance 1 yr. ",
"Unchanged\n\n###### \n\nEventual cause found in seven confirmed PLF patients without a trauma history.",
"\n\n Patient Sex Age Symptoms for Ear and Site Eventual confirmation of traumatic event\n --------- ----- ----- -------------- -------------- ---------------------------------------------------------\n 1 F 51 4 yr Left OW Struck on head by swinging ladder; hit head on a plank\n 4 F 59 8 mo Right OW Not found\n 6 F 37 3 mo Left OW 4 yr prior hit head on galley roof in plunging aircraft\n 9 F 53 2 yr Right RW Not found\n 10 F 45 1 yr Left RW Admitted her husband had \"smacked\" her ear\n 11 F 34 18 mo Right RW Not found\n 17 F 63 3 yr Left OW Not found\n\n[^1]: Academic Editor: Charles Monroe Myer\n"
] | {
"pile_set_name": "PubMed Central"
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[
"Background\n==========\n\nThe neural crest (NC) is a transient embryonic tissue. ",
"NC cells delaminate from the dorsal neural tube as it closes \\[[@B1]\\] and migrate to distinct locations, where they differentiate into various cell types, including neurons, glia, melanocytes, endocrine cells, and mesenchymal cells \\[[@B2]-[@B5]\\].",
"\n\nThe Sox proteins belong to the HMG (high mobility group) domain of transcription factors \\[[@B6],[@B7]\\]. ",
"Sox-E is the earliest marker of a subset of cells at the border of the neural plate that will give rise to NC-lineage cells \\[[@B8]\\]. ",
"Sox10, which is a member of the Sox-E family and shares high sequence homology with other Sox-E member transcription factors, regulates and coordinates diverse developmental processes such as organ development and cell survival and specification. ",
"Sox10 is highly expressed in the emerging NC and later in the developing glial cells of the peripheral nervous system (PNS) and central nervous system (CNS) \\[[@B9],[@B10]\\]. ",
"Whether in mice or humans, Sox family protein deletions or mutations often result in developmental defects and congenital disease, and mutations of the human *SOX10*gene are associated with NC cell abnormalities \\[[@B9],[@B11]-[@B13]\\].",
"\n\nSeveral transgenic mouse strains dedicated to tracing the NC lineage have already been developed, such as *Wnt1*-Cre \\[[@B14]\\], *Protein zero (P0)*-Cre \\[[@B15]\\], and *Ht-PA-*Cre \\[[@B16]\\] mice crossed with Cre-dependent reporter mice. ",
"The Cre recombinase expression was previously visualized by *LacZ*, a β-galactosidase reporter gene inserted in the ROSA26 locus, that is expressed only after the loxP-flanked intervening sequence is excised by Cre \\[[@B17]\\]. ",
"Once a specific promoter is activated, the cell is indelibly tagged with β-galactosidase. ",
"This kind of transgenic mouse is useful for monitoring the transient activation of various promoters, including the NC-specific promoter. ",
"Recently, mouse strains expressing a fluorescence-based reporter upon Cre-mediated conditional gene deletion have been developed for prospective cell sorting or direct observation without fixation \\[[@B18]\\]; the CAG-CAT-EGFP reporter transgenic mouse strain expresses enhanced green fluorescent protein (EGFP) when the loxP-flanked CAT gene located between the modified chicken β-actin promoter (CAG promoter) and the EGFP gene \\[[@B18]\\] is excised with Cre. ",
"In previous studies, we have used mice that enable Cre/loxP-mediated cell labeling with *LacZ*or EGFP to analyze the NC lineage and to trace NC cells after their migration and differentiation \\[[@B5],[@B19]-[@B21]\\].",
"\n\nHowever, for specific gene regulation analysis, transgenic or knock-in mouse lines that express a specific gene profile *in vivo*are more useful, because the reporter gene is expressed only while the specific promoter or enhancer is active, and ceases when the promoter becomes inactive. ",
"Reporter mice have recently been developed to evaluate cell-type specification and maturation in the oligodendroglial lineage; these are the 2\\'-3\\'-cyclic nucleotide 3\\'-phosphodiesterase (*CNP*)-EGFP and myelin proteolipid protein (*PLP*)-EGFP transgenic mouse lines \\[[@B22],[@B23]\\]. ",
"The *CNP*-EGFP transgenic mouse, in which the CNP promoter controls EGFP expression, has been used for the prospective identification of live oligodendroglial cells both *in vivo*and *in vitro*\\[[@B23]\\]. ",
"The *PLP*-EGFP transgenic mouse, in which EGFP expression is driven by the mouse *PLP*gene promoter, has also been developed for investigating oligodendrocyte lineage cells without fixation and immunostaining \\[[@B22]\\].",
"\n\nSox10 expression is closely related to NC-lineage cells. ",
"The *Sox10*^*LacZ*/+^\\[[@B24]\\], *Sox10-*rtTA \\[[@B25]\\], and *Sox10-*Cre \\[[@B26]\\] mouse lines have all been reported to label NC cells and oligodendrocytes. *",
"Sox10*^*LacZ*/+^\\[[@B24]\\], a mutant mouse targeting *Sox10*, was generated by replacing the open reading frame of *Sox10*with *lacZ*sequences. ",
"The *Sox10*^*LacZ*/+^mutation causes haploinsufficiency, in which even heterozygous pups have the phenotype found in mice with a spontaneous mutation in the *Sox10*allele. ",
"Although *LacZ*expression in this knock-in strain faithfully reflects the endogenous Sox10 expression, it is difficult to observe normal developmental behavior in the labeled cells because of the abnormal and pathological condition of the *Sox10^LacZ/LacZ^*homozygous mice \\[[@B24]\\]. ",
"Another unique reporter strain is the *Sox10-*rtTA knock-in mouse \\[[@B25]\\], in which a variant of the reverse tetracycline-controlled transactivator (rtTA) is inserted into the genomic *Sox10*locus, and the mice are crossed with the doxycycline-dependent *LacZ*reporter line. ",
"This strain correctly recapitulates endogenous Sox10 expression in the NC and its derivatives, and also in oligodendrocytes. ",
"This inducible transgenic system is limited in its range of analysis, because the reporter gene expression is temporary and requires X-gal staining \\[[@B25]\\]. ",
"The *Sox10-*Cre transgenic mouse strain, designated as the S4F:Cre mouse, when crossed with the reporter line strain Rosa-*LacZ*, identifies cells expressing Sox10, including NC-derived cells, oligodendrocytes, and cells in the ventral neural tube \\[[@B26]\\]. ",
"These strains are powerful tools for tracing the progeny of Sox10-expressing cells in analyses of NC cell migration and oligodendroglial differentiation. ",
"However, permanent reporter gene expression does not permit the real-time analysis of Sox10 expression. ",
"To overcome these limitations, we generated a new *Sox10-*Venus transgenic mouse, and confirmed that it enables the normal behavior of Sox10-expressing cells to be observed *in vivo*.",
"\n\nResults\n=======\n\n*Sox10-*Venus BAC transgenic mouse generation\n---------------------------------------------\n\nTo examine the Sox10 expression profile *in vivo*, we took advantage of the bacterial artificial chromosome (BAC) transgenic strategy where entire regulatory machinery for a given gene expression might be covered with a single BAC clone. ",
"In short, we modified a 225.6 kb-sized BAC clone *RP24-85O14*by means of homologous recombination to harbor the coding sequence of the fluorescent Venus protein \\[[@B27]\\] in-frame to the *Sox10*translation initiation codon (ATG) that locates at the middle portion of the clone. ",
"This construct yielded seven BAC transgenic founders expressing Venus and we hereafter analyzed the complete expression profile in a particular transgenic founder with the brightest illumination.",
"\n\nFirst, we evaluated the distribution of Venus fluorescence at each developmental stage of the *Sox10*-Venus mouse embryo. ",
"Venus fluorescence in classical NC lineage tissues was directly visible from outside the embryo by using an epifluorescence microscope and a UV light. ",
"At embryonic day 11.5 (E11.5 d), Venus green fluorescence was particularly intense in the dorsal root ganglia (DRG) and the trigeminal ganglia (cranial nerve V) (Figure [1A](#F1){ref-type=\"fig\"}). ",
"We observed that Venus fluorescence was not limited to classical NC lineage tissue, but was also observed in non-NC tissues, including the otic vesicle. ",
"This is consistent with previous studies in which *in situ*hybridization revealed endogenous Sox10 expression in otic vesicle cells \\[[@B28],[@B29]\\], which are the primitive state of the vestibulocochlear nucleus (cranial nerve VIII). ",
"In the facial area of the E11.5 d embryo, aggregated green cells were observed among scattered Venus-positive cells (Figure [1B](#F1){ref-type=\"fig\"}). ",
"The intensity and resolution of the Venus fluorescence allowed us to observe single cells in a pattern suggestive of the NC cell rostral migration process (arrowheads in Figure [1B](#F1){ref-type=\"fig\"}). ",
"As development proceeded from E11.5 d to E15.5 d, Venus fluorescence from the DRGs and nuclei of the cranial nerves located in deep tissues gradually decreased, due to the thickening dermal layer (Figure [1A, C](#F1){ref-type=\"fig\"}, and Additional file [1A - 1C](#S1){ref-type=\"supplementary-material\"}). ",
"However, migrating Venus^+^cells in the superficial layer of the embryonic skin were now detectable from outside the body. ",
"Venus fluorescence was observed in the Schwann cells of the neural network stemming from the spinal nerve\\'s posterior branches, and in peripheral sensory nerve fibers (Figure [1D](#F1){ref-type=\"fig\"}). ",
"In the hind limb, the peripheral nerve network and the adjacent vascular network were visible (Figure [1E](#F1){ref-type=\"fig\"}). ",
"Three-dimensional reconstructions of the peripheral nerve fibers displayed the entire neural network in the craniofacial area, which was mainly derived from the branches of the facial nerve (cranial nerve VII) (Figure [1F](#F1){ref-type=\"fig\"}).",
"\n\n{#F1}\n\nObserving the behavior of individual *Sox10-*Venus cells\n--------------------------------------------------------\n\nThe intensity and resolution of the Venus fluorescence in the new *Sox10-*Venus mice led us to evaluate whether it was possible to monitor the behavior of individual cells. ",
"Time-lapse imaging *ex-vivo*in skin explants from E14.5 d *Sox10-*Venus embryos was first performed using an epifluorescence microscope. ",
"Within this experimental setup, it was easy to detect and follow the movements of single cells (Figure [1G](#F1){ref-type=\"fig\"} and the movie in Additional File [2](#S2){ref-type=\"supplementary-material\"}). ",
"As Sox10 is expressed in deep tissues during the early stages of development, we next examined whether it would be possible to observe Venus fluorescence in whole *Sox10-*Venus embryos. ",
"Whole embryos at E10.5 d were observed using a confocal microscope, and followed over time. ",
"Time-lapse imaging of the front facial area allowed us to monitor the migration of several Venus^+^cells within the embryo over a duration of several hours. ",
"We were also able to observe the shape dynamics of individual migrating cells (movie in Additional File [3](#S3){ref-type=\"supplementary-material\"}).",
"\n\nVenus fluorescence in frozen sections of *Sox10-*Venus mice\n-----------------------------------------------------------\n\nTo confirm the Venus^+^cell distribution, we prepared cryosections of *Sox10-*Venus mice from each embryonic stage and observed the Venus fluorescence directly, without any antibody staining or enhancement procedure (Figure [2](#F2){ref-type=\"fig\"}). ",
"In axial sections of the thoracic region of E15.5 d mouse embryos, Venus fluorescence was intense in the DRG and its proximal and peripheral branches (Figure [2A](#F2){ref-type=\"fig\"}). ",
"Venus^+^cells were diffusely present throughout the spinal cord. ",
"Some ganglion cells were positive for Venus (Figure [2A](#F2){ref-type=\"fig\"}, arrows) in the sympathetic ganglia located at the ventral side of the vertebral disc. ",
"In horizontal cranial sections from E15.5 d *Sox10-*Venus embryos, large numbers of Venus^+^cells accumulated to form the trigeminal ganglia (cranial nerve V) (Figure [2B](#F2){ref-type=\"fig\"}). ",
"Venus was highly expressed in the ocular nerve, which is the first branch of the trigeminal nerve. ",
"Venus^+^cells were randomly distributed in the E15.5 d adrenal gland, most likely due to the incomplete column structure formation at this stage (Figure [2C](#F2){ref-type=\"fig\"}). ",
"In the alimentary tract, Venus^+^enteric ganglion cells originating from the vagal nerve (cranial nerve XII) were found migrating in a rostrocaudal direction through the esophagus, stomach, midgut, and hindgut (Figure [2D](#F2){ref-type=\"fig\"} and [2E](#F2){ref-type=\"fig\"}). ",
"All of these tissues are well-known NC derivatives, demonstrating that the Venus fluorescence observed in the *Sox10-*Venus mice is consistent with known NC cell localization and differentiation \\[[@B1]-[@B3],[@B5]\\]. ",
"In the otic vesicle, which is the primary structure of the inner ear nerve, cells continuously expressed Venus throughout the embryonic period (Figure [2F](#F2){ref-type=\"fig\"} and [2G](#F2){ref-type=\"fig\"}). ",
"The otic vesicle is not a NC derivative, but Sox10 protein expression in otic vesicle cells during the embryonic stage has been reported \\[[@B28],[@B29]\\].",
"\n\n{#F2}\n\nCell type evaluation of the Venus^+^cells in *Sox10-*Venus mice\n---------------------------------------------------------------\n\nTo verify that the Venus expression correctly reflects the endogenous expression of the Sox10 protein *in vivo*, we performed immunohistochemistry of E11.5 d to postnatal 1-week-old (P1 w) whole mouse frozen sections. ",
"Without exception, in all the tissues and stages examined, all the Sox10-positive cells expressed Venus. ",
"In addition to Sox10 immunostaining, we also examined cell-type-specific markers in NC-derived and Sox10^+^tissues. ",
"The enteric ganglion cells in the alimentary tract stained with PGP9.5 antibodies. ",
"In the esophagus, stomach, midgut, and hindgut, most of the migrated enteric ganglion cells were positive for Venus at E15.5 d (Figure [3A](#F3){ref-type=\"fig\"}). ",
"In the E15.5 d adrenal gland stained for tyrosine hydroxylase (TH), a marker for catecholaminergic cells, TH-positive endocrine cells were positive for Venus (Figure [3B](#F3){ref-type=\"fig\"}). ",
"In the early embryonic (E11.5 d) DRG, all Hu-positive sensory neurons were co-labeled with Sox10 and Venus (Figure [3C](#F3){ref-type=\"fig\"}). ",
"These observations confirmed that *Sox10-*Venus is a useful reporter strain, in which Venus expression faithfully reflects the endogenous Sox10 *in vivo*expression.",
"\n\n{#F3}\n\nLoss of Venus-fluorescence correlates with the shutdown of endogenous Sox10 expression\n--------------------------------------------------------------------------------------\n\nTo evaluate the on/off switching of reporter gene activity in *Sox10-*Venus mice, we verified the Sox10 expression with immunohistochemistry, and examined its correlation with Venus fluorescence. ",
"At the late embryonic stage of E15.5 d, the loss of Sox10 expression in Hu-positive DRG neurons coincided with a dramatic decrease in Venus fluorescence, compared to the early embryonic stage (Figure [3C](#F3){ref-type=\"fig\"} and [3D](#F3){ref-type=\"fig\"}). ",
"A similar phenomenon was observed in embryonic sympathetic ganglia: most of the TH^+^neurons were Venus^+^in the early embryonic stage, while TH^+^neurons in the late embryonic stage lost both Venus and Sox10 expression (Figure [3E](#F3){ref-type=\"fig\"} and [3F](#F3){ref-type=\"fig\"}).",
"\n\nThe prompt on/off switching of reporter gene activity is an important characteristic of this transgenic mouse strain. ",
"In mice in which the NC lineage is labeled, such as the *Wnt1*-Cre/CAG-CAT-EGFP double transgenic mouse, NC progeny expressing Cre are indelibly labeled with the reporter gene. ",
"At the late embryonic stage of E15.5 d, neurons in the DRG and sympathetic ganglia of *Wnt1*-Cre/CAG-CAT-EGFP mice were still labeled with EGFP fluorescence even though endogenous Sox10 expression had already diminished (Additional file [4](#S4){ref-type=\"supplementary-material\"}). ",
"In contrast, the sensitive on-off switching of the Venus-fluorescent reporting makes the *Sox10-*Venus mouse an accurate, real-time reporter strain.",
"\n\nIdentification of Venus^+^cells in the intact embryonic spinal cord\n-------------------------------------------------------------------\n\nPrevious reports have suggested that Sox10 is expressed in oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes \\[[@B24]-[@B26]\\]. ",
"We examined the identity of the Venus^+^cells observed in the ventral region of the intact embryonic spinal cord of *Sox10-*Venus mice by immunohistochemistry. ",
"The Venus^+^cells were negative for the pan-neuronal marker Hu (Figure [4A](#F4){ref-type=\"fig\"}), but positive for the oligodendroglial-lineage markers GSTπ and Olig2 (Figure [4B](#F4){ref-type=\"fig\"} and [4C](#F4){ref-type=\"fig\"}). ",
"Therefore, in the spinal cord of the embryonic *Sox10-*Venus mouse, Venus labels oligodendroglial-lineage cells without distinction as to their degree of maturation.",
"\n\n{#F4}\n\nVenus^+^cells in the intact and injured spinal cords of adult *Sox10-*Venus mice\n--------------------------------------------------------------------------------\n\nTo examine the phenotype of Venus^+^cells in intact and injured spinal cords of *Sox10-*Venus mice, we first observed changes in the Venus^+^cells over time (Figure [5A - C](#F5){ref-type=\"fig\"}). ",
"After spinal cord injury (SCI), there was a sharp drop in the number of Venus^+^cells, followed by a gradual accumulation around the lesion epicenter at later stages after the injury.",
"\n\n{#F5}\n\nNext, we identified the Venus^+^cells in intact and injured spinal cords by immunostaining with various cell markers (Figure [6A - H](#F6){ref-type=\"fig\"}). ",
"In the intact spinal cord, Venus^+^cells were easily visualized in both the gray and white matter (Figure [5A](#F5){ref-type=\"fig\"}), and were mostly positive for GSTπ (Figure [6A](#F6){ref-type=\"fig\"}). ",
"After contusive SCI, Sox10-expressing cells disappeared from the lesion epicenter (Figure [5B](#F5){ref-type=\"fig\"}). ",
"In the acute phase of SCI (4 days-post-injury; 4 dpi), cells positive for NG2 and Venus appeared in the residual white matter (Figure [6B](#F6){ref-type=\"fig\"}). ",
"Although NG2 is also known to stain reactive astrocytes and macrophages \\[[@B30]\\], the Venus^+^cells observed in the injured spinal cord were negative for GFAP (Figure [6D](#F6){ref-type=\"fig\"}) and CD11b (Figure [6E](#F6){ref-type=\"fig\"}), indicating that they were Sox10-expressing oligodendrocytes. ",
"We also observed Venus^+^cells that were positive for PDGFRα, an OPC marker (Figure [6C](#F6){ref-type=\"fig\"}), suggesting that OPCs also expressed Sox10 in the injured spinal cord.",
"\n\n{#F6}\n\nIn the later subacute phase of SCI (14 dpi), numerous Venus^+^cells were found in the epicenter and around the lesion site (Figure [5C](#F5){ref-type=\"fig\"}). ",
"Immunohistochemistry revealed that many of the Venus^+^cells were positive for S100β, a marker of the Schwann cell lineage, confirming Schwann cell involvement after SCI (Figure [6F](#F6){ref-type=\"fig\"}). ",
"Some of the Venus^+^cells had bipolar processes and were positive for p75, suggesting that they were immature Schwann cells (Figure [6G](#F6){ref-type=\"fig\"}), while a few Venus^+^mature Schwann cells were also identified by their P0 expression (Figure [6H](#F6){ref-type=\"fig\"}). ",
"The observation that both immature and mature Schwann cells were Venus^+^in the injured spinal cord is consistent with the Schwann cell lineage deriving from the NC.",
"\n\nComparison of the *Sox10-*Venus strain with other NC reporter mouse strains\n---------------------------------------------------------------------------\n\nThe data from several NC reporter mouse lines, such as *Sox10*(S4F)-Cre, *P0*-Cre, *Wnt1*-Cre, and *Ht-Pa*-Cre \\[[@B5],[@B14],[@B16],[@B26],[@B31],[@B32]\\], have already been published. ",
"To compare this body of data to the observations gained from the *Sox10-*Venus mouse, the embryonic expression patterns of various NC-derived tissues are summarized for each strain in Table [1](#T1){ref-type=\"table\"}. ",
"At the early embryonic period (E11.5 d - E12.5 d), the reporter gene activity of all the mouse strains was quite similar. ",
"All the strains demonstrated reporter gene activity in numerous NC-lineage tissues, including the DRG, sympathetic ganglia, melanoblasts, enteric nervous system, superior/jugular ganglion, aorta, and craniofacial mesenchyme. ",
"All the strains also showed reporter expression in the otic vesicle, which does not originate from the NC.",
"\n\n###### \n\nComparison of reporter expression in *Sox10-*Venus and various other mice with NC lineage-labeling\n\n Tissues *Sox10*-Venus *Sox10*-Cre *P0*-Cre *Wnt1*-Cre *Ht-Pa-*Cre\n --------------------------- --------------- ------------- ---------- ------------ -------------\n Dorsal root ganglia \\+ \\+ \\+ \\+ \\+\n Sympathetic ganglia \\+ \\+ \\+ \\+ \\+\n Melanoblasts \\+ \\+ \\+ \\+ \\+\n Enteric nervous system \\+ \\+ \\+ \\+ \\+\n Superior/jugular ganglion \\+ \\+ \\+ \\+ \\+\n Aortae \\+ \\+ \\+ \\+ \\+\n Craniofacial mesenchyme \\+ \\+ \\+ \\+ \\+\n Otic vessicle \\+ \\+ \\+ \\+ \\+\n Oligodendroglia \\+ \\+ \\- \\- \\-\n Ventral neural tube \\+ \\+ \\- \\- \\-\n Developing limb \\+ \\+ \\- \\- \\-\n\nReporter gene expression patterns at the embryonic stage are compared in various mice developed to trace neural crest derivatives: *Sox10-*Venus, *Sox10*(S4F)-Cre \\[[@B26]\\], *P0*-Cre \\[[@B5],[@B15]\\], *Wnt1*-Cre \\[[@B14],[@B16],[@B26],[@B31],[@B32]\\], and *Ht-Pa-*Cre \\[[@B16],[@B26]\\]. ",
"All these lines have similar labeling patterns in both NC-lineage tissues (DRG, sympathetic ganglia, melanoblasts, enteric nervous system, superior/jugular ganglion, aorta, craniofacial mesenchyme) and in tissues not in the NC lineage (otic vesicle, oligodendroglial cells, and OPCs). ",
"In the developing limbs of *Sox10-*Venus and *Sox10-*Cre mice, which reflect the endogenous Sox10 expression profile, the reporter fluorescence clearly labeled oligodendroglial cells and the peripheral nervous network. ",
"Immunohistochemistry did not detect any ectopic reporter gene expression in any tissues from the embryonic *Sox10-*Venus mice.",
"\n\nRegarding the differences in these reporter strains, CNS myelinating glial cells were not labeled in the *P0*-Cre, *Wnt1*-Cre, and *Ht-Pa*-Cre strains; they were only labeled in the *Sox10*-related strains *Sox10-*Venus and *Sox10*(S4F)-Cre. ",
"In the brain and spinal cord, the labeling of oligodendroglial cells and OPCs in the *Sox10-*Venus and *Sox10-*Cre mice reflected the endogenous Sox10 expression in these cells, since they are not derived from the NC. ",
"The peripheral nerve network in developing limbs consists of nerve fibers and their associated Schwann cells, which are both derived from the NC. ",
"Although the *LacZ*expression in the developing limb was ambiguous in the *Sox10*(S4F)-Cre/Rosa-*LacZ*mouse \\[[@B26]\\], the Venus fluorescence observed in the same region with the *Sox10-*Venus mouse clearly originated from the Schwann cells (Figure [1E](#F1){ref-type=\"fig\"}).",
"\n\nDiscussion\n==========\n\nIn this study, we developed and characterized the *Sox10-*Venus BAC transgenic mouse. ",
"Analysis of the early embryonic stages showed that not only NC lineage cells, but also oligodendroglial cells were clearly labeled with high-intensity Venus fluorescence (Figure [1](#F1){ref-type=\"fig\"} and [2](#F2){ref-type=\"fig\"}). ",
"Compared to other published transgenic and knock-in reporter mouse strains, the *Sox10-*Venus mouse has advantages that make it invaluable for future studies.",
"\n\nThe mice with NC-lineage tracing *Wnt1*-Cre, *P0*-Cre, and *Ht-PA*-Cre, crossed with those with Cre/loxP-mediated cell labeling, Rosa-*LacZ*and CAG-CAT-EGFP, can be used only for analyzing cell lineage or migration, because the target cells are irreversibly labeled \\[[@B5],[@B14]-[@B20]\\]. ",
"Although *Sox10-*Venus also labels NC-lineage cells, the fast on/off switching of Venus fluorescence is tightly correlated with endogenous Sox10 expression. ",
"Similarly, the reporter gene activity in *CNP-*EGFP and *PLP-*EGFP mice, which are transgenic mice that label oligodendroglial-lineage cells, truly reflects the *in vivo*expression of specific genes driven by specific promoters or enhancers. ",
"The transgenic system of the *Sox10-*Venus mouse is quite similar to these; however, the Venus fluorescence is brighter and more intense than EGFP fluorescence.",
"\n\nAlthough reporter gene activity occurs in NC cells and oligodendrocytes in all *Sox10*reporter mouse lines, i.e., *Sox10^LacZ/+^*, *Sox10-*rtTA, *Sox10-*Cre strains \\[[@B24]-[@B26]\\], and the new *Sox10-*Venus strain, each line has advantages and disadvantages. *",
"LacZ*knock-in *Sox10*^*LacZ*/+^heterozygous pups are prone to spontaneous mutation phenotypes due to haploinsufficiency. ",
"Also, to observing the *LacZ*expression in *Sox10*^*LacZ*/+^mice requires additional visualization procedures, making live cell imaging difficult. ",
"The *Sox10-*rtTA knock-in crossed with the inducible TRE-*LacZ*transgenic is unique, but the reporter expression is transient and does not fluoresce, making it difficult to observe directly. ",
"The *Sox10-*Cre/CAG-CAT-EGFP double transgenic mouse traces both NC and oligodendrocyte progeny, since it reports past as well as ongoing Sox10 expression. ",
"With this double transgenic mouse, it is possible to carry out cell sorting or live imaging.",
"\n\nThe *Sox10-*Venus strain overcomes most of the disadvantages of the above-mentioned *Sox10*reporter mouse lines. ",
"In this mouse, the intense Venus fluorescence can be directly observed from outside the embryo, without staining or enhancement procedures (Figure [1](#F1){ref-type=\"fig\"}, [2](#F2){ref-type=\"fig\"}, and movies in Additional Files [2](#S2){ref-type=\"supplementary-material\"} and [3](#S3){ref-type=\"supplementary-material\"}). ",
"Venus expression faithfully reflects real-time endogenous Sox10 expression, with prompt on/off switching (Figure [3](#F3){ref-type=\"fig\"}). ",
"Although the choice of strain obviously depends on the purpose of the study, we believe that the *Sox10-*Venus mouse is the most appropriate reporter line for numerous fields of research.",
"\n\nAlthough *in vivo*time-lapse imaging of oligodendroglial cell migration (including OPCs) has recently been reported, it has only been conducted in zebrafish \\[[@B33],[@B34]\\]. ",
"Accurate time-lapse imaging has been difficult to conduct in mice until now. ",
"There are several issues that need to be considered in such studies. ",
"For instance, (1) Is the *normal*and *natural*behavior of the cells or tissues of interest being observed? ",
"In some cases, the invasive procedures required to complete the imaging, including surgical incision, tissue-slice culture, electroporation, dye injection, and virus infection, may affect the tissues observed. (",
"2) To what degree does the transgenic manipulation affect the phenotype? ",
"In *Sox10*^*LacZ*/+^mice, the resulting phenotype, coupled with haploinsufficiency, complicates analysis of the area of interest. ",
"Our analysis of the *Sox10-*Venus transgenic line demonstrates that it has neither developmental defects nor ectopic Venus expression. ",
"Thus, the *Sox10-*Venus strain appears to be a useful tool for investigating normal developmental processes via live cell monitoring, using directly observed fluorescence without invasive intervention procedures (Figure [1G](#F1){ref-type=\"fig\"}, movies in Additional Files [2](#S2){ref-type=\"supplementary-material\"} and [3](#S3){ref-type=\"supplementary-material\"}).",
"\n\nSox10 is a well-known marker of neural crest stem cells (NCSCs), along with *slug, snail*, and *p75*\\[[@B35],[@B36]\\]. ",
"There have been numerous reports recently of NCSCs surviving in a wide range of tissues through the entire lifespan of the animal, suggesting that NCSCs may have the potential to support the regeneration and recovery of damaged tissues. ",
"The Venus fluorescence in *Sox10-*Venus mice will make it possible to prospectively sort Venus^+^cells by flow-cytometry and collect an enriched population of NCSCs. ",
"Since NCSCs are located in easily accessible peripheral tissues such as the skin and bone marrow, NCSCs have been receiving increasing attention for future clinical applications in cell transplantation therapy, because the feasibility of autologous transplantation is anticipated \\[[@B37]-[@B39]\\]. ",
"Autologous cell transplantation therapy avoids the immunological and ethical concerns related to the use of embryonic stem cells. ",
"We hope that the *Sox10-*Venus strain will prove to be a powerful tool for enhancing the progress of NCSC research.",
"\n\nThe mouse is an excellent model system for studying human disease progression and pathogenesis. ",
"We demonstrated the usefulness of our new reporter mouse strain *Sox10-*Venus for monitoring processes occurring after a traumatic disorder (Figure [5](#F5){ref-type=\"fig\"} and [6](#F6){ref-type=\"fig\"}), and crossing it with mutant mouse lines may provide insight into the processes behind numerous developmental defects. ",
"As with the analysis conducted in CNP-EGFP mice to study the behavior of oligodendroglial cells in SCI \\[[@B30]\\], *Sox10-*Venus mice have potential applications not only for oligodendrocyte research, but also for all Sox10^+^-tissue analyses, including disorders of the NC cells and peripheral nerves. ",
"The ability to visualize the processes of disease initiation and progression will help to shed light on the pathophysiology of many human diseases.",
"\n\nConclusions\n===========\n\nWe developed the novel *Sox10-*Venus BAC transgenic mouse line, in which Venus fluorescence labels NC and oligodendroglial lineage cells. ",
"Endogenous Sox10 expression is accurately reported by Venus fluorescence over the course of normal development, without ectopic Venus expression. ",
"The highly intense reporter fluorescence allows for *in vivo*imaging of single-cell migration. ",
"This strain will be especially useful for analyzing spinal cord injury and studying NCSCs.",
"\n\nMethods\n=======\n\nBAC Construction and development of *Sox10-*venus BAC transgenic mice\n---------------------------------------------------------------------\n\nFor generating the *Sox10*-Venus transgenic mouse, we prepared the following BAC construction. ",
"Detailed procedures will be described elsewhere (CA, TI, YUI, manuscript in preparation). ",
"Briefly, a BAC clone *RP24-85O14*(CHORI, BACPAC Resources) that covers 225.6 kb territory of mouse *Sox10*gene locus was electroporated into the recombinogenic bacterial strain EL250 for systematic modifications \\[[@B40]\\]. ",
"To obtain in-frame replacement of the exon containing the *Sox10*translation initiation codon (ATG) to the Venus-polyadenylation signal (pA) cassette in the BAC clone, 1.2 kb homology arms were amplified by PCR and sequentially subcloned into the pBluescriptII vector (Stratagene). ",
"Then the Venus-pA-FRT-*Kanamycin*-resistant gene (*Kan^r^*)-FRT cassette was inserted in between the arms and the fragment containing the Venus-pA-*Kan^r^*cassette with the homology arms was isolated by agarose gel electrophoresis for homologous recombination which was processed in EL250 as was reported previously \\[[@B41]\\]. ",
"Precise insertion of the Venus-pA cassette and excision of the *Kan^r^*in the *Sox10*-BAC was verified by PCR as well as pulse field gel electrophoresis and the modified BAC clone was linearlized by PI-*Sce*I, dialyzed and diluted to \\~2 ng/μl for pronuclear injections as previously described \\[[@B41]\\]. ",
"For BAC transgenic mouse founders, presence of *RP24*BAC vector sequences immediately upstream or downstream of the PI-*Sce*I site was always examined by PCR tail DNA analyses to minimize the possibility that fortuitous deletions occur on the BAC transgene after the chromosomal integrations \\[[@B41]\\]. ",
"The established BAC transgenic mouse lines were bred with wild-type C57BL/6J mice and the tail DNA was used for the PCR genotyping: The PCR primers for the transgene detections are provided in Table S1; Additional File [5](#S5){ref-type=\"supplementary-material\"}.",
"\n\nAnimals\n-------\n\nWe purchased wild-type C57BL/6J and ICR mice from SLC Japan. ",
"The Cre-expressing transgenic lines, *Wnt1*-Cre \\[[@B14]\\] and *P0*-Cre \\[[@B15]\\], were mated with an EGFP reporter line (CAG-CAT-EGFP \\[[@B18]\\]) to obtain *Wnt1*-Cre/CAG-CAT-EGFP and *P0*-Cre/CAG-CAT-EGFP double-transgenic mice. ",
"All mice were housed under specific pathogen-free conditions. ",
"All experimental procedures were approved by the Institutional Animal Care and Use Committee of Keio University, Murayama Medical Center, and Tokyo Medical and Dental University. ",
"All surgical interventions and animal care procedures were in accordance with the Laboratory Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals (National Institute of Health, USA).",
"\n\nHistological analysis\n---------------------\n\nImmunohistochemical analyses were performed as described previously \\[[@B5],[@B42],[@B43]\\]. ",
"Briefly, E9.5 d, n = 3; E10.5 d, n = 10; E11.5 d, n = 9; E12.5 d, n = 5; E13.5 d, n = 6; E14.5 d, n = 3; E15.5 d, n = 7; E16.5 d, n = 3; P0 d, n = 3; and P1 w, n = 3 transgenic embryos (E0 = day of plug) and pups were fixed with 4% PFA, and 16-μm-thick cryosections were prepared with the cryostat CM3000 (Leica). ",
"The detailed information about the primary and secondary antibodies was described in Table S1; Additional File [5](#S5){ref-type=\"supplementary-material\"}. ",
"Antigen retrieval was applied for specific targets (anti-Olig2, anti-hSox10) by incubating them with Target Retrieval Solution (Dako) in an autoclave at 105°C for 5 minutes. ",
"Fluorescence immunostaining with specific primary antibodies was performed overnight at 4°C, followed by one-hour incubation at room temperature with the appropriate secondary antibodies conjugated with Alexa488, Alexa555, or Alexa647 (Invitrogen) along with Hoechst 33258 (10 μg/ml, Sigma) for nuclear staining. ",
"The samples were examined with a laser scanning confocal microscope (LSM700 or Pascal: Carl Zeiss) or fluorescent microscope (BZ-9000: Keyence, MVX-CSU: Olympus).",
"\n\nTime-Lapse Imaging\n------------------\n\nTime-lapse observation (Figure [1G](#F1){ref-type=\"fig\"}, movies in Additional Files 2 and 3) was performed as described previously \\[[@B44],[@B45]\\]. ",
"Briefly, freshly isolated embryos were collected in cold phosphate buffered saline (PBS) and genotyped based on their Venus fluorescence, using an inverted epifluorecence microscope (Leica MZ10F). ",
"The embryos were transferred with 100 - 150 µl of enriched medium to the center of a 35-mm glass-bottom dish (hole size 27 mm; Matsunami) and mixed with 100-150 µl of type I collagen-gel solution (Cellmatrix IA; Nitta Gelatin). ",
"The solution had been previously diluted to 0.5-0.6 mg/ml with distilled water, 5× DMEM, and a neutralizing buffer, with a final concentration about 0.3 mg/ml, according to the manufacturer\\'s protocol. ",
"The gel was incubated at 37°C for 20 minutes. ",
"Once the gel was solidified, up to 600 μl of imaging culture medium was gently added to the gel. ",
"The final concentration of the culture medium was as follows: DMEM/F-12 (1:1), glucose (0.6%), L-glutamine (2 mM), sodium bicarbonate (3 mM), HEPES buffer (50 mM), insulin (25 μg/ml), transferrin (100 μg/ml), progesterone (20 nM), sodium selenate (30 nM), and putrescine (60 μM), with equilibration buffer supplemented with 4% fetal bovine serum. ",
"The dish was attached to a pre-heated microscope stage and incubated at 37°C in 5% CO~2~. Imaging was carried out with an epifluorescence microscope from Keyence (BZ9000) or a confocal Carl Zeiss microscope (LSM5 PASCAL Exciter). ",
"Images were acquired with a 10× objective lens every 10 or 20 minutes, and processed using the Keyence Bz-II application and Zeiss LSM5 software, respectively. ",
"NIH ImageJ 1.44e and Quicktime Pro 7.6.8 were used for preparing movie files.",
"\n\nSpinal cord injury model\n------------------------\n\nAdult female *Sox10-*Venus mice (8-weeks old, n = 4 for each time point) were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg). ",
"The dorsal surface of the dura mater was exposed after laminectomy at the tenth thoracic vertebra, and SCI was induced using an IH (Infinite Horizon) impactor (60 kDyn; Precision Systems & Instrumentation) as described previously \\[[@B46],[@B47]\\]. ",
"The mice were returned to their home cages with free access to water and food. ",
"Intact mice and mice at 4 and 14 days post-injury (dpi) were deeply anesthetized and transcardially perfused with chilled PBS followed by 4% paraformaldehyde (PFA). ",
"The spinal cords were removed and immersed in 4% PFA at 4°C overnight, and then immersed in 15% and 30% sucrose for 24 hours each, at 4°C. ",
"The spinal cords were then embedded in OCT compound and sectioned into 12-µm-thick sagittal sections by cryostat (Leica CM3000).",
"\n\nAbbreviations\n=============\n\nNC: neural crest; OPC: oligodendrocyte progenitor cell; HMG: high mobility group; PNS: peripheral nervous system; CNS: central nervous system; P0: protein zero; EGFP: enhanced green fluorescent protein; CNP: 2\\'-3\\'-cyclic nucleotide 3\\'-phosphodiesterase; PLP: myelin proteolipid protein; TH: tyrosine hydroxylase; DRG: dorsal root ganglia; SCI: spinal cord injury; DPI: days-post-injury; p75: p75 neurotrophin receptor; NSPC: neural stem/progenitor cell; NCSCs: neural crest stem cells; PBS: phosphate buffered saline.",
"\n\nCompeting interests\n===================\n\nThe authors declare that they have no competing interests.",
"\n\nAuthors\\' contributions\n=======================\n\nSS, CA, and HO designed the project. ",
"SS, AY, FRM, SS, TI, YUI, NN, and MS performed experiments and analyzed the data. ",
"SS, AY, and FRM prepared the figures. ",
"SS, AY, FRM, HK, TI, MN, CA, and HO wrote the manuscript. ",
"MN, CA, and HO supervised the project. ",
"All authors read and approved the final manuscript.",
"\n\nSupplementary Material\n======================\n\n###### Additional file 1\n\n**Embryonic age-dependent fluorescence changes compared among the *Sox10-*Venus, P0-Cre/CAG-CAT-EGFP, and *Wnt1*-Cre/CAG-CAT-EGFP mouse strain**. (",
"A-C) Venus fluorescence changes over time were observed from outside of the *Sox10-*Venus embryo. ",
"Deep-tissue fluorescence gradually decreased from E11.5 d to E15.5 d (see Figure [1](#F1){ref-type=\"fig\"} for additional photos). (",
"C-E) At E14.5 d, reporter gene expression patterns were quite similar between the transgenic *Sox10-*Venus mouse and the double-transgenic mice *P0*-Cre/CAG-CAT-EGFP and *Wnt1*-Cre/CAG-CAT-EGFP. ",
"Scale bars (A-E) 1.0 mm.",
"\n\n###### \n\nClick here for file\n\n###### Additional file 2\n\n**Live imaging of single-cell movement: *Sox10-*Venus^+^NC-derivatives in the superficial embryonic skin layer (1)**. ",
"Time-lapse imaging with an epifluorescence microscope (Keyence) showed Venus-positive cell movements in E14.5 d *Sox10-*Venus embryo ex-vivo skin explants. ",
"One frame was captured every 10 minutes over a 6-hour period (motion: 6 fps).",
"\n\n###### \n\nClick here for file\n\n###### Additional file 3\n\n**Live imaging of single-cell movement: *Sox10-*Venus^+^neural crest derivatives in the superficial embryonic skin layer (2)**. ",
"Confocal time-lapse imaging of the front facial area of the whole E10.5 d *Sox10-*Venus embryo captured isolated Venus-positive cells. ",
"The distinctive, intense Venus fluorescence made it possible to follow migrating cells within the embryo over several hours, even capturing the dynamic changes in cell shape. ",
"One frame was captured every 20 minutes using a confocal Pascal microscope (Carl Zeiss). ",
"Scale bar: 50 µm, motion: 4 fps.",
"\n\n###### \n\nClick here for file\n\n###### Additional file 4\n\n**NC progeny were permanently EGFP-labeled in the *Wnt1*-Cre/CAG-CAT-EGFP mouse**. (",
"A-B) Immunohistochemical analysis with anti-GFP and marker antibodies for specific cell types showed that the EGFP reporter gene is continuously expressed in NC derivatives in the DRG (A) and sympathetic ganglia (B) of E15.5 d *Wnt1*-Cre/CAG-CAT-EGFP mice. ",
"Scale bars (A-B) 50 μm.",
"\n\n###### \n\nClick here for file\n\n###### Additional file 5\n\nTable S1: Detailed information about sequences and antibodies.",
"\n\n###### \n\nClick here for file\n\nAcknowledgements\n================\n\nWe are grateful to Dr. R.B. Darnell for the gift of the anti-Hu antibody. ",
"We are grateful to Drs. ",
"C. Hara, N. Kishi, N. Shimojima, M. Mori, A. Iwanami, and H. Kanki for their excellent technical instruction and for critical reading of the manuscript. ",
"We also thank all the members in the Okano Laboratory and Akazawa Laboratory for their encouragement and invaluable comments on this manuscript.",
"\n\nThis work was supported by a Grant-in-Aid for Young Scientists and a Grant-in-Aid for Scientific Research (C) from The Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) to S.S. and F.R-M.; by a Keio University Grant-in-Aid for the Encouragement of Young Medical Scientists to S.S. and F.R-M.; by Keio Gijuku Academic Development Funds to S.S.; by a JST-SORST fellowship to F.R-M.; by grants from Research Foundation ITSUU Laboratory and Takeda Science Foundation to T. I.; and by a Grant-in-Aid from the Global COE Program of the MEXT to Keio University to H.O.\n"
] | {
"pile_set_name": "PubMed Central"
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"Maintaining the reliability of Uber’s mobile apps is crucial to facilitating a seamless and enjoyable user experience. ",
"Alongside a robust plugin architecture, feature flags, and dynamic validation of external data, static analysis tools play a key role in ensuring high code reliability by detecting potential bugs before updates are shipped to users.",
"\n\nPreviously, Uber deployed third-party static analysis tools to detect potential NullPointerExceptions (NPE), a leading cause of app crashes, and maintain reliability in our Android codebase. ",
"However, as our codebase grew, we found that these tools did not quite meet our needs for providing strong checks and quick feedback to engineers.",
"\n\nTo address this, Uber developed NullAway, a fast and practical tool to help eliminate NPEs. ",
"NullAway significantly improved our developers’ productivity, while maintaining the strong checking we required to deploy safely. ",
"And now, we have contributed this tool to the open source community so others can build more reliable apps, too!",
"\n\nIn this article, we discuss our motivation behind developing NullAway, outline how we built the tool, and provide instructions on how to use it for your own Android apps and Java projects.",
"\n\nMotivation behind NullAway\n\nMobile crashes can cause significant problems for our users, such as preventing riders from requesting a trip in a timely manner or drivers from accepting rides. ",
"NPEs, which occur when a null pointer is dereferenced in Java, are a frequent cause of crashes in Android apps. ",
"Our strategy at Uber has been to use static code analysis tools to prevent NPE crashes as much as possible. ",
"In 2016, Uber deployed the Facebook Infer and Eradicate tools for static detection of potential NPEs. ",
"Alongside our Runtime Annotation Validation Engine (RAVE) validation, these tools reduced the number of NPEs observed in our apps in production by an order of magnitude.",
"\n\nTo maximize reliability, we wanted to guarantee that no code could be merged into our apps until all possible NPE warnings were fixed; this way, our master branch would always be in a “green” state (meaning the build has passed all relevant tests) with zero warnings. ",
"Obtaining this guarantee required running these tools on our Submit Queue, the final stage of our continuous integration pipeline, such that any error from the tools would block new code from merging.",
"\n\nWhile increasing app reliability, running bug-finding tools like an NPE checker on the Submit Queue had two side effects that encouraged us to think creatively about our code:\n\nLate feedback: For diffs with NPE problems, developers only received warnings at the final stage of making a code change. ",
"This late feedback could lead to a frustrating experience: a developer’s change could pass code review and all other checks, only to be rejected on the Submit Queue due to an easy-to-fix issue. ",
"The developer may well have moved on to another task by this point, and would have to context-switch to return to the code and address the warning. ",
"Higher latency, decreased developer productivity: The overall latency of the Submit Queue experience increased, thereby reducing developer productivity. ",
"Since many diffs failed on the Submit Queue with NPE warnings, they needed to be submitted multiple times, increasing overall queue lengths.",
"\n\nThe speed of our development (with many diffs in flight at once) and the lengthy runtime of existing NPE checkers prevented us from running them earlier in the process, so we decided to build a new solution that would be fast enough to run with low latency at every stage of our development pipeline, even during local builds. ",
"And an added benefit of developing our own fix is that we could save on machine resources as we continue to grow our codebase.",
"\n\nOur answer? ",
"NullAway.",
"\n\nIntroducing NullAway\n\nAt its core, NullAway is an open source type-based NPE checker for Java code. ",
"To use NullAway, you must first add @Nullable annotations in your code wherever a field, method parameter, or return value may be null. (",
"We already had these annotations in our codebase due to our previous use of Eradicate.) ",
"Given these annotations, NullAway performs a series of local consistency checks to ensure that any pointer that gets dereferenced in your code cannot be null.",
"\n\nNullAway is built as a plugin check to the Error Prone bug-finding framework. ",
"Error Prone runs code checks as part of the standard Java compilation process. ",
"This compiler integration allows checks to reuse much of the work already done by the compiler, such as code parsing and type checking. ",
"Further, NullAway and Error Prone integrate directly into the fast, in-memory parallel builds supported by Buck, the build tool we use for our Android code. ",
"Therefore, NullAway can run much more quickly than tools that run outside the normal build process.",
"\n\nWe found that NullAway added only a small overhead to normal build times (around 10 percent in our measurements). ",
"As a result, rather than only running on the Submit Queue, we configured NullAway to run on every single build of our Android code.",
"\n\nThe value of integrating NullAway into all of our Java builds is threefold:\n\nImmediate feedback: Integration into all builds enables developers to get immediate feedback whenever they introduce a potential NPE, rather than having to wait for the Submit Queue.",
"\n\nNo NPE checker: The build integration means we no longer need to run a nullness checker as a separate job on the Submit Queue, saving significant machine resources.",
"\n\nLower Submit Queue latencies: NullAway enables significantly lower Submit Queue latencies, as failures on Submit Queue due to NPE warnings became very rare; this reduced latency became even more pronounced after our move to a monorepo .",
"\n\nU sing NullAway\n\nTo get an idea of how NullAway works, let us consider how it determines whether some expression in the program can be null, which is frequently required for nullness checking. ",
"Consider the following example:\n\nclass A {\n\n@Nullable Object f;\n\n}\n\nstatic void m(A x) {\n\nif (x.f !",
"= null) {\n\nSystem.out.println(x.f.toString());\n\n}\n\n}\n\nIn the example above, NullAway tries to show that x is not null, to ensure that x.f does not cause an NPE, and also that x.f is not null at the call x.f.toString(). ",
"For expressions that should not be null, NullAway first tries to quickly prove that the expression is obviously non-null, e.g., by checking if its type is not @Nullable or if it is an expression like new Object() that cannot be null. ",
"For the example, since the declaration of x is not annotated @Nullable, NullAway can assume it is not null, thereby showing x.f is safe. ",
"NullAway enforces this assumption by checking that a @Nullable expression is never passed as a parameter to method m.\n\nIf the quick checks fail, NullAway tries to show non-nullness using data-flow analysis, leveraging an existing library from the Checker Framework. ",
"A key purpose of the data-flow analysis is to discover existing null checks in the code. ",
"For the x.f.toString() call in above example, quick checks fail to show that x.f cannot be null, since the A.f field is @Nullable. ",
"However, our data-flow analysis uses the enclosing conditional check that x.f !",
"= null to show that the x.f.toString() call is safe. ",
"Since the data-flow analysis can be expensive (it requires computing a control-flow graph and running a fixed-point computation), NullAway runs the analysis only once per method and caches the result.",
"\n\nOn the NullAway GitHub page, there are detailed instructions for how to run the tool on your Android app or other Java code. ",
"For more details on NullAway’s checks, error messages, and limitations, see our detailed implementation guide.",
"\n\nNext steps\n\nWith NullAway, we are able to maintain strong static checking for NPEs by other tools while also improving developer productivity. ",
"We hope you find NullAway useful for improving the reliability of your Java codebase.",
"\n\nInterested in developing open source tools to improve app reliability and developer productivity? ",
"Apply for a role on Uber’s Mobile Developer Experience Platform team.",
"\n\nManu Sridharan is a software engineer on Uber’s Mobile Developer Platform Team, leading efforts to apply static analysis across Uber’s codebase. ",
"Earlier this year, he delivered a tech talk at Curry On about how static analysis and software architecture are leveraged to improve application quality at Uber."
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"Q:\n\nDraw charts using c# with a lot of data\n\nWhen i drew line charts using c# with a lot of data(maybe 10 million~100 million), it's not loaded. ",
"c# window form was broken.",
"\ni can't reduce these data because all of data are important.",
"\n\nA:\n\nSurely it is impossible to show all 10 million data points on a screen. ",
"My current screen resolution at 1920x1080 only has about 2M pixels. ",
"So even if you show all the points from your data, there will not be enough screen space to show it all.",
"\nSo you'll need to either reduce your data size by smoothing out the graph data or show only parts of your data at a time.",
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"This invention relates to the venting of lead acid storage batteries. ",
"More particularly, it relates to a ceramic body which is placed in the filling cap or the cover of a lead acid storage battery and serves to permit the cell gases to vent through the ceramic stone while at the same time effectively resisting any ingress of flame caused by the ignition of cell vent gases. ",
"The ceramic body is designed to effectively retard flame propagation while preventing the accumulation of large volumes of gases in the battery.",
"\nCeramic materials have been utilized in conjunction with storage batteries of the lead acid type so as to prevent an external spark or flame from causing an explosion inside the battery. ",
"For example, in U.S. Pat. ",
"No. ",
"2,341,382 such an arrangement is described employing a loose ceramic material. ",
"In U.S. Pat. ",
"Nos. ",
"2,471,585 and 3,630,788 a combined filling and venting device employs a ceramic material in the form of a tubular structure. ",
"It is now proposed to utilize flat plate-like slabs of ceramic material in the gang type vent cap as well as a single vent cap. ",
"Such a device is described in U.S. patent application Ser. ",
"No. ",
"354,514 filed Apr. 26, 1973, now abandoned, which was refiled as U.S. patent application Ser. ",
"No. ",
"423,055 filed Dec. 10, 1973, now U.S. Pat. ",
"No. ",
"3,879,227, both of which are commonly assigned.",
"\nThe problem with prior ceramic materials utilized in battery venting devices is the maintenance of open porosity so that the material will adequately vent the battery yet will serve as a barrier to a flame. ",
"Prior to this invention, particle distributions were not uniform which is very important when a small size ceramic disc or platelet is to be employed in a battery vent. ",
"Other problems with available ceramic materials reside in excessive wear in the dies utilized to stamp the green ceramic material for example, fused alumina, prior to their being fired in a kiln. ",
"In order to be effective as a flame barrier as well as a venting material, the ceramic must have a very critical particle size range, be able to withstand normal handling as it is bulk shipped, be acid and heat resistant and not collapse during pressing so as to expose particles which are not wetted with bonding agent.",
"\nIt is an object of the present invention to provide a novel porous ceramic material which very effectively serves to vent explosive gases from storage batteries in a manner that any external ignition is impeded from being transmitted into the battery casing. ",
"It is another object of this invention to provide a porous ceramic material which exhibits a narrow controlled range of back pressure under given gas flow conditions. ",
"It is still another object of this invention to provide a novel unfired ceramic material which reduces the wearing action on the pressing tools during its pelletizing. ",
"It is yet another object of this invention to provide a fired ceramic material which is acid resistant, heat resistant and also has good strength after being fired so that it can be handled in bulk shipments and assembling equipment without cracking or chipping."
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"Literature of Kashmir\n\nLiterature of Kashmir has a long history, the oldest texts having been composed in the Sanskrit language. ",
"Early names include Patanjali, the author of the Mahabhashya commentary on Pāṇini's grammar, suggested by some to have been the same to write the Hindu treatise known as the Yogasutra, and Dridhbala, who revised the Charaka Samhita of Ayurveda.",
"\n\nIn medieval times, philosophers of Kashmir Shaivism include Vasugupta (c. 800), Utpala (c. 925), Abhinavagupta, and Kshemaraja as well as Anandavardhana.",
"\n\nKashmiri language literature \nThe use of the Kashmiri language began with the work Mahānaya-Prakāsha by Rājānaka Shiti Kantha (c.1250), and was followed by the poet Lalleshvari or Lal Ded (14th century), who wrote mystical verses in the vakh or four-line couplet style. ",
" Another mystic of her time equally revered in Kashmir and popularly known as Nund Reshi wrote powerful poetry. ",
"Later came Habba Khatun (16th century) with her own style. ",
"Other major names are Rupa Bhavani (1621–1721), Arnimal (d. 1800), Mahmud Gami (1765–1855), Rasul Mir (d. 1870), Paramananda (1791–1864), Maqbool Shah Kralawari (1820–1876). ",
" Also, the Sufi poets like Shamas Fakir, Wahab Khar, Soch Kral, Samad Mir, and Ahad Zargar. ",
" Among modern poets are Ghulam Ahmad Mahjur (1885–1952), Abdul Ahad Azad (1903–1948), and Zinda Kaul (1884–1965).",
"\n\nDuring the 1950s, a number of well educated youth turned to Kashmiri writing, both poetry and prose, and enriched modern Kashmiri writing by leaps and bounds. ",
"Among these writers are Dinanath Nadim (1916–1988), Rahman Rahi, Ghulam Nabi Firaq Amin Kamil (1923-2014), Ali Mohd Lone, Autar Krishen Rahbar (born 1933), Akhtar Mohiuddin, Sajood Sailani (brn 1933), Som Nath Zutshi, Muzaffar Aazim, and Sarwanand Kaol Premi. ",
"Some later day writers are Hari Krishan Kaul, Majrooh Rashid, Rattanlal Shant, Hirdhey Kaul Bharti, Omkar N Koul, Roop Krishen Bhat, Rafiq Raaz, Tariq Shehraz, Shafi Shauq, Showkat Shehri, M H Zaffar, Shenaz Rashid, Shabir Ahmad Shabir, Shabir Magami, and Moti Lal Kemmu.",
"\n\nContemporary Kashmiri literature appears in such magazines as Sheeraza published by the Jammu & Kashmir Academy of Art, Culture and Languages, Anhar published by the Kashmirri Department of the Kashmir University, and an independent magazine Neab International Kashmiri Magazine published from Boston, Vaakh (published by All India Kashmiri Samaj, Delhi) and Koshur Samachar (published by Kashmiri Sahayak Sammiti, Delhi).",
"\n\nAncient writers in Sanskrit\nLagadha, between 1400-1200 BC. ",
"Wrote Vedanga Jyotisha, the earliest Indian text on astronomy.",
"\nCharaka, c. 300 BC. ",
"One of the most important authors in Ayurveda.",
"\nVishnu Sharma, c. 300 BC. ",
"Author of Panchatantra.",
"\nNagasena, c. 2nd century BC. ",
"One of the major figures of Buddhism, his answers to questions about the religion posed by Menander I (Pali: Milinda), the Indo-Greek king of northwestern India (now Pakistan), are recorded in the Milinda Pañha.",
"\nTisata, c. 500 AD. ",
"A medical writer.",
"\nJaijjata, 5th century, a medical writer and probably the earliest commentator (known) on the Sushruta Samhita, later quoted by Dalhana.",
"\nKalidasa, c. 5th century. ",
"Widely regarded as the greatest poet and dramatist in the Sanskrit language.",
"\nVagbhata, c. 7th century. ",
"Considered as one of the 'trinity' (with Charaka and Sushruta) of Ayurveda.",
"\nBhamaha, c. 7th century\n Ravigupta, 700-725. \"",
"Ravigupta is, perhaps, the earliest among the Buddhist philosophers of Kashmir...\"\nAnandavardhana, 820-890\nVasugupta, 860-925\nSomananda, 875-925\nVatesvara, b. 880, author of Vaṭeśvara-siddhānta.",
"\nRudrata, c. 9th century\nJayanta Bhatta, c. 9th century\nBhatta Nayaka, c. 9th-10th century, considered by Sheldon Pollock as the greatest author on aesthetics in the pre-modern period\n Medhātithi, c. 9th-10th century, one of the most influential commentators of the Manusmriti \nUtpaladeva, 900-950\nAbhinavagupta, c. 950-1020\nVallabhadeva, c. 10th century. ",
"Wrote, amongst other works, Raghupanchika, the earliest commentary on the Raghuvamsa of Kalidasa.",
"\nUtpala, c. 10th century. ",
"An important mathematician. ",
"\nKshemendra, c. 990-1070\nKshemaraja, c. late 10th century/early 11th century\nKathasaritsagara, c. 11th century\nBilhana, c. 11th century\nKalhana, c. 12th century\nJalhana, c. 12th century, the author of Mugdhopadesa (not to be confused with Jalhana who commissioned the Suktimuktavali)\nSarangadeva, c. 13th century. ",
"A musicologist, he wrote Sangita Ratnakara, one of the most important text when it comes to Indian music.",
"\nKesava Kashmiri Bhattacharya, c. 14th century, a major Vedantic philosopher.",
"\nMamatta\nKaihata\nJaihata\nRalhana\nShilhana\nMalhana\nRuiyaka\nKuntaka\nRuchaka\nUdbhatta\nSankuka \nGunadhya\nSomvadeva\nPingala\nJayadata\nVamana\nKshiraswamin\nMankha\nPushpadanta \nJagadhar Bhatta\nRatnakara\nManikyacandra\n\nWriters in Persian\n\nAfter Sanskrit and before the coming Urdu, because of the adoration and patronising policy of foreign culture by the Mughals, Persian became the literary language also of the region.",
"\nKashmir was very richly represented in that tradition, as already before the end of the 18th century \"Muhammad Aslah's tazkira of the Persian-writing poets of Kashmir, written during the reign of the Mughal emperor Muhammad Shah (1131-61/1719-48), alone lists 303 poets\". ",
"Late scholar from Pakistan, Pir Hassam-ud-Din Rashidi, edited, translated, and enlarged this work later, and had it published by the Iqbal Academy.",
"\n\nThe most famous of them was Muhammad Tahir Ghani (d. 1669), better known as Ghani Kashmiri, whose poetry was recently translated into English, for the first time, by Mufti Mudasir Farooqi and Nusrat Bazaz as 'The Captured Gazelle' in the world-renowned Penguin Classics list. ",
"Ghani influenced many generations of Persian-and Urdu writing poets in South Asia including Mir Taqi Mir, Ghalib and most importantly, Iqbal. ",
"Ghani's \"forte\" lies in creating delightful poetic images, usually by stating an abstract idea in the first hemistich and following it up with a concrete exemplification in the other. ",
"He also stands out for his multi-layered poems, which exploit the double meaning of words.",
"\n\nAnother name is the Sheikh Yaqub Sarfi (1521-1595), a 16th-century Sufi poet-philosopher who was internationally acknowledged and who had for students, amongst others, well-known religious scholar Ahmad Sirhindi (more particularly, he taught him hadith) and Persian-language poet Mohsin Fani Kashmiri (d. 1671 or 1672) (himself the teacher of Ghani Kashmiri and author of the pivotal work of comparative religion, the Dabestan-e Mazaheb).",
"\n\nOther of the well-known and influential Persian-language poets of Kashmir would include Habibullah Ghanai (1556-1617), Mirza Dirab Big Juya (d. 1707), Mirza Beg Akmal Kamil (1645-1719), Muhammad Aslam Salim (d. 1718), Mulla Muhammad Taufiq (1765), Muhammed Azam Didamari (d. 1765), Mulla Muhammad Hamid (1848) or Birbal Kachru Varasta (d. 1865), amongst a myriad. ",
"Of course, Kashmiri Pandits too played a role in that school, and one exceptional case was Pandit Taba Ram Turki (1776–1847), who was a celebrity as far as Central Asia.",
"\n\nWriters in Urdu\n\nDespite being a numerically reduced community (less than one million), the Kashmiri Pandits are over-represented in their contribution to Urdu literature. ",
"One important early example is Daya Shankar Kaul Nasim (1811–1845), a renowned Urdu poet of the 19th century, and hundreds of others followed his path.",
"\n\nSome eminent Urdu literary personalities of Kashmiri origins (from both the Valley and the diaspora) include (in chronological order):\nMir Tafazzul Hussain Khan Kashmiri (1727-1800), originally from Kashmir, born in Sialkot where his parents moved and himself based in Lucknow where he served as Prime Minister (or diwan) to the Nawab of Oudh Asaf-ud-Daula thanks his erudition. ",
"He was called \"khan-e-allama\" (the Scholarly Khan) due to his deep scholarship on many subjects but is best known today for having translated Sir Isaac Newton's Philosophiæ Naturalis Principia Mathematica from Latin into Arabic.",
"\nMufti Sadruddin Khan 'Azurda', 1789-1868, apart from being the Grand Mufti of Dehli, he was also a personal friend to Ghalib (whose own mother was from Kashmir) and himself a poet of note in Urdu as well as in Arabic and Persian. ",
"He also wrote a tazkira (biographical anthology of poets).",
"\nMomin Khan Momin, 1801-1852, considered one of the three pillars of the Delhi school of Urdu poetry, with Ghalib and Zauq. ",
"Other fields where he was competent included mathematics, geomancy, astrology, chess or music.",
"\nDaya Shankar Kaul Nasim, 1811–1845\nRatan Nath Dhar Sarshar, 1846-1903\nBrij Mohan Datatriya Kaifi, 1866-1955\nMuhammad Iqbal, 1877–1938\nSyed Akbar Jaipuri (Mujahid-E-Urdu), 1923-1998\nAgha Hashar Kashmiri, 1879–1935 (called \"the Shakespeare of Urdu\" for his works as playwright)\nBrij Narayan Chakbast, 1882–1926\nAziz Lucknawi, 1882-1935\nKhalifa Abdul Hakim, 1896-1959 (a philosopher who has the honour of writing the only book on the metaphysics of Persian mystical poet Jalaluddin Rumi)\nPatras Bokhari, 1898–1958\nGhulam Mustafa Tabassum, 1899–1978\nJustice Anand Narain Mulla, 1901-1997\nMuhammad Din Taseer, 1902-1950 (short-story writer, literary critic and Iqbal scholar. ",
"Father of slain Pakistan's Punjab governor Salman Taseer and first individual from the Sub-continent to get a PhD in English Literature from Cambridge University)\nShaikh Abdullah, 1905–1982\nBashir Ahmed Dar, 1908-1979 (a philosopher and Iqbal scholar)\nMeeraji, 1912-1949\nSaadat Hasan Manto, 1912–1955\nAariz Kashmiri, 1916-1965\nAgha Shorish Kashmiri, 1917-1975\nZaheer Kashmiri, 1919-1996\nRazia Butt, 1924-2012\nAnwar Shemza, 1928-1985\nHakeem Manzoor, 1937–2006\nObaidullah Aleem, 1939-2008\nMuhammed Amin Andrabi, 1940-2001, a scholar who belonged to the Traditionalist School of metaphysics, inspired by authors like Ibn Arabi, Muhammad Iqbal, Frithjof Schuon, Seyyed Hossein Nasr and Henry Corbin. ",
"\nAllama Mustafa Hussain Ansari, 1945–2006\nMirza Muhammad Zaman Azurdah, b. 1945, influential contemporary writer from the Valley\nAbid Hassan Minto\nMuhammad Asim Butt, novelist, translator and critic. ",
"\nMuhammad Younis Butt, writer of the most popular political satire show in Pakistan, Hum Sub Umeed Se Hain\nRasheed Amjad\nShahid Nadeem\n\nWriters in Hindi\n\nAmar Nath Kak\nChandrakanta (author)\nOmkar N. Koul\nRattan Lal Shant\nHari Krishen Kaul\nShashi Shekhar Toshkhani\nBhushan Lal Koul\nShiban Krishen Raina\nAgnishekher\nMaharaj Krishan Santoshi\n\nWriters in English\n\nI. K. Taimni\nM. P. Pandit, prolific writer who authored some 150 books and as many articles exposing in English the thought of Sri Aurobindo.",
"\nChiragh Ali, reformist Islamic scholar \nTaufiq Rafat, called the 'Ezra Pound of Pakistan' for both his innovative writings and his position as one of - if not the - greatest English-language poets of Pakistan.",
"\nJawaharlal Nehru\nVijaya Lakshmi Pandit\nKrishna Hutheesing\nGopi Krishna\nGopinath Raina\nSubhash Kak\nNayantara Sahgal\nM.J. Akbar\nSalman Rushdie\nHari Kunzru\nKailas Nath Kaul\nAgha Shahid Ali\nMohammad Tabish\nBasharat Peer\nHamid Naseem Rafiabadi, contemporary philosopher, affiliated with the University of Kashmir, specialist of Islamic philosophy\nAbdur Rashid Bhat, contemporary philosopher, affiliated with the University of Kashmir, specialist of al Ghazali and Shah Waliullah\n Showkat Ahmad Wani\nA srinagar based poet and writer belongs to bandipora dachigam. ",
"Well known for blank verse and Urdu nazm.",
"His collections are yet to be published.",
"\n\nSee also\n List of Kashmiri poets\n List of topics on the land and the people of Jammu and Kashmir\n Kashmir Shaivism - philosophy gives Kashmir its soul, God is universal, in all equally.",
"\n Kashmiriyat - a socio-cultural ethos of religious harmony and Kashmiri consciousness.",
"\n\nReferences\n\nCategory:Culture of Azad Kashmir\nCategory:Culture of Jammu and Kashmir\nCategory:Indian literature\nCategory:Kashmiri literature\nCategory:Literature by language\nCategory:Pakistani literature"
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"An alleged package thief got more than she bargained for when an eagle-eyed nanny intercepted her.",
"\n\nSurveillance footage shows a woman hopping out of the passenger seat of a vehicle in Everett, Washington on Tuesday, and then running toward a home and returning to the car with a large package.",
"\n\n“HEY!” ",
"a voice calls out. “",
"What the fuck are you doing?”",
"\n\nAfter the woman tosses the purloined package into the vehicle, she falls while trying to get in. ",
"The getaway car then takes off without her:\n\nThat’s when the owner of the voice enters the picture.",
"\n\nNanny Kate Anderson, who was watching a 1-year-old baby inside the home, raced down the driveway and tackled the suspect while shouting for a passerby to call the police.",
"\n\nThe alleged porch pirate was later identified as 29-year-old Rhieanna Schindler, who had an outstanding warrant and a history of arrests, according to CBS station KIRO.",
"\n\n“If someone is doing something wrong, I’m not afraid to put them in check,” Anderson told local Fox station Q13.",
"\n\n“She’s just like a straight baller, she’s amazing and doesn’t take any crap from anybody,” Tanya Smith, the homeowner, told KIRO.",
"\n\nThe local sheriff’s office told the station that while it doesn’t condone Anderson’s actions, they’d like her to know they’re hiring right now.",
"\n\nCORRECTION: This article previously misidentified station KIRO as an ABC affiliate; it is CBS."
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"It was their first time squaring off. ",
"Sen. Mary Landrieu and retired Air Force Col. ",
"Rob Maness are both hoping to get your vote on Election Day. ",
"The candidates wasted no time going back and forth on a number of issues including border security.",
"\n\nManess is a political newcomer who has never run for office. ",
"He says the country is suffering from the lack of leadership and career politicians who don't follow the Constitution.",
"\n\nRepublican Rep. Bill Cassidy is Landrieu's other major opponent for the senate seat. ",
"He declined to participate in the debate.",
"\n\nLandrieu and Maness tackled issues of federal minimum wage and campaign finance. ",
"The most lively exchange came on the issue of the Affordable Care Act.",
"\n\n\"Obamacare is an abomination,\" Maness said. \"",
"I'm going to make it one of my top priorities not just to repeal and defund it, but pull it out by the roots because it's a job killer.\"",
"\n\n\"We hear this all day long and it's so sad because they don't provide any alternative to provide healthcare,\" Landrieu said. \"",
"For people that work 40-50 hours a week. ",
"They deserve healthcare they can never lose.\"",
"\n\nThe room was packed with supporters from both sides. ",
"It's unclear if they swayed any new voters in the audience as many in attendance were already decided."
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"Q:\n\nGraduate program applications that require questionnaires and other non-letter material\n\nIn the December 2014 AMS Notices, a letter to the editor (http://www.ams.org/notices/201411/rnoti-p1311.pdf) by Deconinck and Medlock addresses the problem of (math) graduate programs requiring letter writers to fill out questionnaires about applicants or do other tasks besides uploading a recommendation letter, unlike the quick process for job applications on Mathjobs where all a letter writer has to do is upload a letter (once). ",
"Deconinck and Medlock suggest that letter writers to graduate programs append a postscript to their recommendation letters urging faculty who read the letter to check how their own graduate program handles applications and get the process streamlined if it has any requirements like the despised questionnaires. ",
"\nMany faculty may not know what their own school makes letter writers do (esp. ",
"if they have not served on the graduate admissions committee). ",
" In that spirit, I propose that we collect here on MO a list of schools that make letter writers fill out questionnaires, as a kind of public service to encourage any faculty who see their own school listed here to go to their graduate school administration and insist that the math graduate program applicants -- if not all graduate school applicants -- avoid having any kind of survey as part of the application that letter writers have to fill out. ",
"If, in the future, a graduate program kills off the required questionnaire, the answer listing that school could be updated to make clear its passage from the dark side to the light side, so to speak. ",
"\nOf course the admission websites are designed for an entire graduate school, not just a math department, but math faculty could still tell their graduate school that they make no use of questionnaires, percentage rankings, etc. ",
"from the online form, so it is a waste of time and therefore they do not want to make letter writers for the math graduate program see any of that stuff. ",
"\nIf you are writing graduate program recommendation letters this year and think this question is worthwhile, please keep a record of which graduate programs make you fill out questionnaires or do anything else besides upload a letter so that you can come back here and make a record of it if nobody else has yet.",
"\nPost one school per answer, ideally with the school name first for ease of scanning, and describe what letter writers are asked to do besides upload a letter.",
"\n(There are also some praise-worthy graduate programs where the letter writer has to do essentially nothing besides upload a letter, e.g., UIC and Wisconsin have no questionnaire, and Univ. ",
"Southern California only posts a questionnaire at the very end and makes it clear that filling it is not a requirement. ",
"Perhaps there should be a separate MO community wiki list for those schools.) ",
"\n\nA:\n\nGeorgia Tech \nIt asks letter writers to fill out a questionnaire about the applicant, including asking how the applicant works as part of a team.",
"\n\nA:\n\nOhio State \nIt asks letter writers to fill out a questionnaire about the applicant and also asks if the letter writer knows the applicant well enough to write a recommendation. ",
"Excuse me? ",
"\n\nA:\n\nUniversity of Minnesota\nNot bad -- I was Driven to Discover (SM) that I have to create a password just for using the system that one time. ",
"But was able to bypass the survey completely.",
"\n\n"
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"Job Description\n\nWe are looking for Finance and administration assistant.",
"\n\nEducation: Bachelor\n\nEmployment: Full-Time\n\nRequirements: Bachelor degree in relevant field.",
"\n\nResponsibilities: 1.To provide secretarial and administrative support to the Director.",
"\n2.To attend and service staff meetings and take minutes and distribute after meetings along with any other relevant materials and to attend other meetings/events in a secretariat capacity as and when required.",
"\n\nCompany Profile\n\nAbout Company:\nUSAID is the lead U.S. Government agency that works to end extreme global poverty and enable resilient, democratic societies to realize their potential.",
"When the United States Agency for International Development (USAID) was created, it brought together several existing foreign assistance organizations and programs. ",
"Until then, there had never been a single agency charged with foreign economic development, so with the passage of the Foreign Assistance Act of 1961 (pdf) by Congress, U.S. foreign assistance activities underwent a major transformation."
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"Q:\n\nCharacter advancement - buying new skills with Karma\n\np.105 Core Rule book\n\nThe skill table works on a similar principle, though Active Skill\n ratings costs are computed at new Rating x 2. ",
"If you are purchasing a\n brand new skill, find the desired rating on the table and pay that\n cumulative amount. ",
"For example, if you are purchasing the running\n skill for the first time, and are buying it up to Rating 3, you will\n pay 12 Karma.",
"\n\nIt says cumulative for a Rank 3. ",
"To me that says Add up Rank 1 + Rank 2 + Rank 3 and cumulative reach the Sum of those values. ",
"Rank 1 is 2 Karma, Rank 2 is 6 Karma, Rank 3 is 12 Karma. ",
"To me that is cumulative 2+6+12 = 20 Karma. ",
"\nI can't find somewhere in the errata that covers this.",
"\nAm I missing something?",
"\n\nA:\n\nFollowing the rule you quote, first you calculate \"new Rating x 2\":\n\nRank 1 x 2 = 2 karma\nRank 2 x 2 = 4 karma\nRank 3 x 2 = 6 karma\n\nTo buy a brand new skill, this is cumulative, so for rank 3 from scratch: 2 + 4 + 6 = 12 karma total cost.",
"\nYour error was to take the cumulative rank rating, times by two, and add each result cumulatively. ",
"So for rank 2 you are calculating (1 + 2) x 2 instead of just 2 x 2, and for rank 3 you are calcuating (1 + 2 + 3) x 2 instead of just 3 x 2. ",
"\n\n"
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"Reactions and energy absorption of trees subject to rockfall: a detailed assessment using a new experimental method.",
"\nA new method for investigating the detailed reaction and the energy absorption of trees during a rock impact was developed and applied to 15 subalpine Norway spruce (Picea abies L. Karst) trees. ",
"A wedge-shaped trolley, guided by prestressed steel wires, was mounted on a forested slope to simulate a falling rock. ",
"The trolley accelerates down the wires and hits a tree at a preselected stem height with variable energies. ",
"The tree displacements and accelerations during the impact were recorded to determine reactions and energy absorption for the stem, root-soil system, crown and the entire tree. ",
"Trees absorbed the kinetic energy of the trolley rapidly by mobilizing strain and inertia forces close to the impact location in the stem and the root-soil system. ",
"This energy was then gradually dissipated all over the tree through permanent deformations and damping. ",
"The stem assimilated more energy than the root-soil system. ",
"The tree's energy absorption capacity was limited by stem-bending stresses at impact height, by shear stresses at the stem base and by lack of resistance of the root-soil anchorage. ",
"It was positively and exponentially related to stem diameter at breast height and negatively related to impact height. ",
"The field experiment enabled a physical description of how a tree reacts to a rock impact and highlighted the most important and critical components of the tree for its energy absorption. ",
"Such descriptions should help make computer simulations of rock-forest interrelations more precise and thus improve management strategies to ensure that forests can provide protection against rockfall."
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[
"the new love\n\nwell I don’t know\nI haven’t thought about it\nI suppose it could get messy\neveryone carries baggage\nI’ve got baggage too\nwe’ll work it out\n\nwhat do you mean how much in love am I\nI’m totally in love\nfull on\n\nI can’t compare this love\nwith the last one\nor the one before\nit doesn’t work like that\n\nI’m sorry\nbut no\nit doesn’t\n\nwhat do you mean\n\nma\nwe’re just starting\nshe’s wonderful\nI don’t want to think about what happens\nwhen something goes wrong\nI want to think that nothing\nwill go wrong\nI want to bask in the feeling\nso let’s not discuss\nwhen it all goes wrong\n\nyes I know\nI’ve got a bad track record\ncan we change the subject\n\nreligion doesn’t come into itI’m not religious\nand she can be whatever she wants to be\n\nah crikey\ndon’t jump straight to christenings\nit’s not going to happen\nall right\nno it’s not\n\nlook\nshe’s just a girl I’ve been seeing\nwe like each other\nok\nit’s really nothing more than that\n\nno\nI don’t suppose it’s all that serious\n\nanyway\nI don’t think you’ll be meeting her ma\n\nwell\nI was going to bring her around\nto say hello\nbut we probably won’t be seeing each other\nmuch longer"
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"Kore wa Zombie Desu ka?, ",
"Ore, Twintail ni Narimasu. ",
"Recommendations\n\n- Both anime have villains that fight to obtain magical girl powers.",
"\n- Both anime have comedy and a pretty decent cast of characters.",
"\n- Both anime have the male lead routinely transform into a cross-dresser with magical powers.",
"\n\nWhile Kore wa Zombie Desu Ka takes on a more story and character driven approach, Ore, Twintails ni Narimasu takes on more of a comedic, parody, and fan service approach.",
"\n\nWhile I consider Kore wa Zombie Desu Ka to be a better series, Ore, Twintails ni Narimasu may have you laughing quite a bit, like myself. ",
"There is even a scene in Ore,\nTwintails ni Narimasu where they parody Kore wa Zombie Desu Ka.",
"\n\nIf you liked Kore wa Zombie Desu Ka and want to see a similar anime with a more comedy/fan service spin, then Ore, Twintails ni Narimasu should be enjoyable for you to watch. ",
"read more"
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"SmartBenefits Plu$50\n\nSmartBenefits® \"Plu$50\" is an incentive program that offers employees a free $50 SmarTrip® card just to try transit. ",
"You may be eligible if you are new to bus or rail service and do not already own a SmarTrip® card."
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"No Escape (2015 film)\n\nNo Escape is a 2015 American action thriller film directed by John Erick Dowdle, who co-wrote the screenplay with his brother, Drew Dowdle. ",
"The film stars Owen Wilson, Lake Bell, and Pierce Brosnan, and tells the story of an expat engineer trapped with his family in an unnamed South-East Asian country during a violent uprising.",
"\n\nThe film was released on August 26, 2015. ",
"It had special sneak previews in the Philippines on August 16 and 17, 2015, as well as multiple pre-screenings throughout the United States before its official release on August 26, 2015 by The Weinstein Company. ",
"No Escape received mixed reviews from critics, who praised the action sequences and the acting performances, especially Wilson's dramatic role, but others criticized the lack of character development and anti-climactic ending.",
"\n\nPlot\nIn an unnamed South-East Asian country, the Prime Minister closes a deal with a representative of Cardiff, an American company specializing in water systems. ",
"After the representative leaves, a group of armed rebels initiate a coup d'état and assassinate the Prime Minister.",
"\n\nSeventeen hours earlier, Jack Dwyer (Owen Wilson), a new Cardiff employee, is flying to the country with his wife Annie (Lake Bell) and their daughters Lucy (Sterling Jerins) and Briegel \"Beeze\" Dwyer (Claire Geare). ",
"After landing, they run into a Briton named Hammond (Pierce Brosnan) who offers them a ride with him and his friend \"Kenny Rogers\" (Sahajak Boonthanakit), to the Imperial Lotus Hotel, where many foreigners are staying. ",
"At the hotel, Jack learns that the phone lines, television and internet are down all over the city. ",
"He stops by the bar and chats with Hammond. ",
"Later that night Jack awakens and finds his wife in the bathroom crying.",
"\n\nThe next morning, Jack goes out to buy a newspaper, and inadvertently finds himself in the middle of a confrontation between armed protesters and riot police with riot shields. ",
"The two forces clash violently as Jack makes his escape. ",
"Eventually, the protesters gain the upper hand and begin killing the police. ",
"Jack runs back to the hotel and witnesses the rebels executing an American Cardiff employee out front. ",
"A rebel soldier spots Jack, forcing Jack to quickly climb up a fire escape and enter the hotel through a window. ",
"The rebels break through the main hotel entrance, despite the hotel workers’ efforts to barricade the doors, and begin indiscriminately slaughtering the staff and guests.",
"\n\nJack makes it back to his family's room, but learns that Lucy is swimming in the pool downstairs. ",
"Jack barely gets to Lucy in time before rebels pour onto the pool area. ",
"Meanwhile, a horrified Annie sees the rebels going from room to room, killing the guests. ",
"She narrowly manages to keep them out of their room. ",
"As Jack returns with Lucy, he encounters a rebel in the stairwell, but Hammond saves him and tells him to get to the roof. ",
"Jack's family arrives to the roof and join some of the hotel's guests and staff, who have gathered and blocked the door. ",
"On the roof, other hotel tourists warn Jack away from leaning over the edge of the roof, as the rebels below will take a shot at whoever they can see. ",
"Jack looks over the roof anyway and sees that hundreds of rebels are gathering at the base of the hotel, and that they have seized most of the city. ",
"A French hotel guest interprets what they are chanting (\"Don't resist. ",
"There will be no prisoners, because [they're] going to kill [us] anyway.\", \"",
"Blood for water!\") ",
"Upon questioning an injured hotel bellhop, they learn that the rebels are protesting the foreign corporations' control of the water supply. ",
"An approaching helicopter is then heard. ",
"Everyone's relief turns to horror as they realize it belongs to the rebels, who open fire on the people below. ",
"As Jack's family runs for cover, the helicopter becomes entangled in electrical wires and crashes. ",
"Another band of rebels breaks through the blocked door and shoot most of the survivors as Jack and his family jump onto the roof of an office building next to the hotel. ",
"Jack looks back and sees the rebels executing the remaining hotel guests and staff before spotting the rebel leader holding up the \"Welcome\" banner from Cardiff with his photo on it, realizing he is a high-value target.",
"\n\nAfter climbing to a ledge of the office building they jumped onto, a tank targets the office building and fires into it indiscriminately, killing many people inside. ",
"Jack's family hides under some debris as the rebels swarm the building and murder the office workers. ",
"The family remains there for the rest of the day, until nightfall with a corpse hiding them. ",
"As Jack leaves their hiding place, he is spotted by a looting rebel whom Jack then kills, much to his, and Annie's, horror. ",
"They find a map, take clothes from the dead office workers to disguise themselves as locals, and make their way to the American embassy on a stolen moped. ",
"On the way, they manage to ride through a crowd of rebel demonstrators; one man notices they are foreigners, but says nothing, upon seeing the two young children riding with him. ",
"Upon arriving at the embassy, they find it overrun and deserted and several American guards dead, and have to flee, but not before being seen by a group of rebels, including the leader from the hotel massacre.",
"\n\nThe family takes shelter in a Buddhist shrine garden nearby, and are protected by the old property caretaker. ",
"The rebels enter the compound and start searching for them. ",
"Jack attempts to steal a gun, and Annie comes out from hiding in order to draw attention away from Jack, while Lucy and Beeze hide. ",
"After discovering the gun is unloaded, Jack is beaten and restrained. ",
"As the group's leader is about to rape Annie, Hammond and Kenny enter the garden and shoot most of the rebels except for the leader, who escapes. ",
"The two men take the family to a nearby brothel, which they pass through on their way to the large tower on the roof. ",
"As they eat, Hammond explains that he and Kenny work for the British government. ",
"He and other agents talked the former government into making deals with companies like Cardiff. ",
"As these deals allowed the companies to \"own\" the government through debt, they angered the people, which led to the uprising. ",
"Hammond explains that their plan is to get to the nearby river, commandeer a boat, and sail across the border to Vietnam, where they hope to receive asylum.",
"\n\nAs their children sleep, Annie and Jack tearfully tell each other that they have no regrets on their life together, preparing themselves for the fact that they could likely die the next morning. ",
"Before they can enact their plan, the group is attacked by rebels, who kill Kenny and wound Hammond. ",
"Hammond sacrifices himself to disable a rebel truck following them. ",
"Near the riverbank, Annie and the kids hide as Jack finds a fisherman and trades his watch and shoes for a boat. ",
"The fisherman hears the rebels approaching, and hides Jack beneath an old boat. ",
"Not long after, the leader who escaped earlier comes back with another group, captures Jack, and prepares to execute him. ",
"Lucy leaves her hiding place, distracting the group leader, whose shot hits Jack's shoulder. ",
"The leader then catches Lucy, puts a gun in her hand and one to her head and orders her to kill Jack. ",
"She refuses, but Jack encourages her to shoot him (to potentially save herself). ",
"Before Lucy can make a choice, Annie intervenes and hits the leader in the head, and bludgeons him to death with an oar while Jack grabs the man's gun and kills the remaining rebels.",
"\n\nThe family board a boat and paddle downriver toward the Vietnamese border. ",
"They are spotted by a group of rebels, but keep paddling. ",
"Although the Vietnamese border patrol warns the family, at gunpoint, not to enter Vietnam, they take no action to actually stop them, and as soon as the boat crosses the border marker, the border patrol warn the rebels against attacking the family as they are now in Vietnamese waters and if the rebels shoot, they will consider it as an act of war, and would use lethal force against the rebels. ",
"As the family is retrieved by the border guards, they embrace each other, having finally reached the end of their ordeal. ",
"Later, in a hospital, Jack and Annie narrate to the kids the story of how Lucy was born, a story the two daughters asked to hear about earlier in the movie.",
"\n\nCast\n Owen Wilson as Jack Dwyer, a new Cardiff employee (originally an American civil engineer) and Annie's husband.",
"\n Lake Bell as Annie Dwyer, Jack's wife.",
"\n Sterling Jerins as Lucy Dwyer, Jack and Annie's older daughter.",
"\n Claire Geare as Briegel Dwyer, Jack and Annie's younger daughter, also known as \"Beeze\".",
"\n Pierce Brosnan as Hammond, an operative for Her Majesty's Secret Service.",
"\n Sahajak Boonthanakit as \"Kenny Rogers\", a local man who runs a Kenny Rogers-themed taxi service, but who is actually Hammond's partner.",
"\n\nProduction\n\nDevelopment\nIn 2012, it was reported that Owen Wilson would star in an action film called The Coup, and the tone of the film was described as akin to Taken (2009), centering on an American family that moves to Southeast Asia and finds themselves \"embroiled in a violent coup where rebels mercilessly attack the city\". ",
"Later, during the Cannes Film Festival, it was reported that Pierce Brosnan had joined the project, with his role being a \"mysterious and ultimately heroic government operative\", a nod to his role as James Bond. ",
"John Erick Dowdle, known for several horror films, and who wrote the script with his brother, Drew Dowdle, was set to direct the film. ",
"The two brothers based the script on a near-miss of political upheaval when the Dowdle brothers and their father were going on a trip to Thailand. ",
"John explains, \"Right before we got to Thailand, a coup overthrew the prime minister. ",
"There’d been no previous warning. ",
"There was a feeling of anxiety in the air. ",
"So I started thinking about that. ",
"If it went badly, what would I do?\" ",
"Michelle Monaghan had joined the cast, playing the wife of Wilson's character.",
"\n\nIn August 2013, it was reported that Bold Films would finance the film, replacing Crime Scene Pictures. ",
"Later that year, it was reported that Lake Bell had replaced Monaghan, and her character was said to be named Annie Dwyer, and described as a beloved woman appearing to have the perfect family life. ",
"Principal photography began on October 31, 2013 in Thailand.",
"\n\nFilming\nNo Escape was filmed in Chiang Mai, Thailand.",
"\n\nPrincipal photography began on October 31, 2013, with Thai-based production company Living Films facilitating the shoot. \"",
"The producers of the film had a wide choice of countries in which they could have based this production,\" said Living Films founder and executive director Chris Lowenstein. \"",
"The fact that they chose Thailand is a great testament to the skills of the Thai crews and the resources that Thailand offers. ",
"We are delighted to help bring this project to the screen.\" ",
"Sierra/Affinity handled international sales of the film. ",
"Brosnan joined the crew in December after finishing off his work on How to Make Love Like an Englishman, moving to Cambodia where production was held, with his character reportedly called \"Hammond\".",
"\n\nOn June 10, 2014, it was announced that the film would be released on March 6, 2015. ",
"On February 6, 2015, it was announced that the film was retitled to No Escape, and its release was delayed to September 2, 2015. ",
"It then again changed, this time to August 26, 2015.",
"\n\nThe film was approved for release in Thailand after the film-makers agreed not to identify the country where it was filmed or to portray it negatively. ",
"In an interview for The Straits Times, co-writer Drew Dowdle explained \"We were very careful not to make it Thailand in the movie, so there was no Thai language used ... None of the signage is Thai and most of the language that the native population is speaking is a combination of Laotian, hill-tribe languages and other languages.\" ",
"The film-makers were also instructed not to use images of the Thai monarchy and to \"never show the king or the colour yellow because that's the colour of the king\". ",
"Director John Dowdle added that they were also told \"no Buddhas ... don't do anything bad in front of a Buddha.\".",
"\n\nReception\n\nBox office\nNo Escape grossed $27.3 million in North America and $27.1 million in other territories for a worldwide total of $54.4 million, against a budget of $5 million.",
"\n\nThe film grossed $1.2 million on its opening day and $8.1 million in its opening weekend, finishing 4th at the box office.",
"\n\nCritical response\nReview aggregation website Rotten Tomatoes gives the film a rating of 45%, based on 142 reviews, with an average rating of 4.9/10. ",
"The site's critical consensus reads, \"No Escapes talented cast and taut B-movie thrills are unfortunately offset by its one-dimensional characters and uncomfortably retrograde worldview.\" ",
"On Metacritic, the film has a score of 38 out of 100, based on 33 critics, indicating \"generally unfavorable reviews\". ",
"The film received an average \"B+\" CinemaScore from audiences, on an A+ to F scale.",
"\n\nMovie Rehab said, \"No Escape is a bright star in a sky of dumbed down, carbon-copy action-thrillers.\" ",
"Toronto Stars Peter Howell questioned the film for its \"lack of moral considerations\", but overall praised it as being suspenseful and \"great entertainment.\"",
"\n\nMany of the negative reviews for No Escape have labelled the film as xenophobic for its depiction of Southeast Asians. ",
"One such review, written by Washington Posts Stephanie Merry, made the claim that \"every Asian character is either a ruthless murderer or anonymous collateral damage.\" ",
"Similarly, Seattle Times Moira Macdonald criticized No Escape as offensive, and concluded: \"Just like the Dwyer family, I found myself looking for escape; you might, too.\" ",
"Rogerebert.com's Peter Sobczynski also blasted No Escape for its \"borderline xenophobia\", but ultimately panned the film for John Erick Dowdle's film direction and \"unintentionally comedic\" slow motion scenes, summarizing: \"Why [Wilson and Brosnan] would choose to appear in something so pandering, mean-spirited and manipulative is beyond my ability to compute but for whatever reason, the end result is that they have landed in one of the most unpleasant films of the year.\"",
"\n\nControversy\n\nAfter trailers for the film were released a social uproar occurred in Cambodia over the use of upside down Khmer lettering on the police shields. ",
"The Ministry of Culture and Fine Arts has since prohibited the film from being shown in Cambodia. ",
"Sin Chanchaya, director of the Department of Film said that the decision to ban the film had come solely based on the trailer and was also informed that in order to receive permission to shoot in Thailand, where several real coups d'état had just taken place, the production team had to arrange that no scenes would directly identify Thailand as the setting. ",
"Chanchaya also said that the Cambodian Ministry had approached the film producers to edit the Khmer lettering out of the film but they had not replied by the time of the decision.",
"\n\nReferences\n\nExternal links\n \n \n \n \n\nCategory:2015 films\nCategory:2010s action thriller films\nCategory:2010s chase films\nCategory:American films\nCategory:American action thriller films\nCategory:American chase films\nCategory:English-language films\nCategory:Films set in Cambodia\nCategory:Films shot in Cambodia\nCategory:Films about families\nCategory:Films about terrorism in the United States\nCategory:Anti-modernist films\nCategory:Films directed by John Erick Dowdle\nCategory:Bold Films films\nCategory:Films scored by Marco Beltrami\nCategory:Foreign films shot in Thailand\nCategory:Survival thriller films\nCategory:American survival films"
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[
"Q:\n\nFirebase and google play on different accounts\n\nI want to integrate a Google Play Account to Firebase. ",
"In our company only my boss has owner priviledge for the google play account. ",
"The account used for firebase and other tools like adsense has administrator priviledges.",
"\nIs it possible to integrate the google play account to firebase in this setup?",
"\nHow would I do this?",
"\n\nA:\n\nWhat you can do is add your boss as an owner of the firebase project, link the accounts using your bosses account and then remove it from the firebase project. ",
"This seems to work for me.",
"\n\nA:\n\nLet's say your Google Play Account is A and Firebase Account is B.\n\nLogin to firebase via B. Go to Project Settings (Gear icon) -> Users and permissions. ",
"Add account A as owner. ",
"Verify the same via mail.",
"\nNow switch user and login to firebase via A. Select the recently linked app. ",
"Go to Project Settings -> Integrations. ",
"You'll be now seeing an option to link under Google Play. ",
"Go ahead and complete the step.",
"\n\n"
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[
"import pytest\nfrom vcx.error import ErrorCode, VcxError, error_message\nfrom vcx.api.wallet import Wallet\nfrom vcx.common import update_institution_info\nfrom vcx.api.connection import Connection\nfrom vcx.api.utils import vcx_pool_set_handle\nfrom vcx.api.vcx_init import vcx_init_minimal\n\n\[email protected]\[email protected]('vcx_init_test_mode')\nasync def test_vcx_init():\n pass\n\n\[email protected]\nasync def test_error_message(vcx_init_test_mode):\n assert error_message(ErrorCode.",
"NotReady) == 'Object not ready for specified action'\n\n\ndef test_vcx_init_minimal():\n Wallet.set_handle(1)\n vcx_pool_set_handle(1)\n assert vcx_init_minimal('''{\"institution_name\":\"faber\",\"institution_did\":\"44x8p4HubxzUK1dwxcc5FU\",\n \"institution_verkey\":\"444MFrZjXDoi2Vc8Mm14Ys112tEZdDegBZZoembFEATE\"}''') == 0\n"
] | {
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[
"Q:\n\nCreate the title sliding when hover mouse using Jquery\n\ni have h2 tag and have width just 100px but the text content inside h2 tag is more than 100px, i want to show text content appear just in one line. ",
"I want to make it like on brazzers.com, When user hover the mouse on title of post, the long title of post will be sliding to show all. ",
"Is there a way to create it using jquery? ",
"Sorry about my newbie question\n\nA:\n\nPlease, try this example:\nhttp://jsfiddle.net/QKstB/2/\nThis is a script:\nvar textWidth = $('h1 nobr').outerWidth(),\n totalWidth = $('h1').outerWidth(),\n diff = totalWidth - textWidth;\n\n$('h1').hover( function() {\n $('h1 nobr').animate({ 'margin-left': diff }, 5000, function() { \n $(this).css('margin-left', 0)\n });\n}, function() { \n $('h1 nobr').stop(true, true);\n});\n\n"
] | {
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[
"Q:\n\nRedux-saga doesn't wait for response from API\n\nI use redux-saga and I created a generator checkUsername which perform the API call. ",
"I though that const username will equal to response from API, but I've got undefined. ",
"\nfunction* checkUsername(action) {\n try {\n const username = yield call(Api.checkUsername, action.username);\n yield put({type: actions.",
"USERNAME_CHECK_SUCCEEDED, username});\n } catch (e) {\n yield put({type: actions.",
"USERNAME_CHECK_FAILED, message: e.message});\n }\n}\n\nAlthough in my checkUsername function, which call API res is equal {\"isExist\": false}:\n checkUsername(username) {\n fetch(url, {\n 'GET',\n headers: {\n 'Accept': 'application/json',\n 'Content-Type': 'application/json',\n }\n }).then(response => response.json())\n .then(res => res)\n .catch(error => console.error(error));\n },\n\nWhy my const username is not equal {\"isExist\": false}?",
"\n\nA:\n\nIn your checkUsername function you need to return the call to fetch().",
"\n\n"
] | {
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[
"Within a genome, a gene can encode a mRNA that encodes a protein or a noncoding RNA. ",
"Protein coding genes are first transcribed in the nucleus into a precursor mRNA (pre-mRNA) from which introns are cotranscriptionally or post-transcriptionally spliced, the 5′ end capped, and the 3′ end cleaved and polyadenylated. ",
"The processing of pre-mRNA leads to the generation of mature mRNAs that are transported to the cytoplasm and translated into proteins. ",
"Translation occurs on the ribosome complex and amino acids are provided to the nascent peptide chain via transfer RNAs (tRNAs). ",
"Not all mRNAs are translated at the same efficiency and some may be stored or degraded ([@bib60]; [@bib68]). ",
"The monitoring of not only the steady-state abundance of specific transcripts but also the level at which they are associated with ribosomes can provide insight into the regulation of gene expression. ",
"With advances in sequencing technology, sequencing of cDNAs that are derived from mRNAs (mRNA-seq) has become an efficient and convenient method to quantify transcript abundance, generally interpreted as gene expression levels. ",
"While analysis of mRNA-seq results provides a comprehensive atlas of the transcriptome, post-transcriptional regulation can affect the correlation between transcript and protein abundance. ",
"To more closely estimate protein levels, the abundance of individual mRNAs associated with the ribosome, referred to as the translatome ([@bib22]; [@bib52]), can be used as a proxy of the proteome. ",
"Actively translated mRNAs are associated with multiple ribosomes in polyribosome (polysome) complexes. ",
"As translation is largely regulated during the engagement of ribosomal subunits on the mRNA (initiation phase of translation) in plants and other organisms ([@bib7]), an mRNA associated with polysomes is most likely to be undergoing the elongation and termination phases of translation. ",
"The mapping of the nuclease-protected footprints of individual ribosomes on mRNAs largely supports this conclusion, except for mRNAs with short upstream open reading frames (uORFs) that generally dampen translation of the main protein coding region of mRNAs ([@bib33]). ",
"Intact ribosomes can be immunoprecipitated using an epitope-tagged large ribosomal protein subunit from which polysome-associated mRNAs are prepared, greatly reducing contamination of mRNAs associated with messenger ribonucleoproteins of density similar to ribosome complexes ([@bib82]). ",
"When this approach is combined with mRNA-seq, the translation status of genes can be determined in a genome-wide fashion, a technique called TRAP-seq ([@bib64]).",
"\n\nRice is the world's most important food crop, as it serves as a staple for more than half of the world's population ([@bib38]). ",
"Among the cereal crops, rice has the smallest genome (389 Mb) ([@bib28]), and is a model species for other cereal crops such as maize, sorghum, wheat, and barley. ",
"Rice, along with other cereals and in contrast to dicot plant species such as *Arabidopsis thaliana*, has a distinct bimodal distribution of genes with respect to GC content. ",
"For example, gene GC content in *Arabidopsis* ranges from 40--55%, with a nearly normal distribution ([@bib78]). ",
"However, for the grasses (Poaceae) including rice, the genic GC distribution is more widely dispersed, ranging from 40 to 75% ([@bib11]; [@bib80]). ",
"It has been proposed that GC-biased gene conversion (gBGC) is mainly responsible for the evolution of GC content of genes in monocots ([@bib13]; [@bib20]). ",
"Previous studies have shown that GC-rich genes in rice are associated with more variable expression at the transcription level ([@bib71]) and GC-rich genes demonstrate stronger codon usage bias ([@bib21]); nevertheless, the biological significance of varied GC content of rice (grass) genes is largely unclear, including its potential impact on translation.",
"\n\nThe availability of translatome data for rice would greatly facilitate fundamental and applied research for both protein-coding genes and transposable elements, which are DNA sequence units that can rapidly change their locations and copy numbers in the genome. ",
"Previous proteomics studies on rice provided evidence of translation for a few thousand gene transcripts ([@bib42]; [@bib43]). ",
"In addition, [@bib58]) conducted a genome-wide analysis of total and polysomal mRNAs using a rice 3′ tiling microarray. ",
"However, the focus of the study was on the influence of stresses on a subset of genes, and the translation status of the majority of individual rice genes is still unknown. ",
"In this study, we constructed an epitope-tagged rice Ribosomal Protein L18 cDNA line (*p35S:HF-OsRPL18*) to facilitate the isolation of polysomes and conduct TRAP-seq analysis. ",
"Findings made in this study provide new perspectives regarding the regulation of translation as well as guidance for future crop engineering.",
"\n\nMaterials and Methods {#s1}\n=====================\n\nConstruction of the p35S:HF-OsRPL18 transgene and rice transformation {#s2}\n---------------------------------------------------------------------\n\nAll genes described in this study are referred to by their MSU Rice Genome Annotation Project Release 7 gene identifier (<http://rice.plantbiology.msu.edu/>) ([@bib37]). ",
"For construction of the *p35S:HF-OsRPL18* transgene, the coding region of LOC_Os03g22180 was amplified from rice cDNA, and the PCR product was cloned into the pENTR/D-TOPO TA vector (Invitrogen, Carlsbad, CA) and then recombined into the destination vector p35S:HF-GATA, which contains a His~6~-FLAG tag ([@bib53]). ",
"Thereafter, the *HF-OsRPL18* sequence was amplified by PCR, recloned into the TA vector, and the *HF-OsRPL18* sequence was excised using *Sal*I and *Pst*I and then placed between the same restriction sites in pCAMBIA1300S, which contains a double 35S promoter upstream of the multiple cloning site ([@bib81]). ",
"This yielded the expression construct containing *p35S:HF-OsRPL18* used for transformation of the rice cultivar Nipponbare.",
"\n\nThe basal medium used for transformation was Murashige and Skoog (MS) ([@bib50]) supplemented with 30 g/L sucrose and Gelzan 3 g/L (PhytoTechnology Laboratories, Overland Park, KS) at pH 5.7. ",
"Callus cell growth was induced on callus induction medium (CIM, MS plus 2 mg/L 2,4-dichlorophenoxyacetic acid) using mature seeds and then cocultured for 2 d in the dark at 25° with *Agrobacterium tumefaciens* EHA 105 carrying the expression vector with *p35S:HF-OsRPL18* and 200 µM acetosyringone to enable infection. ",
"Each callus was transferred to selection medium (CIM plus 250 mg/L cefatoxime and 50 mg/L hygromycin B) to cease growth of *Ag. ",
"tumefaciens* and allow the growth of transgenic calli. ",
"Four to eight weeks after selection, each callus was transferred to selection regeneration medium (MS plus 250 mg/L cefatoxime, 50 mg/L hygromycin B, 3 mg/L 6-benzylaminopurine, and 0.5 mg/L 1-naphthaleneacetic acid) for seedling generation.",
"\n\nPlants generated from hygromycin-resistant calli were transferred to soil and allowed to self-pollinate. ",
"Two-wk-old T~1~ seedlings were tested for hygromycin resistance by placing 1 cm leaf tips on Whatman paper moistened with 50 mg/L hygromycin for 4 d. Tips from plants with successful transgene integration remained green (resistant) whereas those without the transgene turned brown (nonresistant). ",
"To determine the copy number of the T-DNA in transgenic plants, DNA was extracted from leaves of resistant T~1~ seedlings using the CTAB method ([@bib15]), and digested with *Sac*I to conduct Southern DNA blot analysis. ",
"The digested DNA was resolved on a 1% (w/v) agarose gel, followed by transfer of the DNA to a nylon membrane (GE Healthcare, Pittsburgh, PA) using capillary flow. ",
"A 419 bp fragment from the hygromycin resistance gene was amplified using a pair of primers (forward 5′-CAAGGAATCGGTCAATACACTAC-3′ and reverse 5′-AAGCTCTGATAGAGTTGGTCAAG-3′) designed from the expression vector and labeled with digoxigenin, which was detected by anti-digoxigenin-AP, Fab fragments (Roche Applied Science, Indianapolis, IN). ",
"The hygromycin-resistant T~1~ plants were advanced to the T~2~ generation and hygromycin resistance was tested with T~2~ seedlings. ",
"If all T~2~ plants from a single T~1~ plant were resistant and the relevant T~1~ plant only harbored a single integration event, the relevant line was considered homozygous. ",
"One such homozygous line was chosen for subsequent analysis (Supplemental Material, [Figure S1](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS1.pptx)).",
"\n\nPlant material and growth {#s3}\n-------------------------\n\nTo examine the assembly of HF-OsRPL18 into polysomes, T~4~ transgenic rice seeds containing *p35S:HF-OsRPL18* were sterilized and grown on MS medium with 10 g/L sucrose. ",
"Plants were grown for 7 d at 28° with a 16 hr day/8 hr night photoperiod under 80 µmol/m^2^/sec photosynthetically active radiation.",
"\n\nFor mRNA-seq and TRAP-seq analysis, 5-wk-old calli were harvested from T~4~ seeds grown on CIM. ",
"For shoot and panicle mRNA-seq and TRAP-seq, T~4~ *p35S:HF-OsRPL18* plants were grown in 5 inch plastic pots filled with Profile Green's Grade sand. ",
"The pots were placed inside a tray filled with water. ",
"Fertilizer (Peters Excel 15-5-15 Cal-Mag special) was applied twice each week as a 200 ml solution from a 10× stock to each tray with eight pots. ",
"All plants were grown in a growth chamber with a 12 hr day/12 hr night photoperiod, with light intensity 500 µmol/m^2^/sec; the above-ground portion of young seedlings (shoots) was harvested at 14 d from plants grown at 30/28° d/night; young panicles of 1--5 cm in length, corresponding to stage R1 (post the formation of panicle branches) according to [@bib14], were harvested from plants grown at 28/24° d/night. ",
"All tissues were harvested directly into liquid nitrogen and stored at −80° until use.",
"\n\nSucrose density fractionation of polysomes and efficiency evaluation of ribosome immunopurification {#s4}\n---------------------------------------------------------------------------------------------------\n\nTo test the association of HF-OsRPL18 with translating ribosomes, polysomal complexes were isolated by differential centrifugation and processed as described previously ([@bib51]). ",
"Approximately 1 g of frozen, pulverized 7-d-old shoot tissue was used to obtain a pellet enriched in ribosomes. ",
"About 3300 OD~260~ were fractionated on a 20--60% (w/v) sucrose density gradient. ",
"Protein in each fraction was precipitated and polypeptides analyzed by standard western blot after separation by 12% (w/v) SDS-PAGE. ",
"HF-OsRPL18 was immunodetected using a mouse monoclonal antibody conjugated to horseradish peroxidase (α-FLAG-HRP; 1:1000) as previously described ([@bib82]). ",
"The small ribosomal subunit protein RPS6 was immunodetected using a rabbit polyclonal antiserum against *Zea mays* RPS6 (1:5000) ([@bib79]) as the primary antibody and a horseradish peroxidase conjugated goat anti-rabbit IgG as the secondary antibody (1:10,000; Bio-Rad, Hercules CA).",
"\n\nTo test the efficiency of immunopurification, ∼30 mg of pulverized shoot tissue of wild-type (Nipponbare) or *p35S:HF-OsRPL18* plants was processed for affinity purification of epitope-tagged ribosomes as described by [@bib51] with the following modification: 5 µg of α-FLAG (Sigma-Aldrich, St. Louis MO, F1804) was bound to 50 µl Dynabeads Protein G (Life Technologies, Carlsbad CA, 1004D) instead of α-FLAG agarose beads (Sigma-Aldrich, F2426). ",
"Fractions obtained during the procedure were separated by 12% (w/v) SDS-PAGE followed by western blot detection of HF-OsRPL18 and RPS6 as described above.",
"\n\nmRNA-seq and TRAP-seq library construction, sequencing, and expression abundance estimation {#s5}\n-------------------------------------------------------------------------------------------\n\nFor mRNA library construction, ∼5 g of pulverized tissue (shoot, callus, or young panicle) was homogenized in 45 ml of Polysome Extraction Buffer (PEB) and centrifuged at 4°, 16,000 × *g*, for 15 min ([@bib51]). ",
"The supernatant was filtered through Miracloth and centrifuged as described above. ",
"Five percent of the supernatant was used for isolation of total RNAs with the remainder used for affinity purification of epitope-tagged ribosomes as described previously ([@bib51]). ",
"RNAs were extracted from the PEB supernatant (for mRNA-seq) or the eluate from the immunoprecipitation (for TRAP-seq) using TRIzol reagent (Invitrogen) and the QIAGEN RNeasy kit.",
"\n\nIllumina TruSeq stranded mRNA libraries (Illumina, San Diego, CA) were constructed and sequenced on an Illumina HiSeq2500 (Illumina,) in paired-end mode for 100 or 150 nucleotides (nt) at the Research Technology Support Facility of Michigan State University. ",
"The read lengths and yield of each library are summarized in [Table S1](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS1.docx). ",
"Reads from libraries sequenced with read lengths greater than 100 nt were trimmed to 100 nt for consistency. ",
"The reads for each library were adapter trimmed and quality filtered using Trimmomatic (v0.32) in paired mode using the parameters: LEADING:5 TRAILING:5 SLIDINGWINDOW:4:10 MINLEN:30 ([@bib5]).",
"\n\nThe cleaned paired reads from the mRNA-seq and TRAP-seq libraries were aligned to the rice pseudomolecules (Os-Nipponbare-Reference-IRGSP-1.0) ([@bib37]) using TopHat (v1.4.1) ([@bib74]) with a minimum intron size of 5 bp and a maximum intron size of 15 kbp. ",
"Transcript abundances for the MSU Release 7 representative gene models ([@bib37]) were calculated as fragments per kilobase per exon model per million mapped reads (FPKMs) from the TopHat alignments using Cufflinks (v1.3.0) ([@bib75]) with the same intron parameters as used for TopHat ([Table S2](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS2.xlsx)).",
"\n\nTranslatomes, translatome enrichment index (TEI), and filtering of transposon genes {#s6}\n-----------------------------------------------------------------------------------\n\nFor each tissue, the translatome was comprised of all genes with a TRAP-seq FPKM value ≥1. ",
"The TEI was calculated as the ratio of the TRAP-seq FPKM *vs.* the mRNA-seq FPKM from the same tissue. ",
"TEIs of different gene groups (see below) were compared using the Kolmogorov--Smirnov (KS) test, and *P*-values were adjusted using the Benjamini--Hochberg method ([@bib4]). ",
"Representative gene models from MSU Release 7 (<ftp://ftp.plantbiology.msu.edu/pub/data/Eukaryotic_Projects/o_sativa/annotation_dbs/pseudomolecules/version_7.0/all.dir/all.locus_brief_info.7.0>) were used for all analyses, with the exception of analysis of alternative splice isoforms in which all gene models were considered. ",
"In MSU Release 7, 16,937 transposon genes (including both transposons and retrotransposons) were annotated. ",
"To confirm that transposon-related genes were correctly tagged, a custom rice transposon library was used to mask the predicted cDNAs of the 16,937 transposon genes. ",
"If 50% or more of the cDNA length was masked by the library, the transcript was validated as a true transposon gene; 15,461 transposon-related genes met this criterion and were used for subsequent analyses.",
"\n\nClassification of genes by expression breadth and abundance {#s7}\n-----------------------------------------------------------\n\nTo determine the expression breadth of nontransposon genes, 23 mRNA-seq samples were downloaded from the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) (<http://www.ncbi.nlm.nih.gov/sra>). ",
"After exclusion of redundant samples (those from similar tissues), 12 distinct mRNA-seq samples were retained, in addition to the three mRNA-seq samples from this study, resulting in a total of 15 samples for the expression breadth analysis ([Table S3](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS3.docx)). ",
"The SRA-obtained raw reads were cleaned, aligned to the reference genome as described above, and expression abundance was estimated as described above with an FPKM value ≥1 considered as expressed. ",
"Nontransposon genes were categorized into three groups with an increasing order of expression breadth: Breadth Group 1 comprised nontransposon genes expressed in 1--7 samples; Breadth Group 2 were nontransposon genes expressed in 8--14 samples; and Breadth Group 3 consisted of nontransposon genes with expression evidence in all 15 samples and were considered constitutively expressed genes.",
"\n\nThe three mRNA-seq datasets generated in this study were used to classify nontransposon genes based on their expression abundance for each tissue. ",
"In each tissue, nontransposon genes were categorized into six groups with FPKM values increasing from 1 to over 1000. ",
"Each group contains comparable number of genes ([Table S4](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS4.docx)).",
"\n\nIdentification of conserved and lineage-specific genes {#s8}\n------------------------------------------------------\n\nRice genes were assigned to a green plant lineage based on their placement within orthologous gene clusters generated with OrthoMCL (v1) ([@bib48]). ",
"OrthoMCL was used to cluster protein sequences from 13 species: *Amborella trichopoda* (v1.0, phytozome.jgi.doe.gov), *Aquilegia coerulea* (v1.1, phytozome.jgi.doe.gov), *A. thaliana* (TAIR10, phytozome.jgi.doe.gov), *Brachypodium distachyon* (v2.1, phytozome.jgi.doe.gov), *Musa acuminata* (v1, banana-genome.cirad.fr), *Oryza sativa* (v7, rice.plantbiology.msu.edu), *Phoenix dactylifera* (v3, Qatar-weill.cornell.edu/research/datepalmGenome), *Phyllostachys heterocycla* (v1.0, bamboogdb.org), *Populus trichocarpa* (v3.0, phytozome.jgi.doe.gov), *Setaria italica* (v2.1, phytozome.jgi.doe.gov), *Solanum lycopersicum* (iTAG2.3, phytozome.jgi.doe.gov), *Sorghum bicolor* (v2.1, phytozome.jgi.doe.gov), and *Z. mays* (5b; maizegdb.org). ",
"Based on species content, orthologous gene clusters were classified as conserved in all angiosperms, monocot and dicot-restricted, monocot-restricted, Poaceae-restricted, or *O. sativa*-specific. ",
"Transposon-related genes were not assigned a lineage. ",
"To visualize the relative translation status (or TEI) of expressed genes in each lineage, kernel density plots were generated for the three tissue types (shoot, callus, and panicle) surveyed. ",
"Nucleotide content for gene and coding sequences (CDS) was calculated using BEDTools (v2.20.1) ([@bib62]).",
"\n\nGene ontology (GO) analysis {#s9}\n---------------------------\n\nGO assignment table of rice genes (Release 7) was downloaded from the Rice Genome Annotation Project (<http://rice.plantbiology.msu.edu/>), from which, genes were grouped according to their associated biological processes. ",
"The assignment table also contains the corresponding *Arabidopsis* orthologous gene for each rice gene, which was used to synchronize the analysis between rice and *Arabidopsis* (see below). ",
"Information of gene features, including length and GC content of CDS and untranslated regions (UTRs), were obtained based on the rice genome annotation (Release 7), and only genes with both 5′ UTRs (at least 20 bp in length) and 3′ UTRs (at least 110 bp in length) were retained for the following analysis. ",
"The minimum length of UTRs (20 bp for 5′ UTRs and 110 bp for 3′ UTRs) was defined using genes with full-length cDNA evidence ([@bib40]), where 97.5% of these gene have UTRs equal or longer than the minimum length. ",
"These values were used for all analysis related to the specific roles of UTRs in translation. ",
"For each tissue, the mean values of TEIs of all genes within each category (each GO term) were calculated and only the categories with at least 40 genes were included in the comparison.",
"\n\nSimilar analyses were conducted in *Arabidopsis* using mRNA-seq levels and TRAP-seq levels published from *Arabidopsis* seedlings under normal conditions ([@bib33]). ",
"The CDS of *Arabidopsis* genes were downloaded from TAIR10 (<https://www.arabidopsis.org/>). ",
"To ensure comparability between *Arabidopsis* and rice, only genes corresponding to the genes used for GO analysis in rice shoots with TEIs were included (7966 genes for *Arabidopsis* and 11,600 for rice). ",
"Only processes with 40 or more genes were considered for comparison, as described above.",
"\n\nEstimation of recombination rate and codon usage frequency {#s10}\n----------------------------------------------------------\n\nThe recombination rate in rice was adapted from [@bib73], where 3982 markers were anchored to the rice genome, IRGSP Build 4.0 pseudomolecules. ",
"To be consistent with the other analyses conducted in this study, these markers were aligned to the rice genome MSU Release 7, where markers having the best match with ≥ 99% identity over the entire marker sequences were used for the following analysis. ",
"The recombination rate (cM/Mb) was measured in 1 Mb bins (some bins are \\>1 Mb if there is no marker in a region \\>1 Mb). ",
"Pearson correlation between recombination rate and CDS GC content, as well as that between recombination rate and TEI, were conducted using SAS/9.3.",
"\n\nThe occurrence frequency of all 64 codons (61 for amino acids and 3 for stop codon) was determined using a perl script kindly provided by Kevin Childs and Tiffany Liu (Michigan State University). ",
"Briefly, codon usage frequency was calculated for genes with the lowest (\\<0.2) and the highest (≥3.0) TEIs and synonymous codon usage between the two gene groups were compared; chi-square tests were conducted using SAS/9.3.",
"\n\nData availability {#s11}\n-----------------\n\nRNA-sequencing reads (mRNA-seq and TRAP-seq) are available in the NCBI SRA under BioProject PRJNA298638. ",
"The mRNA-seq and TRAP-seq expression abundances are available in [Table S2](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS2.xlsx) and on individual gene report pages at the Michigan State University Rice Genome Annotation Project (<http://rice.plantbiology.msu.edu/>).",
"\n\nResults and Discussion {#s12}\n======================\n\nExpression of epitope-tagged RPL18 and its incorporation into ribosomes {#s13}\n-----------------------------------------------------------------------\n\nIn *A. thaliana*, it has been demonstrated that HF-AtRPL18 is efficiently incorporated into the 60S subunit and that ribosomes containing HF-AtRPL18 accumulate in polysomal complexes ([@bib82]). ",
"To test whether this can be replicated in rice, we constructed an expression vector that contains the orthologous rice *RPL18* gene with a His~6~-FLAG tag at the N-terminus of the protein (HF-OsRPL18, see *Materials and Methods* for details). ",
"Transgenic *p35S:HF-OsRPL18* rice plants used for subsequent analyses contained a single copy of the transgene and were similar to the wild-type Nipponbare plants in terms of plant height, days to flower, number of tillers, seed number per plant, and seed weight ([Figure S1](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS1.pptx)).",
"\n\nTwo experiments were performed to confirm that the FLAG-epitope-tagged OsRPL18 was appropriately assembled into functional ribosomes that can be efficiently purified by TRAP. ",
"In the first experiment, the association of HF-OsRPL18 with the large ribosomal subunit and multi-ribosome complexes (polysomes) was confirmed by preparation of a shoot extract with a polysome-stabilizing buffer followed by pelleting of ribosome complexes at 170,000 × *g*, and further fractionation of the complexes by centrifugation through a sucrose density gradient. ",
"A UV absorbance profile of a representative gradient was obtained and western blot analysis was performed to evaluate the fractionation of HF-OsRPL18 and the core 40S ribosomal subunit protein RPS6. ",
"Both RPL18 and RPS6 had similar abundance in the small-to-large polysome complexes ([Figure 1A](#fig1){ref-type=\"fig\"}; fractions 6--10), confirming assembly of the epitope-tagged protein into functional ribosomes. ",
"RPS6 and HF-OsRPL18 were enriched in fractions 4 and 5, respectively, consistent with their independent assembly into the 40S and 60S subunits, which separated into distinct peaks in the sucrose density gradient.",
"\n\n{#fig1}\n\nThe second experiment was carried out to determine if ribosomes with HF-OsRPL18 could be directly and efficiently immunopurified from cell extracts prepared with polysome-stabilizing buffer. ",
"To accomplish this, the presence of HF-OsRPL18 and the 40S subunit RPS6 were monitored in the initial crude extract (total) and in the proteins obtained by immunopurification of FLAG-tagged HF-OsRPL18 and associated proteins using magnetic beads conjugated to an anti-FLAG monoclonal antibody (TRAP). ",
"As a control for the efficiency of the purification, the supernatant from the immunopurification (unbound) was also evaluated in the western blot analysis. [",
"Figure 1B](#fig1){ref-type=\"fig\"} shows a representative experiment that demonstrates that HF-OsRPL18 is efficiently purified along with RPS6, consistent with isolation of the 40S and 60S subunits in a complete 80S ribosome. ",
"A small amount of HF-OsRPL18 remained in the supernatant, even when an excess of antibody was used in the purification. ",
"This suggests that a small proportion of HF-OsRPL18-containing ribosomes may not have the epitope accessible to the immune-affinity matrix. ",
"RPS6 was also present in the unbound fraction. ",
"This was anticipated because 40S ribosomal subunits not coupled with HF-OsRPL18-containing 60S subunits would not be purified, as the *p35S:HF-OsRPL18* transgene was expressed in the wild-type Nipponbare background with three endogenous *RPL18* genes that are all expressed in shoots. ",
"These experiments confirm that TRAP can be used efficiently to purify functional ribosomes from *p35S:HF-OsRPL18* transgenic rice.",
"\n\nRice transcriptome and translatome profiles {#s14}\n-------------------------------------------\n\nTo elucidate the regulation of rice gene expression at the transcriptional and translational levels, we conducted mRNA-seq and TRAP-seq with three different rice tissues (shoot, callus, and panicle) using the *p35SHF-OsRPL18* line. ",
"Rice genes were categorized into transposon and nontransposon gene sets to validate the efficiency of transcription (mRNA-seq) and translation (TRAP-seq). ",
"In this study, 16,937 transposon-encoding genes are annotated in Release 7 and we performed further filtering to yield a total of 15,461 transposon-related genes (see *Materials and Methods*), of which the majority encode a putative transposase or other proteins required for transposition and are therefore putative autonomous transposons or derivatives from autonomous elements. ",
"The nontransposon gene set contains 39,049 nontransposon protein-coding genes.",
"\n\nFor simplicity, we defined a gene as transcribed (for mRNA-seq) and translated (for TRAP-seq) if it has an FPKM value ≥1. ",
"Moreover, we defined the ratio of FPKM values between TRAP-seq and mRNA-seq as a TEI of mRNAs associated with ribosomes ([@bib25]). ",
"As shown in [Table 1](#t1){ref-type=\"table\"}, over half (55%) of the nontransposon genes have evidence of translation in at least one of the three tissues sampled. ",
"If only genes with transcription evidence (*i.e.*, mRNA-seq ≥ 1 FPKM) are considered, ∼90% of the transcribed nontransposon genes are associated with ribosomes, suggesting that, once transcribed, the majority of nontransposon genes are recruited to ribosomes for translation ([Table 1](#t1){ref-type=\"table\"}). ",
"Of the 22,896 nontransposon genes with an annotated function in Release 7, 16,151 (71%) are translated in at least one of the three tissues examined, suggesting that most of them are true protein-coding genes consistent with their similarity to known genes. ",
"In the rice genome, 16,153 genes are annotated as \"expressed proteins\" or \"hypothetical proteins\": of these, 5496 (34%) are translated in at least one of the three tissues examined. ",
"This suggests that, of the unknown proteins annotated solely based on transcription evidence and/or *ab initio* gene predictions, a substantial portion could be *bona fide* protein-coding genes. ",
"For a comparison, we examined 4095 genes with proteomic evidence in OryzaPG-DB ([@bib23]); 3884 (94.8%) have a TRAP-seq FPKM value ≥1 in this study. ",
"Nontransposon genes with transcripts that were not detected in this study may be functional in tissues not evaluated in this study.",
"\n\n###### Gene expression evidence from transcriptomes and translatomes of three tissues of rice\n\n No. ",
"of Genes Fraction of gene set Callus Panicle Shoot Total Unique Genes\n ------------------------ ----------------- ---------------------- ----------------- ----------------- ----------------- --------------------\n Nontransposon genes 39,049 mRNA-seq (%total) 18,793 (48.13%) 19,311 (49.45%) 17,713 (45.36%) 22,589 (57.85%)\n TRAP-seq (%total) 18,013 (46.13%) 17,987 (46.06%) 15,943 (40.83%) 21,647 (55.44%) \n Overlap (%mRNA-seq^b^) 16,931 (90.09%) 16,804 (87.02%) 15,030 (84.85%) 20,457 (90.56%) \n Transposon genes 15,461 mRNA-seq (%total) 293 (1.90%) 255 (1.65%) 202 (1.31%) 381 (2.46%)\n TRAP-seq (%total) 148 (0.96%) 149 (0.96%) 85 (0.55%) 211 (1.36%) \n Overlap (%mRNA-seq) 138 (47.10%) 122 (48.03%) 77 (38.31%) 180 (47.24%) \n\nNo., ",
"number; mRNA, messenger RNA; TRAP-seq, Translating Ribosome Affinity Purification followed by mRNA-sequencing; %total, the percent of annotated genes with mRNA-seq or TRAP-seq FPKM ≥ 1; %mRNA-seq, the percent that are translated among the genes with transcription evidence.",
"\n\nIn contrast to nontransposon genes, very few transposon genes are transcribed and even fewer are translated (2.5 and 1.4% of the total transposon genes, respectively). ",
"Less than half (48%) of the transcribed transposons are translated compared to 90% for nontransposon genes ([Table 1](#t1){ref-type=\"table\"}), suggesting that transcripts encoding transposon proteins are much less likely to be translated than nontransposon transcripts. ",
"Among the transposons that are translated, the median TEI value is 0.65, which is substantially lower than that of nontransposon genes (0.93). ",
"To assess whether the lower fraction of translated transposon genes is an artifact of low sensitivity of TRAP-seq, we examined the translation status of autonomous transposons reported to be active in Nipponbare. ",
"Among the nine transposons with reported activity in Nipponbare ([@bib24]; [@bib30]; [@bib39]; [@bib54]; [@bib61]; [@bib66]), translational evidence was detected for six in this study ([Table 2](#t2){ref-type=\"table\"}). ",
"The distinction in translatome profiles between transposons and nontransposon genes, high concordance of translatome evidence with genes supported by previous proteomic studies, and detection of the most active transposons in the translatome suggests that the TRAP-seq data generated in this study effectively separates mRNAs associated with ribosomes from pre/mRNAs in the nucleus or untranslated mRNAs in the cytosol.",
"\n\n###### Translational status of transposable elements documented to be active in Nipponbare\n\n Element Superfamily Locus Tissue[*^a^*](#t2n1){ref-type=\"table-fn\"} mRNA-seq (FPKM) TRAP-seq (FPKM) TEI Translation Evidence[*^b^*](#t2n2){ref-type=\"table-fn\"}\n ----------- ----------------- ---------------- ------------------------------------------- ----------------- ----------------- ------ ---------------------------------------------------------\n *Tos17* *LTR/Copia* LOC_Os10g29650 Callus 15.03 0.58 0.04 Maybe\n *Lullaby* *LTR/Copia* LOC_Os06g38480 Callus 13.01 15.61 1.20 Yes\n *Osr10* *LTR/Copia* LOC_Os04g32750 Panicle 0.01 0.00 NA Not expressed\n *Osr37* *LTR/Gypsy* LOC_Os03g43750 Callus 10.12 4.83 0.48 Yes\n *RIRE2* *LTR/Gypsy* LOC_Os03g36279 Callus 2.26 2.56 1.14 Yes\n *RIRE3* *LTR/Gypsy* LOC_Os06g32890 Shoot 0.13 0.08 NA Not expressed\n *RN363* *LTR/Gypsy* LOC_Os02g24150 Panicle 1.92 2.02 1.05 Yes\n *Ping* *PIF/Harbinger* LOC_Os06g39624 Panicle 16.50 9.41 0.57 Yes\n *Pong* *PIF/Harbinger* LOC_Os11g19864 Callus 6.40 6.36 0.99 Yes\n\nmRNA-seq, messenger RNA sequencing; FPKM, fragments per kilobase per exon model per million mapped reads; TRAP-seq, Translating Ribosome Affinity Purification followed by mRNA-sequencing; TEI, translatome enrichment index; NA, not applicable.",
"\n\nIf the transposon is expressed in multiple tissues, the one with the highest TRAP-seq level is listed.",
"\n\nTRAP-seq FPKM ≥ 1 is considered to be translated; mRNA-seq FPKM ≥1 is considered to be expressed.",
"\n\nIt should be noted that a high TEI could be interpreted in two ways as the abundance of mRNA on ribosomes is largely determined by three factors: initiation, elongation, and termination. ",
"The predominant regulation is the rate of initiation of translation, which is positively correlated with protein production ([@bib7]). ",
"If the rate of elongation and termination is comparable between transcripts, then a high TEI indicates preferential translation, *i.e.*, translation is initialized on a higher fraction of available transcripts than for other individual mRNAs. ",
"Translation can be initialized by newly recruited ribosomes (*de novo* initiation) or, when translation is completed on an mRNA, the recently terminated ribosomes may reinitiate translation on the same mRNA, a process called ribosome recycling ([@bib7]; [@bib65]; [@bib68]). ",
"However, a high TEI could be due to other factors. ",
"One is a slower rate of translation elongation or termination, such that more transcripts are associated with ribosomes ([@bib7]; [@bib65]). ",
"Factors including the structure of the mRNA coding region, abundance of tRNAs, and codon usage contribute to the variation of elongation speed ([@bib27]). ",
"Another factor is the presence of one or more upstream ORFs (uORFs) preceding the main protein CDS on the transcript. ",
"uORFs in the 5′ region of transcripts typically reduce the overall translation of the main CDS, in a metabolite or condition-regulated manner ([@bib33]; [@bib65]). ",
"Moreover, these contributions to TEI are not mutually exclusive. ",
"Although slow elongation/termination rate or uORFs may contribute to high TEI values, thereby uncoupling this statistic from protein production, a very low TEI most likely indicates limited translation.",
"\n\nTranslatome enrichment associated with a short coding region and higher GC content {#s15}\n----------------------------------------------------------------------------------\n\nIn rice, the length of gene CDS varies substantially with a median value of 1095 bp ([Table 3](#t3){ref-type=\"table\"} and [Table S5](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS5.xlsx)). ",
"To test whether CDS length is related to translatome enrichment, the level of mRNAs associated with ribosomes (TRAP-seq FPKM) was plotted against total mRNA abundance (mRNA-seq FPKM) for rice genes with different length of CDS. ",
"As shown in [Figure 2A](#fig2){ref-type=\"fig\"}, genes with a large CDS tend to have a relatively low TRAP-seq level. ",
"When the CDS is shorter than 500 bp, the median value of TEI is about 2 ([Figure S3](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS3.pptx)). ",
"When the CDS length is longer than 1500 bp, the median value of TEI is about 0.5 ([Figure S3](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS3.pptx)). ",
"The difference between each group is significant (*P* \\< 0.0001, KS test). ",
"A similar trend in TEI with CDS length was observed in calli and young panicles ([Figure S2](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS2.pptx) and [Figure S3](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS3.pptx)). ",
"These results are consistent with previous observations that short genes are associated with higher translation levels in other organisms ([@bib2]; [@bib32]; [@bib45]; [@bib47]; [@bib68]). ",
"It is feasible that, when the number of initiation factors or ribosomes is limiting and the two termini of a long transcript are further apart, the first initiation event and/or the efficiency of ribosome recycling and reinitiation is reduced and therefore fewer transcripts are translated.",
"\n\n###### The effect of length and GC content of different portions of transcripts on TEI\n\n Feature 5′ UTR (bp)[*^a^*](#t3n1){ref-type=\"table-fn\"} CDS (bp) 3′ UTR (bp) \n ---------------------------- ------------------------------------------------ -------------------------- ------------- --\n Size (bp) \n Mean
Median
Correlation 215 1234 433 \n 147 1095 354 \n Negative Negative Optimal size 200--400 bp \n GC content (%) \n Mean
Median
Correlation 58.3 56.1 39.3 \n 59.2 54.0 39.1 \n Weak negative Positive Weak positive \n\nUTR, untranslated region; CDS, coding sequence; TEI, translatome enrichment index.",
"\n\nOnly genes with both UTRs meeting size criterion (see *Materials and Methods* for details) and with TEI in at least one tissue were considered for calculation of mean and medium values.",
"\n\n{#fig2}\n\nAs described in the introduction, the GC content of transcripts in grasses has a bimodal distribution ([Figure S4](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS4.pptx)) with the high GC fraction largely absent from dicot genomes. ",
"As shown in [Figure 2B](#fig2){ref-type=\"fig\"} and [Figure S2](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS2.pptx), the TEI value is positively correlated with GC content in all tissues. ",
"We then divided the rice genes into four groups (GC \\< 50%, 50--60%, 60--70%, and ≥ 70%) and examined the TEI. ",
"The average TEI of the highest GC group (≥70%) is nearly two whereas that for the lowest GC group is about 0.5 (*P* \\< 0.0001, KS test) ([Figure S3](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS3.pptx)). ",
"The preferential association of ribosomes with GC-rich genes is consistent with the results from a recent study in maize ([@bib47]). ",
"Since the correlation between GC content and TEI is only reported in grasses, and GC-rich genes are often associated with small size ([@bib21]), it was reasoned whether the elevated TEI of GC-rich genes is due to their small size. ",
"To this end, we divided rice genes into six groups with increasing CDS size and calculated the correlation between CDS size and GC content in each group. ",
"The result showed that the relationship between CDS length and GC content varies among different size ranges ([Table S6](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS6.docx) and [Table S7](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS7.xlsx)). ",
"When the CDS length is between 1100 and 1400 bp, no significant correlation between CDS length and GC content was observed ([Table S6](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS6.docx), *P* = 0.33). ",
"Nevertheless, significant positive correlation (*P* \\< 2.2e−^16^) between GC content and TEI was still observed, suggesting that CDS length and GC content played independent roles in translation.",
"\n\nThe high TEI associated with increased GC content suggests that the evolution of GC-rich genes in grasses may be associated with their increased translational activity. ",
"However, high GC transcripts are often associated with stronger secondary structure that may hinder the elongation process and/or cause ribosome stalling or pausing because the GC content variation is correlated with distinctions in codon usage bias ([@bib12]; [@bib18]; [@bib35]; [@bib41]), thereby resulting in a higher TEI. ",
"In a previous study, it was shown that GC-poor and GC-rich genes are subject to differential constraints in codon usage ([@bib49]). ",
"The codon usage in GC-poor genes is largely selected for tRNA gene abundance; whereas that in GC-rich genes is selected both by tRNA gene abundance and by stable secondary structure ([@bib49]). ",
"Accordingly, the selection for secondary structure in GC-rich genes could be due to its benefit in association with ribosomes. ",
"In mammalian cells, high GC content is associated with enhanced transcription activity ([@bib44]) and our analysis indicates that high GC content may also favor ribosome association of relevant transcripts. ",
"Application of the ribosome footprint profiling (Ribo-seq) method, which maps individual ribosomes along transcripts, could provide further insight into the underlying mechanisms associated with the higher TEI of GC-rich mRNAs.",
"\n\nAs mentioned above, about one third of the \"expressed proteins\" or \"hypothetical proteins\" are likely translated. ",
"In general, the CDS of those \"expressed proteins\" or \"hypothetical proteins\" is much smaller than that of genes with known function (median 615 *vs.* 1179 bp, [Table S8](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS8.docx)), and they are also more GC-rich (57 *vs.* 53%). ",
"The shorter CDS and higher GC content result in a higher TEI (1.14 *vs.* 0.88) compared to genes with known function. ",
"As a result, the transcripts derived from \"expressed proteins\" or \"hypothetical proteins\" are more enriched on ribosomes.",
"\n\nTranslatome enrichment for genes with different expression breadth and abundance {#s16}\n--------------------------------------------------------------------------------\n\nIn yeast, shorter genes are more efficiently translated ([@bib2]; [@bib45]), which was thought to be a consequence associated with the shortened length of constitutively expressed housekeeping genes ([@bib26]; [@bib68]). ",
"As such, it minimizes the possibility that transcript length itself may have a mechanistic role in translational regulation. ",
"To test whether this is the case in rice, we examined the translatome enrichment of constitutively expressed genes and putative housekeeping genes. ",
"To this end, 12 mRNA-seq datasets ([Table S3](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS3.docx)) obtained from the NCBI SRA database along with the three mRNA-seq samples generated from this study (15 total mRNA-seq samples) were used to determine expression breadth. ",
"To annotate a gene as expressed, a FPKM of ≥ 1 in at least one tissue was required. ",
"With this criterion, three groups of genes were generated. ",
"One group includes genes expressed in 1--7 samples, the second group includes genes expressed in 8--14 samples, and the third group includes genes expressed in all 15 samples (constitutively expressed genes).",
"\n\nAs shown in [Figure 3A](#fig3){ref-type=\"fig\"}, there is a minor yet negative correlation between expression breadth and TEI, with constitutively expressed genes having slightly lower TEI than other genes. ",
"This is consistent with the fact that the CDS of constitutively expressed genes are slightly longer and less GC-rich than other genes ([Figure S5](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS5.pptx)). ",
"We further examined the TEI of 23 known reference (housekeeping) genes ([@bib55]). ",
"The median value of TEI for those genes ranges from 0.98 to 1.05 in three tissues, which is comparable with that of other genes (0.93) ([Table S9](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS9.docx)). ",
"The median length of the reference housekeeping genes is similar to that of other genes (1071 and 1095 bp, respectively, [Table 3](#t3){ref-type=\"table\"} and [Table S9](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS9.docx)). ",
"Taken together, the high TEI value for short genes in rice is not due to the enrichment of constitutively expressed housekeeping genes, suggesting that there is a mechanistic role of a small CDS size in translation. ",
"Moreover, there is no evidence that housekeeping genes are preferentially translated in rice. ",
"If a high TEI value does imply a high amount of protein produced per transcript, the low transcript abundance of short GC-rich genes, such as the Poaceae lineage-specific genes ([@bib10]), maybe compensated by the higher translation efficiency, at least to some degree.",
"\n\n{#fig3}\n\nTo explore the relationship between transcript level and translatome enrichment, genes were divided into six groups based on their expression abundance, with each group containing a similar number of genes ([Table S4](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS4.docx)). ",
"As shown in [Figure 3B](#fig3){ref-type=\"fig\"}, the TEI and expression abundance (relative steady-state transcript abundance) demonstrate a quadratic relationship, *i.e.*, the TEI is higher for the genes with the highest or lowest expression abundance, whereas the genes with intermediate expression abundance have the lowest TEI; the differences between the two extreme groups and other intermediate groups are significant (*P* \\< 0.0001, KS test). ",
"To understand the underlying mechanism of this relationship, the GC content and CDS length of each group were examined ([Figure S5](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS5.pptx)). ",
"Interestingly, the GC content of genes shows a similar quadratic relationship, *i.e.*, the genes with the lowest and highest transcription level have higher GC content than the genes with intermediate transcription abundance ([Figure S5](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS5.pptx)). ",
"Moreover, the length of CDS has a negative quadratic relationship with expression abundance, which suggests that genes with the highest and lowest transcription levels are associated with a smaller CDS. ",
"As a result, the nonlinear relationship between TEI and expression abundance can be largely explained by the GC content and CDS length of the relevant transcripts.",
"\n\nRegulation of alternatively spliced transcripts at the translational level {#s17}\n--------------------------------------------------------------------------\n\nWhen pre-mRNAs from genes with multiple exons are processed, a single transcript could be alternatively spliced into multiple isoforms. ",
"In humans, the majority of multi-exon genes have alternative spliced transcript isoforms ([@bib57]; [@bib77]), which allow the generation of multiple protein isoforms from a single gene. ",
"In plants, isoforms are not as prevalent as in mammals, yet they still play important roles in protein diversity. ",
"Previous studies in rice indicate that the majority of alternative splice forms result from the retention of individual introns ([@bib9]; [@bib84]; [@bib76]). ",
"Among the 16,809 isoforms annotated in MSU Release 7, 8164 isoform pairs were SI *vs.* RI, referring to isoforms of genes with spliced introns and retained introns, respectively ([@bib9]). ",
"Among them, a small subset are both transcribed and translated, with calli containing the highest number of expressed SI/RI pairs (732 pairs, [Table S10](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS10.docx) and [Table S11](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS11.xlsx)). ",
"Whereas the median TEI of the SI isoform is comparable to other genes, the median TEI for RI isoforms is much lower than that of SI isoforms ([Table S10](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS10.docx)), suggesting that the RI may have a negative impact on translation or that the transcripts with RIs may be inaccessible to ribosomes due to nuclear localization or cytoplasmic sequestration ([@bib46]).",
"\n\nThe RIs were grouped based on their location in the mRNA, including those in the 5′ UTR, CDS, and 3′ UTR. ",
"The abundance of the RI transcript isoform, as reflected by the median FPKM value through mRNA-seq, is very similar to that of their SI counterpart ([Figure 4](#fig4){ref-type=\"fig\"}). ",
"Nevertheless, when the RI is in a 5′ UTR, the TRAP-seq level of the RI isoforms is substantially lower than that of the corresponding SI isoforms (*P* \\< 0.0003, KS test) and the trend is similar in all three tissues ([Figure 4](#fig4){ref-type=\"fig\"}, [Figure S6](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS6.pptx) and [Table S10](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS10.docx)). ",
"For RIs in the CDS and 3′ UTR, the TRAP-seq level of RI isoforms is slightly lower than that of the SI isoform, but the difference is not significant (*P* \\> 0.3, KS test). ",
"It should be noted that the lower TRAP-seq level is unlikely due to nonsense-mediated mRNA decay (NMD) ([@bib34]). ",
"This is because NMD involves a functional 80S ribosome and therefore occurs after the initiation of translation ([@bib67]), so a more substantial reduction of transcript abundance is expected but this is not the case here.",
"\n\n{#fig4}\n\nTo test whether the effect of the RI in different portions of the transcripts was due to the size and/or GC content of the RI, the relevant intron sequences were characterized. ",
"The median size of RIs is \\< 150 bp, much smaller than the median intron size of 418 bp in rice, suggesting that small introns are more likely to be retained ([Figure 4](#fig4){ref-type=\"fig\"}). ",
"The size of the RI in the 5′ UTR is slightly larger than that in the 3′ UTR ([Figure 4](#fig4){ref-type=\"fig\"}). ",
"The RIs in the CDS are the smallest, with a median value \\< 100 bp. ",
"As for GC content, the RIs in the CDS are associated with the highest GC content ([Figure 4](#fig4){ref-type=\"fig\"}), followed by that in the 5′ UTR, with the RIs in the 3′ UTR having the lowest GC content. ",
"Not surprisingly, the GC content of the RIs is lower than the corresponding genomic average GC content of the 5′ UTR, CDS, and 3′ UTR. ",
"Moreover, the difference in GC content between RI in the 5′ UTR and other 5′ UTR sequences is the most significant (40 *vs.* 57%, [Figure 4](#fig4){ref-type=\"fig\"} and [Table 3](#t3){ref-type=\"table\"}). ",
"As a result, the dramatically lower TRAP-seq level caused by RI in 5′ UTRs may be due to its slightly larger size and/or its lower GC content than average 5′ UTRs (see below).",
"\n\nIf RIs in the CDS leads to the generation of different protein isoforms, the evolutionary advantage for RIs in UTRs is unclear. ",
"Emerging evidence suggests that RIs followed by cytoplasmic splicing provide a newly recognized regulation of gene expression, especially for developmentally controlled genes. ",
"In the fern *Marsilea vestita*, large amounts of RI-containing transcripts are stored and later spliced in the microspore during spermatogenesis ([@bib6]). ",
"In this way, proteins can be rapidly generated without the need for *de novo* transcription. ",
"These RI transcripts are hypothesized to be \"sentinel RNAs\" ([@bib8]). ",
"Our analysis suggests that, for some rice genes, the RI forms are transcribed similarly to their corresponding SI forms but are underrepresented on ribosomes, suggesting that \"sentinel RNAs\" may also apply to those rice genes. ",
"To determine what types of genes are more likely to show intron retention, the GO terms were assigned to the SI/RI isoforms and compared with that to all genes. ",
"The genes that are most enriched (χ^2^ test, *P* \\< 0.001) in SI/RI isoforms are those involved in the response to abiotic stimuli, followed by those in postembryonic development, growth, and the generation of precursor metabolites and energy (χ^2^ test, *P* \\< 0.05, [Table S12](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS12.xlsx)). ",
"Given that the SI/RI isoforms are enriched in genes involved in the response to abiotic stimuli and some development processes, it is conceivable that the splicing and translation of the preexisting RI transcripts would allow a rapid response to abiotic stimuli as well as important developmental signals.",
"\n\nThe role of UTRs in translation {#s18}\n-------------------------------\n\nThe differential TEI between RI/SI isoform pairs allows further dissection of factors involved in translation. ",
"To explore the roles of the UTRs in translation, we extended our analysis to all nontransposon genes with annotated 5′ and 3′ UTRs. ",
"To minimize the effect of CDS, we divided the genes into different groups based on CDS length and examined the effect of UTR length within each group. ",
"In general, there is a negative correlation between the size of 5′ UTRs and TEI (coefficient \\< 0, *P* \\< 10^−7^ for all gene groups except the group with CDS \\> 1700 bp) ([Figure 5](#fig5){ref-type=\"fig\"}). ",
"The effect is more dramatic among genes with CDS lengths smaller than 800 bp (coefficient \\< 0, *P* \\< 10^−15^), which includes about one-third of all translated transcripts. ",
"For genes with CDS shorter than 800 bp, if the 5′ UTR is smaller than 200 bp, the TEI is significantly higher than for genes with a 5′ UTR longer than 200 bp ([Figure 5](#fig5){ref-type=\"fig\"}, *P* \\< 0.0001, KS test). ",
"Particularly, when the 5′ UTR is longer than 400 bp, all genes have a low TEI (\\<1) regardless of their CDS length ([Figure 5A](#fig5){ref-type=\"fig\"}), suggesting that an extended 5′ UTR could be detrimental to translation. ",
"The same trend is observed in calli and panicles ([Figure S7](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS7.pptx)). ",
"For the 3′ UTR, there seems to be an optimal size for TEI, when the CDS is smaller than 500 bp ([Figure 5](#fig5){ref-type=\"fig\"}) (*P* \\< 10^−12^, quadratic regression). ",
"The same trend is observed in calli but not in panicles ([Figure S7](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS7.pptx)). ",
"Overall, the size effect of the 5′ UTR on TEI is more substantial and consistent than that of the 3′ UTR.",
"\n\n{#fig5}\n\nIf the GC content of the UTR is examined in relationship to the TEI, the TEI value declines with increasing GC content in the 5′ UTR, if both the CDS and the 5′ UTR are small (CDS \\< 500 bp and 5′ UTR \\< 200 bp; [Figure S8](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS8.pptx)). ",
"This is consistent with the observation that high GC content in a 5′ UTR region significantly reduces ribosome loading ([@bib36]). ",
"In contrast, TEI values increase slightly with increasing GC content of 3′ UTRs ([Figure S8](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS8.pptx)), when CDS is \\<500 bp. ",
"However, compared with the effect of size of the UTR, the correlation between GC content of UTRs and TEI is rather weak and the difference between most data points is not significant (*P* \\> 0.05, KS test). ",
"Based on results from this analysis, the impact of RI in a 5′ UTR on translation is most likely due to its effect of increased size of the 5′ UTR, not due to the influence on GC content *per se*. ",
"Taken together, each portion of the transcript (5′ UTR, CDS, and 3′ UTR) plays a role in translation, depending on length, GC content, and possibly other sequence features or elements within these regions. ",
"The impact of UTRs is most significant for small genes. ",
"A summary of the correlation between these features and TEI is given in [Table 3](#t3){ref-type=\"table\"}.",
"\n\nTranslation in eukaryotes is initialized by the recruitment of the 40S ribosome preinitiation complex and then the 60S ribosomal subunit to the 5′ end of the transcript, followed by subunit joining and ribosome translocation from codon-to-codon as elongation proceeds ([@bib1]; [@bib7]). ",
"It is conceivable that a short 5′ UTR is favorable for translation over a long 5′ UTR because of a lower energy requirement for unwinding the 5′ UTR during the preinitiation complex scanning process. ",
"Many 5′ UTRs also harbor one or more uORFs or upstream start codons (uAUGs), which often reduce frequency of initiation of translation of the main open ORF encoding the gene product. ",
"A large fraction of uORFs are indeed translated in *Arabidopsis* ([@bib33]). ",
"Based on mammalian studies, some of the peptides encoded by uORFs might be functional ([@bib29]), and translation of uORFs seems to play key roles in the integrated stress response ([@bib70]). ",
"However, when a uORF is translated, the ribosome reinitiation for the downstream main ORF is inefficient, which causes translational suppression of the main ORF ([@bib65]). ",
"Since longer 5′ UTRs more likely contain uORFs or uAUGs, it might be anticipated that longer 5′ UTRs are associated with lower TEI. ",
"It is worthy of mention that RPL18 is a component of the 60S ribosomal subunit, which only assembles on the mRNA once the start codon AUG is identified by the scanning preinitiation complex composed of the 40S subunit and initiation factors. ",
"As a result, only mRNAs that are associated with at least one 80S ribosome can be obtained by TRAP and hence are detected in this study. ",
"Moreover, translation is reduced by stable secondary structures present in the 5′ UTR ([@bib1]). ",
"This is likely to explain the minor negative impact of GC content of the 5′ UTR on TEI because GC-rich sequences are more likely to form thermodynamically stable structures ([@bib36]; [@bib56]).",
"\n\nTranslatome enrichment of genes in different plant lineages {#s19}\n-----------------------------------------------------------\n\nTo consider GC content and TEI in the context of the evolutionary origin of rice genes, nontransposon genes were compared with genes from 12 other flowering plants and assigned to nonoverlapping plant lineages based on their placement within orthologous gene clusters generated with OrthoMCL. ",
"Genes in a lineage may have arisen in a specific evolutionary time frame. ",
"Classifications included genes conserved in all angiosperms (most ancestral), genes conserved between monocots and dicots (second ancestral), monocot-specific (third ancestral), Poaceae-specific (fourth ancestral), and rice (*O. sativa*)-specific genes (most recent) (see [Table S13](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS13.xlsx) for list of rice genes in each lineage). ",
"When the GC content of the CDS of gene transcripts of each lineage was profiled ([Figure 6A](#fig6){ref-type=\"fig\"}), genes conserved in all angiosperms had the lowest GC content, and the most recent genes (rice-specific) were associated with the highest fraction of GC-rich genes, indicating that the GC-rich module has been progressively enriched in the evolutionary history of rice. ",
"Notably, the GC-rich module is largely absent for transposable elements ([Figure 6](#fig6){ref-type=\"fig\"}), which explains why transposons have rather low TEIs compared to nontransposon genes. ",
"The fluctuation of the GC content among different gene lineages may reflect the variation in activity of different gene duplication mechanisms. ",
"For example, it is known that Pack-MULEs, which refer to *Mutator*-like transposable elements carrying gene or gene fragments, have been highly active recently in the rice genome and they specifically duplicate GC-rich gene fragments ([@bib31]). ",
"As a result, they may contribute to the high GC content of rice-specific genes. ",
"It is worthy of mention that, due to their ability to duplicate genes, Pack-MULEs have distinct GC content compared to other transposable elements ([@bib19]).",
"\n\n{#fig6}\n\nThe TEIs of genes in these different lineage groups were examined ([Figure 6B](#fig6){ref-type=\"fig\"}, [Figure S9](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/FigureS9.pptx), and [Table S13](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS13.xlsx)). ",
"In each lineage and in all three tissues, there is a broad range of TEIs ranging from near \"0\" to \\> 3. ",
"Consistent with our analyses based on GC content and the bimodal nature and enrichment of high GC content genes in rice, genes that are conserved among all angiosperms and those with overall lower GC content had the lowest fraction of genes with a TEI ≥ 1. ",
"This is also reflected in TEI distribution profiles; rice genes that are conserved in all angiosperms have a more discrete TEI distribution with a clear peak TEI value of ≤1, whereas all other rice genes have a broader TEI distribution regardless of whether they are restricted to monocots and dicots, monocot-specific, Poaceae-specific, or *O. sativa*-specific. ",
"Overall, these data suggest the evolutionarily recent genes in rice are more likely to be associated with ribosomes than core genes present in all angiosperms. ",
"Whether this is due to unique functions that arose through evolution or is a consequence of higher GC content found in rice and the Poaceae remains to be determined.",
"\n\nGenes involved in distinct biological processes are differentially enriched on ribosomes {#s20}\n----------------------------------------------------------------------------------------\n\nThe dramatic difference in TEI of different genes suggests that the translation process is tightly regulated; however, the functional relevance of such regulation is unclear. ",
"To this end, we examined the translatome enrichment of genes involved in different biological processes according to GO terms. ",
"The TEI values of genes for different processes vary significantly, with mean values ranging from 0.53 to 1.78 in shoots ([Table 4](#t4){ref-type=\"table\"} and [Table S14](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS14.xlsx)). ",
"Interestingly, the process that is associated with the highest TEI in shoots is translation itself, followed by DNA metabolic process and photosynthesis ([Table 4](#t4){ref-type=\"table\"}). ",
"Other processes associated with high TEIs are those involved in the generation of precursor metabolites and energy, cellular homeostasis, secondary metabolic processes, and the response to stress including both abiotic and biotic stresses. ",
"Most of these processes seem to be critical for the survival of the plants. ",
"The process associated with the lowest TEI is related to \"regulation of gene expression, epigenetic,\" followed by those involved in carbohydrate metabolism, lipid metabolism, growth, cell cycle and differentiation, protein modification, and multicellular organismal development ([Table 4](#t4){ref-type=\"table\"}), which might be less critical for survival. ",
"Importantly, the trend observed in shoots is also seen in calli and panicles except that in calli, photosynthesis is not among the top three processes ([Table S14](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS14.xlsx)). ",
"This is understandable since photosynthesis is not active in calli, suggesting that translation regulation may be dependent on cellular energy status. ",
"In general, the genes involved in processes with low TEIs are associated with moderate expression abundance (mRNA-seq FPKM values ranging from 17 to 46), while genes in processes with high TEIs could be associated with very high expression abundance (mRNA-seq FPKM values ranging from 28 to 449) ([Table 4](#t4){ref-type=\"table\"}).",
"\n\n###### Ten biological processes in which genes are associated with the highest and lowest TEI in rice shoots\n\n GO Term (Process) TEI mRNA-seq (FPKM)[*^a^*](#t4n1){ref-type=\"table-fn\"} TRAP-seq (FPKM) CDS size (bp)[*^b^*](#t4n2){ref-type=\"table-fn\"} 5′ UTR Length[*^b^*](#t4n2){ref-type=\"table-fn\"} CDS GC Content (%)[*^b^*](#t4n2){ref-type=\"table-fn\"}\n ----------------------------------------------------- ------- ---------------------------------------------------- ----------------- -------------------------------------------------- -------------------------------------------------- -------------------------------------------------------\n GO processes with high TEI \n Translation 1.78 69.6 173.6 956 (−59) 141 (34) 54.5 (8.6)\n DNA metabolic process 1.47 44.2 87.8 1183 (−133) 175 (47) 53.6 (9.0)\n Photosynthesis 1.47 430.9 986.3 1019 (−46) 138 (30) 59.6 (12.9)\n Generation of precursor metabolites and energy 1.36 190.3 387.5 1174 (−33) 168 (54) 57.1 (10.8)\n Cellular homeostasis 1.34 68.1 248.4 1207 (−36) 201 (60) 55.9 (10.5)\n Response to stress 1.31 48.0 67.9 1305 (−21) 200 (59) 56.5 (11.0)\n Response to abiotic stimulus 1.29 77.6 126.8 1294 (−17) 205 (59) 57.4 (11.5)\n Secondary metabolic process 1.27 26.4 32.3 1215 (−59) 160 (44) 61.0 (15.7)\n Biological process 1.22 27.6 37.0 1171 (12) 206 (60) 55.5 (10.5)\n Response to biotic stimulus 1.19 47.4 56.9 1385 (−86) 209 (66) 56.9 (11.1)\n Mean 1.37 103.0 220.4 1191 (−48) 180 (51) 56.8 (11.2)\n GO processes with low TEI \n Regulation of gene expression, epigenetic 0.53 16.9 10.2 2084 (−79) 207 (58) 47.7 (3.2)\n Carbohydrate metabolic process 0.73 43.3 42.6 1577 (−44) 222 (73) 54.8 (9.8)\n Lipid metabolic process 0.74 28.8 20.7 1383 (−32) 208 (54) 54.6 (9.9)\n Cell differentiation 0.86 20.8 18.1 1589 (−82) 238 (51) 54.5 (9.2)\n Protein modification process 0.86 28.8 42.1 1496 (−37) 270 (81) 52.3 (7.7)\n Cell cycle 0.87 16.7 13.7 1492 (−230) 247 (78) 51.0 (6.9)\n Catabolic process 0.90 44.5 45.2 1502 (−84) 220 (77) 52.6 (7.5)\n Cell growth 0.91 19.9 17.4 1560 (−92) 191 (36) 55.1 (9.5)\n Growth 0.92 22.5 21.2 1605 (−32) 245 (102) 53.6 (8.2)\n Multicellular organismal development 0.92 21.3 18.1 1556 (−91) 235 (63) 54.9 (9.8)\n Mean 0.82 26.3 24.9 1584 (−80) 228 (67) 53.1 (8.2)\n Genome-wide mean[*^c^*](#t4n3){ref-type=\"table-fn\"} 1.21 33.4 56.0 1208 212 55.6\n Difference with high TEI processes −0.55 −76.7 −195.5 394 (−33) 48 (16) −3.7 (−3.0)\n \\% Variation[*^d^*](#t4n4){ref-type=\"table-fn\"} 67.10 291.6 785.1 33.1 l26.7 7.0\n\nGO, gene ontology; TEI, translatome enrichment index; mRNA-seq, messenger RNA sequencing; FPKM, fragments per kilobase per exon model per million mapped reads; TRAP-seq, Translating Ribosome Affinity Purification followed by mRNA-sequencing; CDS, coding sequence; UTR, untranslated region.",
"\n\nOnly processes with 40 or more genes are considered. ",
"The values are mean values in each process.",
"\n\nNumbers in parentheses indicate difference compared with the corresponding *Arabidopsis* processes.",
"\n\nGenome-wide mean of 5′ UTR is derived from nontransposon genes with TEI in shoots and UTRs ≥ minimum (20 bp for 5′ UTR and 110 bp for 3′ UTR).",
"\n\n%Variation equals difference divided by the lower values of the two means, then times 100.",
"\n\nConsistent with the analyses above, a large portion of the variation in TEI of genes in different processes can be attributed to the properties of the transcripts. ",
"All features (TEI, mRNA-seq level, TRAP-seq level, CDS size, 5′ UTR length, and GC content of CDS) described in [Table 4](#t4){ref-type=\"table\"} are significantly different between the genes with high TEIs and low TEIs (KS test, *P* \\< 0.0001). ",
"In general, genes with high TEIs have short CDS, a short 5′ UTR, and high GC content in coding regions ([Table 4](#t4){ref-type=\"table\"}). ",
"Conversely, genes involved in the processes with low TEIs are longer than average (both CDS and 5′ UTR) and the GC content is lower than average ([Table 4](#t4){ref-type=\"table\"}). ",
"Finally, the GC content of 5′ UTRs is not significantly different between the high TEI and low TEI groups (59.0 *vs.* 59.5, KS test, *P* = 0.56) ([Table S14](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS14.xlsx)). ",
"The GC content of 3′ UTRs is only slightly different (39.2 *vs.* 39.7 KS test, *P* = 0.06). ",
"Again, this is consistent with the notion that the GC content of UTRs is associated with a minor influence on translation in rice.",
"\n\nRelationship between codon usage bias, recombination rate, and TEI {#s21}\n------------------------------------------------------------------\n\nAs discussed above, the preferential association of GC-rich transcripts with ribosomes could be due to the physical property of the transcript, such as secondary structure. ",
"Nevertheless, it could be also due to preference on codon usage, which is often linked to tRNA abundance. ",
"It has been well established that codon usage differs among and within organisms, which is referred to as codon usage bias ([@bib3]). ",
"Studies showed that highly expressed genes exhibited high codon bias in *Escherichia coli*, *Caenorhabditis*, *Drosophila*, and *Arabidopsis* ([@bib16]; [@bib69]). ",
"To determine whether the codon usage bias is associated with differential ribosomal enrichment, the codon usage of genes with the extremely low (\\<0.2) and extremely high (≥3) TEIs were compared in shoots. ",
"As shown in [Table S15](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS15.xlsx), all 18 amino acids with multiple synonymous codons exhibited different codon usage frequency. ",
"Overall, genes with low TEIs showed a minor preference to codons with A/U at the third codon position whereas those with high TEIs had extremely significant bias toward G/C at the third codon position. ",
"Further dissection of codon usage revealed that base composition of the first codon position also plays a role toward the usage bias ([Table S16](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS16.xlsx)). ",
"For all four pairs of synonymous codons differing only at the first codon position, genes with high TEIs showed significant preference to C than to A/U. The pair with the most dramatic difference is CUG *vs.* UUG for leucine, where the ratio of these two codons increased from 0.83 for low TEI genes to 4.75 for high TEI genes ([Table S16](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS16.xlsx)). ",
"The impact of codon composition at the third codon position was also further investigated. ",
"In addition to the general preference for G/C for high TEI genes, the frequency varies between G and C ([Table S16](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS16.xlsx)). ",
"For some pairs of synonymous codons, G is more preferred to C in high TEI genes (*e.g.*, the ratios between CCG and CCC for proline is 0.95 for low TEI genes and 1.77 for high TEI genes). ",
"Other pairs demonstrate the opposite trend (*e.g.*, the ratios between CUG and CUC for leucine declines from 1.16 for low TEI genes to 0.68 for high TEI genes). ",
"Different frequency is also observed for codons with A and U at the third codon position ([Table S16](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS16.xlsx)). ",
"Among nine pairs of synonymous codons with A *vs.* U at the third codon position, five pairs showed significant usage bias between low and high TEI genes (*P* \\< 0.05). ",
"The codon discrimination between G and C as well as between A and U at the third codon position clearly suggests that codon usage plays a role in differential association of transcripts with ribosomes.",
"\n\nThe significant correlation between GC content and TEI suggests that the emergence of GC-rich genes in grasses could be a result of selection for translation efficiency. ",
"However, other factors have been proposed to be responsible for the evolution of the GC content of genes. ",
"gBGC is a process that results in gene alleles with G/C at heterozygous sites being preferentially retained compared with alleles with A/T at heterozygous sites during recombination, which would lead to a high GC content at regions with high recombination rates. ",
"Recently, a large body of evidence suggested that gBGC is likely a major force in shaping chromosomal base compositions in both plants and animals ([@bib17]; [@bib59]; [@bib63]). ",
"To test if the GC content of genes is associated with the genetic recombination rate in rice, we used the local recombination rate from a previous study ([@bib73]) and compared it with CDS GC content and TEI. ",
"A negligible correlation (correlation coefficient = 0.03, *P* \\< 10^−4^) was detected between the GC content of CDS and the recombination rate in rice, which was in contrast to the situation observed in *Gallus gallus*, where GC content was well correlated with recombination rate (correlation coefficient = 0.89, *P* \\< 10^−4^) ([@bib59]). ",
"This is consistent with the results from previous studies showing a lack of significant correlation between GC content and recombination rate in rice ([@bib59]; [@bib73]). ",
"Moreover, the influence of recombination rate on TEI seems to be even more minor (correlation coefficient = 0.019801, *P* = 0.01526). ",
"Accordingly, it is unclear whether gBGC has played a major role in shaping the GC content of genes in rice. ",
"Nevertheless, it should be noted that the recombination map that is used in this study contains \\< 4000 markers, which is insufficient to distinguish the recombination rate of individual genes. ",
"Future studies with higher resolution recombination maps will facilitate our understanding of the contribution of gBGC to GC content evolution in rice. ",
"In addition, the contribution of selection on translation efficiency and gBGC to GC content variation could be complimentary instead of mutually exclusive. ",
"It is possible that GC-rich sequences were generated through gBGC and were retained because of their advantage in translation.",
"\n\nConservation and divergence of translational features in rice and Arabidopsis {#s22}\n-----------------------------------------------------------------------------\n\nTo test whether the differential enrichment of transcripts on ribosomes is present in other plants, a comparative analysis was conducted using the data from *Arabidopsis* seedlings growing under standard conditions on MS media ([@bib33]). ",
"To make the two datasets as comparable as possible, our analysis only included the *Arabidopsis* genes that correspond to genes used for GO term analysis in rice (see *Materials and Methods* for details). ",
"The relative order of TEI among genes in different biological processes is largely conserved between the seedlings of *Arabidopsis* and shoots of rice. ",
"For example, 9 of the top 10 processes with the highest TEI are shared in the two species, including photosynthesis, translation, generation of energy, cellular homeostasis, and responses to stresses ([Table 4](#t4){ref-type=\"table\"} and [Table S17](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS17.doc)). ",
"Similarly, 7 of the 10 processes with the least enriched transcripts on ribosomes are shared between the two species ([Tables 4](#t4){ref-type=\"table\"} and [Table S17](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS17.doc)), suggesting that divergent plants prioritize their biological processes similarly at the translational level.",
"\n\nAlthough the relative order of transcript enrichment on ribosomes is largely conserved between *Arabidopsis* and rice, the degree of variation is quite different. ",
"In *Arabidopsis*, the mean TEI ranges from 0.91 to 1.14 (22% variation, [Table S17](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS17.doc)) for different processes, whereas that for rice is from 0.53 to 1.78 ([Tables 4](#t4){ref-type=\"table\"} and [Table S14](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS14.xlsx)), with over threefold variation. ",
"The variation in CDS size as well as in 5′ UTR length between high TEI and low TEI processes is rather comparable between rice and *Arabidopsis* (33 *vs.* 32%, 27 *vs.* 20%, [Table 4](#t4){ref-type=\"table\"} and [Table S17](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS17.doc)). ",
"In contrast, the variation of GC content of CDS is considerably higher in rice than that in *Arabidopsis* (7.0 *vs.* 1.7%). ",
"Genome-wide, the TEI of genes in *Arabidopsis* demonstrates a nearly normal distribution, with a maximum fraction of genes around 1.0 ([Figure 7](#fig7){ref-type=\"fig\"}). ",
"Most genes (over 80%) are associated with a TEI ranging from 0.6 to 1.4; only a small portion of the genes (∼2%) are associated with a TEI ≥ 2 ([Figure 7](#fig7){ref-type=\"fig\"}). ",
"Furthermore, there is little variation in the GC content of CDS in different TEI bins in *Arabidopsis*. ",
"In contrast, distribution of the TEI in rice is widely dispersed. ",
"Less than 40% of the genes are associated with a TEI of 0.6--1.4, and 17% of the genes are associated with a TEI ≥ 2. ",
"Moreover, the GC content and GC3 content (GC content of the third codon position) of CDS of rice genes progressively increases as the TEI does ([Figure 7](#fig7){ref-type=\"fig\"}). ",
"As a result, the variation of GC content of genes in rice could contribute to the more dramatic variation of TEIs observed in rice. ",
"It should be pointed out that the *Arabidopsis* and rice plants were not grown under exactly the same conditions and were not sampled at equivalent developmental stages. ",
"Nevertheless, highly similarly trends were observed among three distinct rice tissues, so it is unlikely that the dramatic difference in TEI distribution between *Arabidopsis* and rice is solely due to tissue or developmental specificity.",
"\n\n{#fig7}\n\nOn average, the CDS of rice genes is about 10% more GC-rich than that in *Arabidopsis* (55.6 *vs.* 45.1%, [Table 4](#t4){ref-type=\"table\"} and [Table S17](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS17.doc)), and GC-rich genes are associated with stronger codon usage bias ([@bib18]). ",
"If the GC content of individual processes is examined, the increase of the GC content of rice genes (compared with that of *Arabidopsis*) in all the processes with low TEIs is less than the average value ([Table 4](#t4){ref-type=\"table\"}). ",
"In contrast, genes in 8 out of the 10 GO categories with high TEIs are associated with a GC content increase equal to or higher than average ([Table 4](#t4){ref-type=\"table\"}). ",
"The two exceptions are genes in translation and DNA metabolism; nevertheless, genes that encode proteins that function in translation have the smallest coding region in rice, and genes in DNA metabolism have experienced the largest reduction in CDS size (from *Arabidopsis* to rice) compared to other genes ([Table 4](#t4){ref-type=\"table\"}). ",
"As a consequence, in most cases the high TEI in rice is correlated with increased GC content of CDS but could be due to the relatively small size of genes. ",
"Again, it should be noted that high TEI does not necessarily mean high protein abundance; however, if GC-rich or short mRNAs are more likely associated with ribosomes, it may increase the competition for GC-poor or long mRNAs to be translated due to limited availability of the translation machinery.",
"\n\nA strong example of such a relationship is the genes involved in \"regulation of gene expression, epigenetic\" (GO: 0040029) process. ",
"The genes in this process are associated with the largest and comparable mean CDS size in both *Arabidopsis* and rice (2163 and 2084 bp, respectively, [Table 4](#t4){ref-type=\"table\"} and [Table S17](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS17.doc)). ",
"In *Arabidopsis*, the mean TEI of genes in this process is 0.92 whereas in rice it is 0.53 ([Table 4](#t4){ref-type=\"table\"} and [Table S17](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS17.doc)). ",
"In rice, genes in all other GO categories have a substantially higher GC content (compared to their counterparts in *Arabidopsis*), ranging from 7 to 16% ([Table 4](#t4){ref-type=\"table\"}). ",
"In contrast, the GC content difference between *Arabidopsis* and rice genes associated with epigenetic regulation of expression was only 3%. ",
"In addition, genes associated with this GO category had the lowest average GC content (47.7%) among all GO-associated rice genes ([Table S14](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS14.xlsx)). ",
"The extremely low GC content of those genes is associated with the lowest mean TEI in rice and this was observed in all three rice tissues (mean TEI = 0.53, 0.60, 0.46 in shoots, calli, and panicles, respectively, [Table S14](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.020040/-/DC1/TableS14.xlsx)). ",
"Since genes that function in epigenetic regulation are responsible for the regulation of transposable element activity, it raises the question whether the compromise in translation of these genes in rice has contributed to the high degree of amplification of transposable elements in rice compared to *Arabidopsis* ([@bib28]; [@bib72]). ",
"Future analysis is required to test this hypothesis.",
"\n\nConclusions {#s23}\n-----------\n\nIn this study, we provide a genome-wide analysis of the translation status of genes in rice. ",
"Based on our analysis, it is clear that, for individual gene transcripts, the fraction that is ribosome-associated can vary dramatically. ",
"In rice, a large portion of the variation can be attributed to the length and the GC content of the coding region, suggesting that the evolution of GC-rich genes in monocots (especially in grasses) may be associated with an advantage in translation. ",
"In addition, UTRs, especially 5′ UTRs, play a critical role in translation. ",
"Small genes are preferentially associated with ribosomes; however, if the transcript has a 5′ UTR that is longer than 400 bp, the favorable effect of the short transcript is masked by the inhibitory effect of a long 5′ UTR.",
"\n\nGenes encoding proteins associated with different processes are differentially enriched on ribosomes. ",
"Genes involved in processes that are critical for plant survival, such as those related to photosynthesis, translation, and stresses responses, are more likely associated with ribosomes. ",
"Compared to corresponding translation status in *Arabidopsis*, mRNAs in rice have a more dramatic variation of TEI, which may result in differential regulation at the translational level that could be linked to phenotypic diversity. ",
"The wide variation of TEI in rice is correlated with more substantial variation of the GC content of genes, which is largely due to the emergence of GC-rich genes after the formation of angiosperms. ",
"Clearly, genes in different biological processes evolve differentially in terms of GC content, which may alter the dynamics of the relative translation efficiency of these processes. ",
"Since high TEI genes demonstrate an extraordinary bias toward GC-rich codons, it is likely that the genes in critical biological processes are more likely to retain AT to GC mutations. ",
"However, from this study, it is unclear whether AT to GC mutations are more frequently generated in some genes than in other genes, through processes such as gBGC. ",
"Future analysis with high resolution recombination maps will determine the role of gBGC in GC content evolution in rice. ",
"Despite the uncertainty of sources of GC biased mutation, we demonstrated that the low GC content of genes in epigenetic pathways in rice may be disadvantageous for their translation.",
"\n\nFuture experimentation is required to test whether an enhanced TEI value is associated with greater protein production. ",
"If it is, factors that impact TEI can be utilized for future crop engineering. ",
"For example, more efficient translation of a target gene can potentially be achieved by using optimal (high frequency codons found within genes with high TEI) codons or minimizing the 5′ UTR. ",
"For genes with very short coding regions, a 3′ UTR with an appropriate length is beneficial for its translation. ",
"It should be noted that, in this study, the observations are made based on only three rice tissues, with two of them (callus and young panicle) composed of a mixture of rather divergent cells. ",
"Experiments with more tissues, especially those from more specialized organs, will reveal whether translational regulation is controlled in a tissue-specific fashion. ",
"In addition, all experiments conducted in this study are under standard growth conditions, and it will be intriguing to study the impact of environmental factors on translation such as the inhibition of translation initiation under hypoxia stress in *Arabidopsis* ([@bib33]). ",
"Furthermore, it would be interesting to test where the RI transcript isoforms are located (nucleus or cytoplasm) and whether their relative abundance is reduced under stressed conditions.",
"\n\nSupplementary Material {#S13}\n======================\n\nSupplemental material is available online at [www.g3journal.org/lookup/suppl/doi:10.1534/g3.116.036020/-/DC1](http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.116.036020/-/DC1).",
"\n\n###### \n\nClick here for additional data file.",
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"\n\n###### \n\nClick here for additional data file.",
"\n\n###### \n\nClick here for additional data file.",
"\n\nWe are grateful to Yinong Yang and Chuansheng Mei for providing the vector pCAMBIA1300S and Takeshi Fukao for preparing the RPL18 cDNA from rice. ",
"We thank Kevin Childs and Tiffany Liu for providing custom scripts for calculation of codon usage frequency. ",
"This study is supported by National Science Foundation grants MCB-1121650 (Y.C., J.J., C.R.B., and N.J.) and DBI-1238243 (J.B.-S.). ",
"It is also supported by the US Department of Agriculture National Institute of Food and Agriculture and AgBioResearch at Michigan State University.",
"\n\nCommunicating editor: E. Akhunov\n"
] | {
"pile_set_name": "PubMed Central"
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"Food Meat Burger Vegetables\n\nIf it is helpful to you, please share with your friends. ",
"Our team was selected carefully before show at here. ",
"In addition, you can also thank for them by inviting them one cup of Coffee.",
"\n\nOur contributor was tagging for this image: Burger, Food, Meat, Vegetables. ",
"It is our selection and stored in the category \"Food/Drink\". ",
"resolution of picture 2730×1536 pixels, you can download it with JPEG format."
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[
"Share\n\nIn 2008:60 journalists were killed1 media worker was killed673 journalists were arrested929 were physically attacked or threatened353 media outlets were censored29 journalists were kidnapped\n\nInternet:1 blogger was killed59 bloggers were arrested45 bloggers were physically attacked1,740 websites were blocked, shut down or suspended\n\nBy comparison, in 2007:86 journalists were killed20 media workers were killed887 journalists were arrested1,511 journalists were physically attacked or threatened528 media outlets were censored67 journalists were kidnapped\n\nReporters Without Borders only counted cases in which a link between the violation and the victim's work as a journalist was clearly established or very likely. ",
"The figures cover the violations the organisation learned about. ",
"They do not cover violations which the victims chose not to report (usually for security reasons). ",
"In other words, the same method was used to compile the figures as in previous years, making comparisons possible.",
"\n\nOverview\n\nThe Asia-Pacific and Maghreb-Middle East regions are still the deadliest for the press. ",
"After Iraq (with 15 journalists killed), the two countries with the highest death tolls are Pakistan (7 killed) and the Philippines (6 killed). ",
"The bloodshed continues in Mexico, where four journalists were murdered in connection with their work. ",
"The fall in the death toll in Africa (from 12 in 2007 to 3 in 2008) is due above all to the fact that many journalists stopped working, often going into exile, and to the gradual disappearance of news media in war zones such as Somalia.",
"\n\nThe number of arrests (for periods of more than 48 hours) is particularly high in Africa, where it is almost routine for journalists to end up in police cells when they upset senior officials or cover subjects that are off-limits. ",
"In Iraq (31 arrests), the US military's handling of the security situation often results in Iraqi journalists, including those working for foreign news media, being imprisoned. ",
"In China (38 arrests), many cases of detention were attributable to the Olympics. ",
"In Burma (17 arrests), outspoken journalists and bloggers were jailed in a crackdown by the military government.",
"\n\nReporters Without Borders comment:\n\n\"The figures may be lower than last year's but this should not mask the fact that intimidation and censorship have become more widespread, including in the west, and the most authoritarian governments have been taking an even tougher line. ",
"The quantitative improvement in certain indicators is often due to journalists becoming disheartened and turning to a less dangerous trade or going into exile. ",
"We cannot say that 60 deaths, hundreds of arrests and systematic censorship offer grounds for optimism.\"",
"\n\nRepression shifts to the Internet\n\nThe fall in the number of journalists from the traditional media killed or arrested in 2008 does not mean the press freedom situation has improved. ",
"As the print and broadcast media evolve and the blogosphere becomes a worldwide phenomenon, predatory activity is increasingly focusing on the Internet.",
"\n\nIn this respect, the figures speak for themselves. ",
"In 2008, someone was, for the first time, killed while acting as a \"citizen journalist.\" ",
"It was Chinese businessman Wei Wenhua, who was beaten to death by \"chengguan\" (municipal police officers) while filming a clash with demonstrators in Tianmen (in Hubei province) on 7 January. ",
"Cases of online censorship were recorded in 37 countries, above all China (93 websites censored), Syria (162 websites censored) and Iran (38 websites censored).",
"\n\nThere are democracies that do not lag far behind in terms of online surveillance and repression. ",
"Taboos established by the monarchy in Thailand and by the military in Turkey are so tenacious that incautious Internet users are increasingly being monitored and punished by the police. ",
"Video-sharing websites such as YouTube and Dailymotion are favourite targets of government censors. ",
"It is becoming more and more common for sites to be blocked or filtered because of content that officials have deemed \"offensive.\" ",
"A visceral reaction from some governments towards participatory websites, especially social networking sites, is beginning to give rise to cases of \"mass censorship.\" ",
"The censorship of sites such as Twitter (in Syria) or Facebook (blocked in Syria and Tunisia, and filtered in Turkey and the United Arab Emirates) leads to massive amounts of content being blocked - an effect that is considerably compounded when combined with other standard methods of control.",
"\n\nGovernments are increasingly using imprisonment as a response to criticism by bloggers. ",
"In China, 10 cyber-dissidents were arrested, 31 were physically attacked or threatened, and at least three were tried and convicted. ",
"In Iran, Reporters Without Borders registered 18 arrests, 31 physical attacks and 10 convictions. ",
"Online free expression is also curtailed in Syria (8 arrests and 3 convictions), Egypt (6 arrests) and Morocco (2 arrests and 2 convictions).",
"\n\nInternet freedom has been crushed with particular severity in Burma, where the military government has arrested and tried blogger and comedian Zarganar and the young cyber-dissident Nay Phone Latt in a disgraceful manner and sentenced them to incredibly severe jail terms (59 years for the former, 20 years for the latter). ",
"These two men join Burma's many other political prisoners, who include 16 journalists.",
"\n\nReporters Without Borders comment:\n\n\"The growth in the Internet's influence and potential is being accompanied by greater vigilance on the part of some governments with already marked security concerns. ",
"Every year, repressive governments acquire new tools that allow them to monitor the Internet and track online data. ",
"The Internet is gradually becoming a battleground for citizens with criticisms to express and journalists who are censored in the traditional media. ",
"As such, it poses a threat to those in power who are used to governing as they wish with impunity.\"",
"\n\nIFEX publishes original and member-produced free expression news and reports. ",
"Some member content has been edited by IFEX. ",
"We invite you to contact [email protected] to request permission to reproduce or republish in whole or in part content from this site."
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" #\n#####################################################\n\n### deb\n\n# This port was possible thanks to the invaluable help of ipdev99 and xxhoeckyxx.",
"\n\ndevice_checkDevice() {\n\n checkTool getprop\n\n case \":$(getprop ro.product.device):$(getprop ro.build.product):\" in\n *:deb:*) ;;\n *)\n fatal \"this package is for '$deviceName' devices; this device is '$(getprop ro.product.device)'\"\n ;;\n esac\n\n}\n"
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"This invention relates generally to surgical tools and specifically to a novel surgical tool that includes a powered rotary work wheel.",
"\nConventional surgical tools, such as scalpels, have been miniaturized to enable a surgeon to perform minute incisions, often in closely confined areas. ",
"A major drawback of such cutting tools is that the surgeon must supply the required cutting action by using a reciprocal sawing or slicing motion. ",
"Consequently, even miniature tools are restricted to exposed areas of the body to which the surgeon has access or to areas that have been exposed by major surgery. ",
"Miniature scissors are frequently used in confined areas because their action traps the tissue as it is being snipped. ",
"However, they are difficult to control and leave a jagged incision due to the multiple cuttings required.",
"\nA surgical cutting tool that is powered by a remote motor means, and which therefore removes the necessity for the surgeon to provide the cutting action, is described in U.S. Pat. ",
"No. ",
"5,059,203, issued Oct. 22, 1991 to Royce H. Husted. ",
"All the surgeon need do is guide the tool since it is powered remotely. ",
"The drive system of the patented tool uses a monofilament line for driving a work wheel to which a rotary cutting blade is affixed. ",
"The present invention incorporates an inproved drive system for powered surgical tools."
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"\n\nYour Co-founder is Much More than Just a Business Partner - rishtal\nhttp://www.rishtal.com/post/29474760589/your-co-founder-is-much-more-than-a-business-partner\n\n======\nrdegges\nI've got lots of friends in tech startups (all programmers), and one thing I\nhear over and over again is how much they hate their cofounders.",
"\n\nA lot of the time, information like that isn't really made public through\nblogs and such, so reading articles like this which enumerate the ways in\nwhich your cofounder and yourself should get along are nice, as they help\nprevent issues in the future.",
"\n\nMy current cofounder is great. ",
"We talk often, debate about various technical\nand non-technical topics, and keep each other interested in our projects and\nsuccess.",
"\n\nI think more than anything, having a cofounder who can keep you interested in\nyour work and daily struggles is the best kind, as motivation is one of the\nhardest resources to come by.",
"\n\n~~~\nrishtal\nWell said! ",
"Thanks for reading and glad you could relate to the post.",
"\n\n------\nzio99\n\"Get comfortable with being uncomfortable\" was the best advice I've heard.",
"\nPrecisely why we should team up with co-founders that push our boundaries and\nbring out the best in us.",
"\n\n~~~\nrishtal\nYeah, that is sound advice. ",
"It is easier said than done but the first step is\nto realize that and then face it. ",
"Thanks for reading! ",
"I appreciate it.",
"\n\n"
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