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Raqqa – Under the guidance of the Civil Council, the Reconstruction Committee is continuing its work in rehabilitating the water lines and connecting them to the city in a healthy and sound manner to ensure that the pure water for the safety of the citizens. After all kinds of pipes and spare parts were available, work became better with alternative to damage. Director of the Water and Sanitation Project Abdullah Al-Omar told us about the work mechanism of the Reconstruction Committee in Raqqa on the water project. He said that the project was actually started on 2018/6/20 to secure the basic requirements of the project including spare parts and plastic pipes of all sizes and connections and securing sufficient number of workers who are experienced in the extension of water pipes and sufficient vehicles to ensure the cleanliness of the land of mines planted by a terrorist on the roads. “The water was connected to the main lines and all the neighborhoods of the city on 2018/7/31. Today, the work has begun on repairing the small problems by informing the committee by the people. Director of the Water and Sanitation Project Abdullah Al-Omar said”: water delivery to the upper floors due to poor water pressure, and he confirmed and said in the coming days it will be increased water pressure to deliver water to the upper floors, when we finish from increasing the pressure, we have finished the last stage and water will be in all Houses of Raqqa. SDF, Media Center	{ "pile_set_name": "OpenWebText2" }
You just layed new clothes out? i'll just sit on them and make them all hairy 134 shares	{ "pile_set_name": "OpenWebText2" }
According to Matt Kindt who talked with CBR about the new series, each issue will feature a major character (Han, Luke, Leia and Chewbacca) with the characters being described and followed by a new character. Thus it's a way of seeing the characters from a new light. Quote: CBR News: Much has been made out of your busy writing schedule as of late, so presumably a "Star War" miniseries was something you were uniquely interested in. Are you a big Star Wars fan? Matt Kindt: Yeah, I was like 4 or 5 when the first one came out. That was one of my earliest memories, seeing it in the theater, and people being dressed up in the theater -- the theater workers were actually dressed up. It's kind of a scary memory, because I was pretty young, but it definitely stuck with me. [Laughs] I've always been a fan. [Dark Horse] asked me if I wanted to do something, and I was like, "I don't know" -- partly because I'm so busy. "Man, I really don't have time, as much as I want to do it." I need to learn how to say no. I was like, "This is going to be a good test for me, if I say no to writing a Star Wars comic, which is ridiculous," because growing up with it I was like, "Man, that would be my dream come true." I got myself into such a busy schedule this summer, so I told them no. Then, the next day, I was taking a shower or something, and I just had an idea. "That's what I could do!" I wasn't trying to think of an idea for it; an idea just popped into my head. So I called them back the next day. "If it can't be this, I don't know if I have time to think of another thing." They were really great about it. It seems like a tricky prospect, with Star Wars especially, and a story set in the timeline of the original trilogy -- there's so much territory covering that era, so many novels and comics and stories told in that time period -- that going into it has to be almost intimidating, figuring out what you're going to do. Yeah, that was why it was kind of easy for me to be like, "No, I'm too busy." It's a combination of all the worst things I hate about properties that I don't own. [Laughs] A rabid fanbase, huge amounts of continuity, all this history. As much as I love it, I'm not steeped in Star Wars mythology. Since I was a kid, I was like, "If it didn't happen in the movies, it didn't happen." Other than the movies, that's what I draw from. This was definitely intimidating, and if this idea hadn't literally dropped in my lap, I wouldn't have done it. Honestly, the idea came from my reverence for those characters. I guess I was inspired by the intimidation factor of those characters. I thought, "How great would it be to do a series where you get to see Han Solo from a regular dude's point of view?" Which is basically my point of view! What if I got to tag along with Han Solo, and we had to do some mission for the rebellion? What would that be like? I thought something like that would be awesome. So that was the springboard. It would be cool to have four core characters, and each issue would play with that idea -- Princess Leia and a spy character who she teams up with, but it's all from the point of view of the character Princess Leia teams up with. Viewing Princess Leia, viewing Han Solo, viewing Chewbacca, viewing Luke through the guise of a normal dude. Han Solo is like the coolest character ever, so it was fun to write that, where this guy's sort of starstruck by him -- just like I would be. Then they've got this mission to do, and doing a real mission where everything's on the line, and your life is in danger -- by the end of that issue, Han Solo's not so cool anymore. This guy's scared out of his mind. Han Solo's kind of reckless. That was my way in, almost viewing those characters in a childlike way, like I did when I was a kid, and you look up to Han Solo as the coolest. It was easy to write after that. So it's a different new character in each issue, paired up with one of the established figures? Yeah. There's a different character in each one, and there's a narrator that pulls you through the story. Each issue is centered on one of the main characters. They're all tied together, though. Without spoiling too much, the fourth issue it all comes together, and you realize all these separate missions are part of something bigger. Like Han and Leia and Chewie they are actually separate from each other, but they're all working together towards some secret mission -- that kind of spoils it a little bit. [Laughs] How's it been, working with artist Marco Castiello thus far? He turned in [his] first page, a splash page of Han Solo -- he totally cheated, he skipped ahead to draw the coolest page. [Laughs] It looks good. It's going to be good. Source: http://www.comicbookresources.com/?page=article&id=49918_________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood Posted: Fri Dec 27, 2013 10:06 pm Message Darth_HenningMaster Joined: 12 Apr 2011Posts: 535Location: Canada nteresting premise. I really like the idea of seeing the Big3 through the eyes of the more average rebel soldier. That's a new take on the franchise. Similarly, splitting them up, even if they're working towards a common goal brings an interesting dynamic to the story that I don't believe we've seen in Star Wars before. I hope the focus is more on the 'average rebel' than the big3, but that's most likely a pipe dream. (Would be nice to get something between ANH and ESB that didn't focus on the big3 actually though) However, his comment "If it didn't happen in the movies, it didn't happen." scares me significantly about what additional continuity problems this might cause (see Star Wood). By the sounds of it, it will only occur over a few days or so, so can still be squeezed into the ANH-ESB timeline (perhaps in 2 ABY which is much more empty), crammed as it is, but hopefully Leland takes a look at it._________________ A young Rebel meets one of the Alliance’s best for his first mission. But the young man’s hero worship is crushed by the reality of Han Solo. A botched escape, a ship that doesn’t work—could it be that Solo is just a lucky bumbler whose luck has run out? _________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood Posted: Tue Jan 14, 2014 9:51 am Message Taral-DLOSMaster Joined: 23 Nov 2010Posts: 1743Location: Ontario, Canada I'm not the least bit interested. Also, I didn't see the thread for this, so could an admin lock the one I made a few days ago (when the solicit information came out)?_________________"I'm...from Earth." I always look forward to more Star Wars comics. I'm not a fan of Matt Kindt's artstyle, but he won't be handling the interior art for this series. Then again, Marco Castiello did Knight Errant: Escape, which I wasn't a big fan of artwise._________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood Posted: Sat Mar 15, 2014 12:45 pm Message Darth SkuldrenModerator Joined: 04 Feb 2008Posts: 6580Location: Missouri Cover art for 'Rebel Heist #3' Han Solo is in an Imperial jail, and a crime boss has the information that will free him. Enter Chewbacca, who pounds and pummels his way through the mission, accompanied by an untrusting ex-Imperial who can’t understand a word Chewie says. Not that words matter much to a Wookiee on a rampage! • Covers by Adam Hughes and Matt Kindt! Release Date: June 25 Details: FC, 32 pages, $3.50_________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood Posted: Thu Apr 24, 2014 7:29 am Message Darth SkuldrenModerator Joined: 04 Feb 2008Posts: 6580Location: Missouri Cover art for issue #4. Quote: Rebel Heist #4 (of 4) The Rebellion’s plan is coming together. All Luke Skywalker has to do is elude an Imperial spy—and perform some unanticipated rescues! But this farm boy is on the edge of greatness, and he is not about to stop saving the galaxy now! • Matt Kindt writes the Leia, Han, and Luke from the classic era of Star Wars! _________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood Posted: Wed May 28, 2014 9:29 am Message Darth SkuldrenModerator Joined: 04 Feb 2008Posts: 6580Location: Missouri Rebel Heist #2 is out today and stars Leia and also feature a female Rebel agent named Sarin. Pretty good issue. I liked this one a lot better than issue #1._________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood Posted: Sat May 31, 2014 4:14 pm Message Murray1134Padawan Joined: 16 Jan 2012Posts: 94Location: Roanoke, VA Issue #1 was a bit weird, but this one was really good. This is a very original series. Looks like Dark Horse is going out with a bang._________________EUCantina Comic Book Reviewer "That's just my opinion, I could be wrong" TK-5990 www.FanboysTalking.com Posted: Sat May 31, 2014 4:33 pm Message 1337JediKnight Joined: 02 Sep 2012Posts: 496Location: Florida I think the end of issue #2 is a secret introduction to Hera the pilot in Rebels. An much better issue than the last, it's nice to see a fresh way to tell stories about the big 3_________________Mara: "Not many people Dare to hug me" Lando: "That leaves more of you for me then!" "Sure I can't move a rock with my mind, but, boy can I make that rock think its been moved." Posted: Mon Jun 02, 2014 7:59 am Message Darth SkuldrenModerator Joined: 04 Feb 2008Posts: 6580Location: Missouri Yeah, issue #1 was very weird. I'm still not sure if they meant for Han Solo to look like an incompetent blow hard or if it's a trick and we'll eventually see this was all part of his plan._________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood Posted: Mon Jun 02, 2014 8:28 am Message Mad WookKnight Joined: 14 Apr 2011Posts: 464 Surely this will all come around and it will show what a genius Han is by the end. Posted: Mon Jun 02, 2014 11:31 am Message Skywalker2BKnight Joined: 15 Nov 2013Posts: 127 Decent story, but still non-canon. The only thing DH is doing that is canon is the Darth Maul story. Posted: Tue Jun 03, 2014 11:07 am Message Darth SkuldrenModerator Joined: 04 Feb 2008Posts: 6580Location: Missouri Well it doesn't matter if it's canon to me. I certainly enjoyed the Tales stories and those weren't canon. One of the funniest Star Wars comics I ever read was Fett Club._________________ "I believe toys resonate with us as humans, we can hold them them, it's tactile, real! They are totems for our extended beliefs and imaginations. A fetish for ideas that hold as much interest and passion as old religious relics for some. We display them in our homes. They show who we are. They are signals for similar thinking people. A way we connect with each other...and I guess thats why I do toys. That connection." -Ashley Wood	{ "pile_set_name": "Pile-CC" }
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Q: va_arg returns only parts of my integer I am trying to write my own va_args functions for the first time and I am having a problem that large integers (still within the range of int) are getting truncated to 3 digits, and out of order! Here is the implementation void __sprintf(char * _string, ...) { int i = a_sizeof(_string); char _arg; int j =0; int format = 0; va_list args; va_start (args,_string); for(; j < i; j++) { if(_string[j] == '\0') break; else if(_string[j] == '%') { format=1; continue; } else if(format==1) { switch(_string[j]) { case 'd': _arg = va_arg(args,int); printi(_arg); //Prints integers over serial by converting to ASCII break; default: continue; } format = 0; } else SerialPutChar(_string[j]); } va_end(args); } What I get when I try __sprintf("%d %d %d\n",32141,6400,919911); is 141 32 then it exits. I have set break points and sometimes it looks like Im getting total crap passed. Suspicions: IAR's implementation of stdarg complete bone-head miss-use of va_arg missing fine-print details (which are probably in bold 14pt but no one reads it anyway) Thanks in advance! A: You have declared char _arg instead of int _arg, therefore the "truncation" of the integer values.	{ "pile_set_name": "StackExchange" }
Sky Gate Bridge R , also known as the , serves as a link between the mainland of Osaka, Japan to the artificial island in Osaka Bay on which Kansai International Airport is built. It is the longest double-decked truss bridge in the world. The bridge carries six lanes of automobile traffic on top and two of rail below, over nine truss spans. Structural specifications The Sky Gate Bridge is a continuous truss bridge that measures 3,750 meters long, 29.5 meters wide (6 lanes), and 25 meters at its highest point in the center. History The bridge commenced construction in June 1987, and was completed in March 1994. On 21 April 2009, management of the expressway portion of the bridge was handed over to the West Nippon Expressway Company. This expressway was numbered E71 alongside the Kansai-Kūkō Expressway in 2016. Typhoon Jebi The bridge was damaged on 4 September 2018, by Typhoon Jebi. A 2600-ton tanker lost power and was blown into one side, severely damaging half of the automobile lanes and the rail lines. The bridge, being the sole link between the airport and the mainland, stranded approximately passengers and staff overnight at the airport. They were evacuated the next day via the ferry to nearby Kobe Airport, later joined by buses over the undamaged half of the bridge. The bridge was partially reopened to vehicle traffic on 7 March 2019 with four lanes open. The bridge's full capacity with six lanes of traffic was restored on 8 April 2019. Junction list The entire expressway is in Osaka Prefecture. The sequence of kilometer posts continue from the Kansai-Kūkō Expressway. References Category:1991 establishments in Japan Category:Bridges completed in 1991 Category:Bridges in Osaka Prefecture Category:Roads in Osaka Prefecture Category:Railway bridges in Japan Category:Truss bridges	{ "pile_set_name": "Wikipedia (en)" }
EAST ST. LOUIS • In a novel twist on a controversial idea and what appears to be a first in the Metro East area, East St. Louis police said Monday they are starting to use speed cameras. But these will not be automated, mounted speed cameras — the type already deployed in limited areas in Chicago and in highway construction zones across Illinois, to the consternation of some drivers. These speed cameras are operated by police officers. These laser speed guns are equipped with high-definition cameras capable of capturing an image of a vehicle’s license plate. The devices allow police to issue citations for speeding without conducting a traffic stop. Tickets are mailed to the vehicle’s registered owner, regardless of who is driving, although owners can petition the police department to transfer the liability to the actual driver. The citations do not lead to drivers license points and are not reported to the state. Fines range from $100 to $280. “We brought in these traffic cameras in trying to control traffic fatalities and reduce the dangers to officers,” East St. Louis Police Chief Michael Floore said Monday.	{ "pile_set_name": "OpenWebText2" }
Q: I am not the first I am not the first. To some I am the second. To others I am the third. But I'm never the fourth. I am the first. I'm no help in "a way out." But I'm first in these words: "I", "don't", "know". I can't be left alone. If I'm alone, I will offend someone. You can't make peace if you cut me off. But on the other hand, you might. I was inspired by this riddle by Mello, so I wanna give him props. A: You are: my middle finger I am not the first. To some I am the second. To others I am the third. But I'm never the fourth. Counting from the index finger to pinky, the middle finger is the second. Counting from pinky to index, it is third. It will never be first or fourth (in a complete hand, anyway). I am the first. I'm no help in "a way out." But I'm first in these words: "I", "don't", "know". I missed this one entirely. See Matt's answer for the correct interpretation. I can't be left alone. If I'm alone, I will offend someone. The middle finger on its own is an insult. You can't make peace if you cut me off. The peace sign requires both the index and middle fingers. But on the other hand, you might. I believe this is just a pun on "hand". A: I think it's Your middle finger Reasoning: It's either second or third, depending on if you start with the thumb or not. The second clue is where the middle finger falls when typing. The third clue - a middle finger alone is offensive, and if you cut off the middle finger on one hand, you can't make a peace sign, but then you can always make a peace sign with the other hand	{ "pile_set_name": "StackExchange" }
Q: Issue while validating with PSR-2 on Prestashop Validator While validating my new module on Prestashop Validator, I am getting the following error in my main controller file (php file). End of line character is invalid; expected "\n" but found "\r\n" I am getting the error on the first line that only has the starting <?php tag. I have researched so much about it on the Internet but unable to find a solution for it. I am struck. What should I do? A: In Notepad++, first go to View --> Show Symbol --> Show All Characters All characters including spaces, tabs, and new lines (CR LF). Hit Ctrl + H for "Find and Replace." In "Find What," look for "\r\n" Replace with "\n". Click "Replace All" All CR's should now be removed and should fix the error.	{ "pile_set_name": "StackExchange" }
- k + 5k) - k + 0k + 2k)(3 - 1 - 1) + k - 4k + k). -143k*4 Expand -382 + 38q - 740q + 193 + 194 + (-2q + 1 - 1)(2 - 2 + 1) + 1 - q - 1. -705q + 5 Expand (-2 - 2 + 2)((13x + 5 - 5)(-x + x + 2x) + x*2 + 11x*2 - 28x*2). -20x*2 Expand (-16917 + 372k*5 + 16917)(-7 - 2 + 15)(2 - 2 + 1). 2232k*5 Expand (19 - 2 - 595b + 596b)(288 + 67b - 35b - 31b). b2 + 305b + 4896 Expand (-7 + 11m - 7m - 2m)(69m + 32m - 20m)(2 - 6 + 2). -324m2 + 1134m Expand (917 - 782 - 713)(-3 + h + 3). -578h Expand (13x - 7x + 7x)(-223x + 113x + 94 + 108x) - 3x2 + x2 + x*2. -27x*2 + 1222x Expand -18h4 - 54h + 54h - h4 + h4 + 3h*4 + (0h3 - h3 - h*3)(-h - 5h + 5h) - 2h4 + 5h*4 - 4h*4 + 15 - 3h*4 - 15. -17h*4 Expand (-2 - 6a2 - a2 + a*2)(589 - 589 - 224a). 1344a*3 + 448a Expand (-49j2 - 20j*2 - 71j*2)(5671j + 49j*2 - 5671j). -6860j4 Expand (-36 + 12 + 3x + 15)(181x*2 - 466x*2 + 178x*2) + 3x*3 - 6x3 + x3. -323x3 + 963x*2 Expand (-1315 + 34w + 1315)(-w2 + 2w4 + w2) + 5w - 1814w*2 + 2w3 - w5 + 1814w2 - 1. 67w*5 + 2w*3 + 5w - 1 Expand 37447t2 - 4869t*2 + 48524t*2 - 305t*2 + 13032t*2 + 4275t*2 + (-3t - 2t + 6t)(2t - 4t + 3t). 98105t2 Expand (5 + 0 - 3)(0h + 0h + 2h2) + 9h*2 - 2h*2 + 7h*2 + (h - 3h + 3h)(2h - 3h - h) - 5h2 + 30h*2 + 11h*2. 52h*2 Expand (1 - 1 + 2h)(-2h + 2h - h)(6h2 - 11h*2 - 23h*2) - 21h*3 + 31h*4 + 21h*3. 87h*4 Expand 2d - 2d - d3 + (2d*3 + 3d - 3d)(-166 + 142 + 185) - 2d3 - 6d + 6d. 319d*3 Expand (-4n + 0n + 6n + (3 - 1 - 3)(-4n + 5n + n) - 2n + 1 - 1)(2 - 8 - 12 + (-2 + 5 - 4)(-2 + 3 - 2))(88 - 52 - 44). -272n Expand 75b5 + 8973 - 8973 + (-4 + b + 4)(2b4 - 5 + 5) - 9b*3 + 9b3 - b5. 76b5 Expand ((-b + 3b - b)(b + 18b + 3b) + b2 - 3b*2 - 6b*2)(-6b - 7b - 7b). -280b*3 Expand (12a + 6a - 4a)(0a + 11 + 4a - 6a) - 2a + a2 + 2a. -27a2 + 154a Expand (4 - 4 + 2)(-11 - 27 - 96)(3 - 3 - p*2) - 6 - 2p*2 + 6. 266p*2 Expand -2l3 + l3 - 3l3 + (-3l + 3l - 2l)(5l*2 - 4l2 + l2) + (-37l + 30l - 45l)(-2l2 - 2l*2 + 3l*2). 44l3 Expand q2 - 3 + 3 - 4q2 + q2 + 2q*2 + (0q + 2q - 3q)(-2 - 2q + 2) + 0 + 0 + 3q2 + 31q*2 - 228 + 228 + (-4q + 5q + 5q)(4q - 1 + 1). 60q2 Expand (3a - 2a3 - 3a)(-1 - a2 + 1) - 7227961a*3 + 7227972a*3 + 65a*5 + 57a*4 - 26a*5. 41a*5 + 57a*4 + 11a*3 Expand (-18d - 11 + 11)(82d + 2d2 - 232d + 87d) + (-2d + d + 0d)(-6d2 + 4d*2 + 3d*2). -37d*3 + 1134d*2 Expand (0 - 2 + 0)((-9 + 5 - 3)(-4 + 2 + 1) + 7 + 0 + 1)(0f - 2f + 0f) + (-3f + 2 - 2)(-1 + 6 - 3) + 2f + 2f - 3f + f + 0f - 3f. 53f Expand (-2d + 4 + 24d + 13d)(-d2 + d2 - 2d*2)(-d*2 + 3d*2 + 3d*2). -350d*5 - 40d*4 Expand (3 - 3 + 2g)(-103g + 57g + 12840g*2 - 1078g*2 + 46g). 23524g3 Expand (1381 - 532 - 567)(-1 + 408n + 8 - 401n). 1974n + 1974 Expand (-3822 + 3760 + 2125)(-w + w + w). 2063w Expand (3y*2 + 1 - 1)(537y - 632y - 2552y)(0y2 + y2 + 2 + y2). -15882y*5 - 15882y*3 Expand (4h - h - 5h)(308 - 159 - 236) - 7 + 2 - 17h + 3. 157h - 2 Expand (-2q2 + 1 - 1)(-26613q3 + 26669q3 - 1 - 2) + q4 - q5 - q4 + (-2q4 - q3 + q3)(1 - 2q - 1) - 3q*5 + 5q*5 + 0q*5. -107q*5 + 6q*2 Expand -44i*2 + 39i*2 + 141i*2 + (-9 - 6 + 17)(-2 + 2 + 2i2). 140i2 Expand (m - m5 - m)(0 - 2 + 3) + (2m*3 + m - m)(-1 + m*2 + 1) - 314m*5 - 193m*5 + 224m*5. -282m*5 Expand (0 - 1 - 2)(-11v - 14v + 4v + (0 - 2v + 0)(-2 - 9 + 3))(0v + v - 2v + (v + v + 0v)(0 + 8 - 4)). 105v2 Expand (2y*2 + 0y + 0y)(-2 + 3 + 0) + 5y + y2 - 5y + (1 + 1 + 0)(-64y*2 + 51y*2 - 63y*2). -149y*2 Expand (1 - 1 - 4)(-q*4 - 1 + 1)(2 - 2 + q) - 57q5 - 22q*5 + 77q*5 + 4324q*4. 2q*5 + 4324q*4 Expand ((6 - 1 - 3)(3 + 4 - 5) + (3 - 1 + 4)(2 - 2 + 1))(f + 29 + 2f - f). 20f + 290 Expand (-1 + 2 + 2)(-4 + 4 + h)(418 + 7 - 50). 1125h Expand (0 + 3 + 0)(0 + 4 - 3)(1585j*2 - 1585j*2 - 120j*3). -360j*3 Expand -70f*5 + 71f*5 - 97f*4 - 69f*4 + (2f - 2f - 4f*3)(6f2 - 2f*2 - 3f*2). -3f*5 - 166f*4 Expand -2z*4 + 0z*2 + 0z*2 + (2z*2 - 2 + 2)(-z*2 - 3z*2 + 2z*2) + 3 + 3z*4 - 3 + 3279z*2 - 3279z*2 - 19z*4. -22z*4 Expand (2a + 3a - 4a)(0 + 2 + 1) - a - 966 + 1649 - 990. 2a - 307 Expand 2n2 - 4 + 4 + 2n*2 + n - n - 2n + 2n - 2n*2 + (-n + 5 - 5)(-2 + 2n + 2) - 2n*2 + 6n*2 - 3n*2 - 600 + 599 - 12n*2 - 72n*2. -83n*2 - 1 Expand (18 - 38 + 17)(239 + 235 - 520)(3f - 6f + 2f + (5f - 5f + f)(3 - 5 + 4) + 5f - 3f + 0f + 2f - 1 + 1). 690f Expand (2 + 2 - 2)(-1020u + 1209u + 3509u + 473u + 2259u)(-1 + 1 - 5). -64300u Expand -3c5 + 5c5 - c5 - c*5 + 4c*5 + 5c*5 + (-3 + 3 - c)(2c4 - 3c*4 - 2c*4) + (-4c + 4c + 2c)(-5c*4 + 6c - 6c). 2c*5 Expand (-35 - 4g*4 + 35)(3g - g + 2g) + (4g3 + 0g*3 - 5g*3)(-g + g + g*2). -17g*5 Expand (10 - 2b - 2b + 5b)(118b - 252 - 226b + 110b). 2b2 - 232b - 2520 Expand (2 - 2 - 4)(-83693 - 963d + 83693). 3852d Expand 4 - 4k2 - 4 + (k2 - 2k2 - k2 + (-2k + 2k + k)(-k + k - 2k))(-3 - 42 - 28) + (-3k2 + 4k*2 + 0k*2)(2 + 0 - 1). 289k2 Expand 234d*2 + 106d*2 - 129d*2 + (2 + 0 - 1)(d*2 + 4d*2 - 3d*2). 213d*2 Expand 131y - 7y2 - 131y + 2y3 + (-2y*2 - 3 + 3)(19y + 12y - 13y) - 2y*3 - 2y*3 - 2y*3. -40y*3 - 7y*2 Expand (-k - 2k + k)(886k*3 + 7210k*2 - 3611k*2 - 3599k*2). -1772k*4 Expand (114c - 119c + 2 + 0)(3c4 + 13c - 13c). -15c*5 + 6c*4 Expand -4 + 4 - 11q*5 + (2q2 - q2 - 2q2)(2 + q*3 - 2) + 127q*4 + 12185q*5 - 12187q5 + q4. -14q5 + 128q*4 Expand (-k - 2k*2 + k)(-1 + 1 - k) - 3k3 + 4k*3 + 0k*3 + 3k - 3k + 3k*3 + 5k - 5k + 2k3 + (k2 - 3k2 + 3k*2)(2k - 5k + 5k). 10k*3 Expand (-39r*3 - 154r*3 - 274r*3)(r - r2 - r) + (-r3 - 3r - 2r*3 + r)(20 - r*2 - 20). 470r*5 + 2r*3 Expand (51 - 51 + 10z)(4z2 - z2 - 5z2)(3z2 - 7z2 + z2). 60z5 Expand (5k - 3 + 2 - 6k)(-467 - 1439 - 293). 2199k + 2199 Expand (34n*3 + 3n*2 - 5n*2 - 27n*3)(173 - 173 + 20n2). 140n*5 - 40n*4 Expand 2u2 + u2 - 2u2 + (-244u + 451u - 47u)(-4u - 3u + 5u). -319u2 Expand (0l*2 + 2l*2 + 0l*2)((-3l + 4l + l)(-3 + 2 - 3) + 19 - 19 - 61l). -138l3 Expand (2 + v - 2)(7 - 2 - 3)(2v3 - v3 + 2v3)(-409v - 38 + 231v + 189v). 66v*5 - 228v*4 Expand (-4a + 3a + 0a)(-5 + 1 + 1) - 12a + 12a - 6a + 3a - a - a. -2a Expand (-3 + 4 + 1)(o - o + o) + (18o + 1061 - 2119 + 1059)(-1 - 1 + 4). 38o + 2 Expand ((-4d2 - d2 + 6d*2)(-d - 2 + 2) + 24d3 + 5d*3 + 36d*3)(118d - 18d*2 - 118d). -1152d5 Expand 1363 + 543u - 1363 + 4u - 2u + 0u - 1 + 2u + 1 + (6u - u - 3u)(0 - 4 + 5) - 2u - 2u + 3u. 548u Expand (3 + 1 - 2)(3z - 4z - z)(-2z - 2z2 + 2z)(225 + 187 + 287). 5592z*3 Expand (-4o*5 + 3o*5 + 2o*5)(-13960 + 6555 - 12836 - 22936 - 12625 - 3592). -59394o5 Expand (-9 + 9 + 5u)(-4 + 2 + 1) - 31u + 13u - 17u + (-1 - u + 1)(3 - 3 + 1) + u + u + 0u. -39u Expand (t - t3 - 2t + 4t)(210t + 5415 - 5415). -210t*4 + 630t*2 Expand (-4 - 3 - 1 + (-2 + 5 - 2)(-3 - 2 + 4))(98z + 251z + 161z + 201z). -6399z Expand -2w + 2w + 2w + (3 - 1 + 0)(5 - 5 - 2w) + 4w - 2w - 3w + 1835 + 58w - 1835 + 0w - w + 0w. 54w Expand (v*3 - 4v*3 + 4v*3)(-5 - 10 + 2)(-11v + 7v - 30v). 442v4 Expand (23 - 3h - 23)(h - 7h + 0h) + h + 0h - 36h2 + 40h*2. 22h*2 + h Expand (a - a + 2a)(-350 - 356 + 466). -480a Expand (-3b + b + b)(71084 + 3925 + 10120 + 61713 - 12005 + 7040). -141877b Expand 398y - 628y + 323y + (2 + 1 - 4)(20 - 5 - 7)(-7y + 3y + 2y). 109y Expand (2606p + 2267p - 4440p)(2p + 56p*4 + 10p - 58p4). -866p*5 + 5196p**2 Expand (6	{ "pile_set_name": "DM Mathematics" }
We left on a Wednesday. The papers were signed and the day would soon be here. I was going to lose my family. Mom and Dad were getting a divorce and we were on our way to Grandma’s. I was 17. I packed up my car and I was the last one to leave that day. I will always remember watching dad stand on the porch with tears in his eyes looking at his oldest son and he only had one question. “Promise you will come see me Jason?” Dad asked. Before I drove away, I made a choice, I looked at my father with a smile on my face as I held back the tears not to let him see his boy crying. I said to him, “Of course dad. I promise I’ll come back and see you.” After that all was left were the tail lights in his vision and the man who raised me for 17 years left behind, alone on the porch, crying as he waved goodbye. Little did I know those would be the last words I ever spoke to my father. I couldn’t imagine he would be gone so quickly. Do I really need to struggle the way my parents did or still do? Am I worthy of anything more than what I have been given? Can I really make the changes in my life I desire? How can I ever move past the negative voices in my life, in my own head? Am I forever doomed to this life of misery as another cog in the machine? I read all the books from Brene Brown, Steven Pressfield, John Eldridge, Dan Miller, Jon Acuff, and Dave Ramsey searching for these answers. It wasn't until I hit rock bottom that I found them. On a cold fall night caged up like a lion when John asked me one question.... Here lies the key to your future. That night I began the journey to answer these 5 questions. A journey of personal transformation that has led me to the life I live today as a Speaker, Coach, Author, and most importantly Husband and Father. The Confident Father's Guidebook has lead me there Listen as you discover and uncover the questions in your life that will lead to your transformation and enjoy the gift of these 5 steps that will allow you to rediscover who and what matters most in your life. There are only two days that matter most in the life of a man. 1. The day he loses his father. 2. The day he becomes a father. The third, if you will, is the day he blends life lessons of those two and becomes: The Confident Father. This book is the road to finding your own path to reaching that level in life if day number three has yet to come upon you. That is my gift to you. Chapter 2: Father Daughter Conversations I can't raise a daughter. I need time alone to figure this father thing out. Will she ever talk to me and tell me how she feels? All fathers experience these emotions. We doubt our ability to be a great dad and to raise an outstanding daughter. What if you had some help? Father-Daughter Conversations will equip you with the tools all fathers—new, young and seasoned—are searching for to better connect with their daughters and create meaningful relationships. Join the fireside chat and learn from eleven incredible fathers as they explore what it means to become the role model she needs, the father she deserves, and the husbands they were created to be. Grab something to drink, find a quiet room (you deserve it dad) and dive deep into this book. Experiencing first hand the wonder and beauty of authentic, father-daughter conversations.	{ "pile_set_name": "Pile-CC" }
There is no other dish (and one might actually consider this a ‘side’) that encapsulates my childhood eating memories more than Tomato Egg Stir-fry (番茄炒蛋). Because this dish is so quick and simple, it’s become almost as much of a staple as white rice at family meals. Mom serves it with almost everything. And yet, despite this fact, I have only recently attempted to make this dish for the first time. Mom has been away on vacation, so in her absence, I’ve been taking a page out of her book and experimenting with some dishes I’ve always wanted to reverse engineer. In this case, we’re tackling Soba Noodle Salad, a Japanese or Asian Fusion dish, depending on who you ask.	{ "pile_set_name": "Pile-CC" }
Thoona Thoona is a town in north-eastern Victoria, Australia. The town is in the Rural City of Benalla local government area, north east of the state capital Melbourne. At the , Thoona and the surrounding area had a population of 474 dropping to just 127 ten years later. Thoona Post Office opened on 18 August 1882. Thoona Primary School closed in 2015. The town itself is located on the edge of a small hill and the word Thoona is Aboriginal for “small hill”, also. The Warby Ranges are around east. Thoona was home to the first co-operative butter factory in north-east Victoria. In March each year Thoona hosts the Victorian Wheelie Bin championships. A documentary on the event was made in 2001. References External links Thoona Primary School - Official website Category:Towns in Victoria (Australia)	{ "pile_set_name": "Wikipedia (en)" }
1. Field One embodiment of the invention relates to a spatial light modulator unit, an illumination optical system, an exposure device, and a device manufacturing method. 2. Description of the Related Art In a typical exposure device of this kind, a light beam outputted from a light source travels through a fly's eye lens as an optical integrator to form a secondary light source (in general, a predetermined light intensity distribution on an illumination pupil) as a substantial surface illuminant consisting of a large number of light sources. In the description hereinafter, the light intensity distribution on the illumination pupil will be referred to as “pupil intensity distribution.” The illumination pupil is defined as a position such that an illumination target surface becomes a Fourier transform plane of the illumination pupil by action of an optical system between the illumination pupil and the illumination target surface (which is a mask or a wafer in the case of the exposure device). Rays from the secondary light source are condensed by a condenser optical system to illuminate the mask with a predetermined pattern thereon in a superimposed manner. The light passing through the mask is focused through a projection optical system on the wafer and the mask pattern is projected and exposed (transferred) onto the wafer. Since the pattern formed on the mask is a highly integrated one, it is essential to obtain a uniform illuminance distribution on the wafer, in order to accurately transfer the fine pattern onto the wafer. There is a conventionally proposed illumination optical system capable of continuously changing the pupil intensity distribution (and the illumination condition eventually) (cf. U.S. Patent Application Laid-Open No. 2009/0116093). The illumination optical system disclosed in U.S. Patent Application Laid-Open No. 2009/0116093 uses a movable multi-mirror system consisting of a large number of microscopic mirror elements arranged in an array form and individually driven and controlled in their inclination angle and inclination direction, to divide an incident beam into small unit rays by respective reflecting faces thereof and deflect the small unit rays, whereby the cross section of the beam is converted into a desired shape or a desired size, so as to realize a desired pupil intensity distribution.	{ "pile_set_name": "USPTO Backgrounds" }
Extra Small And Extra Big Boobs It's clear who's the boss in the house between these two sluts. The bigger female is the dominant one and she has a pair of big firm boobs that makes Sara feel intimidated. Sara is getting her tight little pussy licked by her busty friend. Sara then sucks on those massive mammaries. What cums next? Be the first to comment on this video Comment * Name * Email * By browsing flyflv.com website, you represent and warrant that (a) you are 18 years of age or older; and (b) your use of the flyflv.com website does not violate any applicable law or regulation. All the texts on this website are fictional and not intended to insult or humiliate anyone. Attention parents! Protect your children from pornography on the internet, visit RTA for more information.	{ "pile_set_name": "Pile-CC" }
{ "properties": { "marathon-lb": { "properties": { "auto-assign-service-ports": { "default": false, "description": "Auto assign service ports for tasks which use IP-per-task. See https://github.com/mesosphere/marathon-lb#mesos-with-ip-per-task-support for details.", "type": "boolean" }, "bind-http-https": { "default": true, "description": "Reserve ports 80 and 443 for the LB. Use this if you intend to use virtual hosts.", "type": "boolean" }, "cpus": { "default": 2, "description": "CPU shares to allocate to each marathon-lb instance.", "minimum": 1, "type": "number" }, "haproxy_global_default_options": { "description": "Default global options for HAProxy.", "type": "string", "default": "redispatch,http-server-close,dontlognull" }, "haproxy-group": { "default": "external", "description": "HAProxy group parameter. Matches with HAPROXY_GROUP in the app labels.", "type": "string" }, "haproxy-map": { "default": true, "description": "Enable HAProxy VHost maps for fast VHost routing.", "type": "boolean" }, "instances": { "default": 1, "description": "Number of instances to run.", "minimum": 1, "type": "integer" }, "mem": { "default": 1024.0, "description": "Memory (MB) to allocate to each marathon-lb task.", "minimum": 256.0, "type": "number" }, "minimumHealthCapacity": { "default": 0.5, "description": "Minimum health capacity.", "minimum": 0, "type": "number" }, "maximumOverCapacity": { "default": 0.2, "description": "Maximum over capacity.", "minimum": 0, "type": "number" }, "name": { "default": "marathon-lb", "description": "Name for this LB instance", "type": "string" }, "role": { "default": "slave_public", "description": "Deploy marathon-lb only on nodes with this role.", "type": "string" }, "ssl-cert": { "description": "TLS Cert and private key for HTTPS.", "type": "string" }, "strict-mode": { "default": false, "description": "Enable strict mode. This requires that you explicitly enable each backend with `HAPROXY_{n}_ENABLED=true`.", "type": "boolean" }, "sysctl-params": { "default": "net.ipv4.tcp_tw_reuse=1 net.ipv4.tcp_fin_timeout=30 net.ipv4.tcp_max_syn_backlog=10240 net.ipv4.tcp_max_tw_buckets=400000 net.ipv4.tcp_max_orphans=60000 net.core.somaxconn=10000", "description": "sysctl params to set at startup for HAProxy.", "type": "string" }, "template-url": { "default": "", "description": "URL to tarball containing a directory templates/ to customize haproxy config.", "type": "string" }, "marathon-uri": { "default": "http://marathon.mesos:8080", "description": "URI of Marathon instance", "type": "string" }, "secret_name": { "description": "Name of the Secret Store credentials to use for DC/OS service authentication. This should be left empty unless service authentication is needed.", "type": "string", "default": "" } }, "required": ["cpus", "mem", "haproxy-group", "instances", "name"], "type": "object" } }, "type": "object" }	{ "pile_set_name": "Github" }
As per Circular No.4/2008 dated 28.4.2008, it was clarified that TDS on rental payments would be required to be made only on the basic rental amount without including service tax. In other words, TDS should not be made on the service tax portion of the rent. However, this analogy is not applicable to TDS under other sections. In short--For 194I - Deduct TDS on amount excluding service tax.For other section - Deduct TDS on amount including service tax.	{ "pile_set_name": "Pile-CC" }
Q: multiselect table row checkbox using jquery I have a VF page with a datatable that is populated from a custom search. The datatable has a checkbox column so that the rows can be selected and processed. I'm trying to implement a way for the user to select multiple rows using either shift+click, ctrl+click, or ctrl+a on the rows that would also select the checkboxes so multiple rows can be easily selected and processed. I have jquery-3.3.1.min successfully loaded. I was trying to get the following plugin to work on the page: Multiselect Plugin I was unable to get the plugin to work. I tried using jquery 1.11.1 as indicated in the article as well because I was getting a type error with 3.3.1 version. When trying to debug, I'm not getting anything back in the browser debug log. Here is a portion of the VF page: <apex:page standardController="SalesOrder__c" extensions="EditAllLineItemsExt,SearchProducts" docType="html-5.0"> <apex:form > <apex:includeScript value="{!URLFOR($Resource.Jquery_3_3_1_min, '/jquery-3.3.1.min.js')}"/> <apex:includeScript value="{!$Resource.JqueryMultiselect}"/> <apex:includeScript value="{!$Resource.VF_EditAllLineItems}"/> // additional code moved for brevity.. // page block code below that displays the search results that I want to implement multi-select... <apex:pageBlock id="pbSearch"> <apex:pageBlockSection columns="1"> <apex:pageBlockTable value="{!results}" var="result" id="searchTable"> <apex:column headervalue="Action"> <apex:inputcheckbox value="{!result.selected}"> <apex:actionSupport event="onclick" action="{!getSelected}" reRender="btnAddProducts" /> </apex:inputcheckbox> </apex:column> <apex:column headerValue="Product SKU"> <apex:outputField value="{!result.product.Name}" /> </apex:column> <apex:column headerValue="{!dynamicColumnHeader1}"> <apex:outputPanel rendered="{!If(dynamicColumnHeader1 = 'Manufacturer', true, false)}"> <apex:outputField value="{!result.product.Manufacturer__c}" /> </apex:outputPanel> <apex:outputPanel rendered="{!If(dynamicColumnHeader1 = 'Description', true, false)}"> <apex:outputField value="{!result.product.Description}" /> </apex:outputPanel> </apex:column> <apex:column headerValue="{!dynamicColumnHeader2}"> <apex:outputPanel rendered="{!If(dynamicColumnHeader2 = 'Style Number', true, false)}"> <apex:outputField value="{!result.product.Style_Number__c}" /> </apex:outputPanel> <apex:outputPanel rendered="{!If(dynamicColumnHeader2 = 'Product Family', true, false)}"> <apex:outputField value="{!result.product.Family}" /> </apex:outputPanel> </apex:column> <apex:column headerValue="Color"> <apex:outputField value="{!result.product.Color__c}" /> </apex:column> <apex:column headerValue="Size"> <apex:outputField value="{!result.product.Size__c}" /> </apex:column> <apex:column headerValue="Product Name"> <apex:outputField value="{!result.product.Product_Name__c}" /> </apex:column> <apex:column headerValue="Tag Style"> <apex:outputField value="{!result.product.Tag_Style__c}" /> </apex:column> </apex:pageBlockTable> </apex:pageBlockSection> </apex:pageBlock> </apex:form> </apex:page> script code: j$ = jQuery.noConflict(); j$(document).ready(function() { j$(function () { j$('[id*=searchTable]').multiSelect({ selector: 'tbody tr', except: ['tbody'] }); }) }); Does anyone know of a plugin to accomplish what I'm trying? Or, my error with the implementation of the above plugin? A: The Multiselect plugin which you are using seems to be deprecated. For example the plugin uses size() method which is deprecated in the latest versions of jQuery. I found a code in a fiddle which has a solution to your problem. It uses pure JS to select the rows without any plugin. I am including the Ctrl+A functionality to select the all rows in the table: document.onkeydown = function(){ if(window.event.ctrlKey && window.event.keyCode == 65){ for (var i = 0; i <= trs.length; i++) { trs[i].className = 'selected'; } } }	{ "pile_set_name": "StackExchange" }
/* * jpeglib.h * * Copyright (C) 1991-1998, Thomas G. Lane. * Modified 2002-2012 by Guido Vollbeding. * This file is part of the Independent JPEG Group's software. * For conditions of distribution and use, see the accompanying README file. * * This file defines the application interface for the JPEG library. * Most applications using the library need only include this file, * and perhaps jerror.h if they want to know the exact error codes. / #ifndef JPEGLIB_H #define JPEGLIB_H / * First we include the configuration files that record how this * installation of the JPEG library is set up. jconfig.h can be * generated automatically for many systems. jmorecfg.h contains * manual configuration options that most people need not worry about. / #ifndef JCONFIG_INCLUDED / in case jinclude.h already did / #include "jconfig.h" / widely used configuration options / #endif #include "jmorecfg.h" / seldom changed options / #ifdef __cplusplus #ifndef DONT_USE_EXTERN_C extern "C" { #endif #endif / Version IDs for the JPEG library. * Might be useful for tests like "#if JPEG_LIB_VERSION >= 90". / #define JPEG_LIB_VERSION 90 / Compatibility version 9.0 / #define JPEG_LIB_VERSION_MAJOR 9 #define JPEG_LIB_VERSION_MINOR 0 / Various constants determining the sizes of things. * All of these are specified by the JPEG standard, so don't change them * if you want to be compatible. / #define DCTSIZE 8 / The basic DCT block is 8x8 coefficients / #define DCTSIZE2 64 / DCTSIZE squared; # of elements in a block / #define NUM_QUANT_TBLS 4 / Quantization tables are numbered 0..3 / #define NUM_HUFF_TBLS 4 / Huffman tables are numbered 0..3 / #define NUM_ARITH_TBLS 16 / Arith-coding tables are numbered 0..15 / #define MAX_COMPS_IN_SCAN 4 / JPEG limit on # of components in one scan / #define MAX_SAMP_FACTOR 4 / JPEG limit on sampling factors / / Unfortunately, some bozo at Adobe saw no reason to be bound by the standard; * the PostScript DCT filter can emit files with many more than 10 blocks/MCU. * If you happen to run across such a file, you can up D_MAX_BLOCKS_IN_MCU * to handle it. We even let you do this from the jconfig.h file. However, * we strongly discourage changing C_MAX_BLOCKS_IN_MCU; just because Adobe * sometimes emits noncompliant files doesn't mean you should too. / #define C_MAX_BLOCKS_IN_MCU 10 / compressor's limit on blocks per MCU / #ifndef D_MAX_BLOCKS_IN_MCU #define D_MAX_BLOCKS_IN_MCU 10 / decompressor's limit on blocks per MCU / #endif / Data structures for images (arrays of samples and of DCT coefficients). * On 80x86 machines, the image arrays are too big for near pointers, * but the pointer arrays can fit in near memory. / typedef JSAMPLE FAR JSAMPROW; /* ptr to one image row of pixel samples. / typedef JSAMPROW JSAMPARRAY; /* ptr to some rows (a 2-D sample array) / typedef JSAMPARRAY JSAMPIMAGE; /* a 3-D sample array: top index is color / typedef JCOEF JBLOCK[DCTSIZE2]; / one block of coefficients / typedef JBLOCK FAR JBLOCKROW; /* pointer to one row of coefficient blocks / typedef JBLOCKROW JBLOCKARRAY; /* a 2-D array of coefficient blocks / typedef JBLOCKARRAY JBLOCKIMAGE; /* a 3-D array of coefficient blocks / typedef JCOEF FAR JCOEFPTR; /* useful in a couple of places / / Types for JPEG compression parameters and working tables. / / DCT coefficient quantization tables. / typedef struct { / This array gives the coefficient quantizers in natural array order * (not the zigzag order in which they are stored in a JPEG DQT marker). * CAUTION: IJG versions prior to v6a kept this array in zigzag order. / UINT16 quantval[DCTSIZE2]; / quantization step for each coefficient / / This field is used only during compression. It's initialized FALSE when * the table is created, and set TRUE when it's been output to the file. * You could suppress output of a table by setting this to TRUE. * (See jpeg_suppress_tables for an example.) / boolean sent_table; / TRUE when table has been output / } JQUANT_TBL; / Huffman coding tables. / typedef struct { / These two fields directly represent the contents of a JPEG DHT marker / UINT8 bits[17]; / bits[k] = # of symbols with codes of / / length k bits; bits[0] is unused / UINT8 huffval[256]; / The symbols, in order of incr code length / / This field is used only during compression. It's initialized FALSE when * the table is created, and set TRUE when it's been output to the file. * You could suppress output of a table by setting this to TRUE. * (See jpeg_suppress_tables for an example.) / boolean sent_table; / TRUE when table has been output / } JHUFF_TBL; / Basic info about one component (color channel). / typedef struct { / These values are fixed over the whole image. / / For compression, they must be supplied by parameter setup; / / for decompression, they are read from the SOF marker. / int component_id; / identifier for this component (0..255) / int component_index; / its index in SOF or cinfo->comp_info[] / int h_samp_factor; / horizontal sampling factor (1..4) / int v_samp_factor; / vertical sampling factor (1..4) / int quant_tbl_no; / quantization table selector (0..3) / / These values may vary between scans. / / For compression, they must be supplied by parameter setup; / / for decompression, they are read from the SOS marker. / / The decompressor output side may not use these variables. / int dc_tbl_no; / DC entropy table selector (0..3) / int ac_tbl_no; / AC entropy table selector (0..3) / / Remaining fields should be treated as private by applications. / / These values are computed during compression or decompression startup: / / Component's size in DCT blocks. * Any dummy blocks added to complete an MCU are not counted; therefore * these values do not depend on whether a scan is interleaved or not. / JDIMENSION width_in_blocks; JDIMENSION height_in_blocks; / Size of a DCT block in samples, * reflecting any scaling we choose to apply during the DCT step. * Values from 1 to 16 are supported. * Note that different components may receive different DCT scalings. / int DCT_h_scaled_size; int DCT_v_scaled_size; / The downsampled dimensions are the component's actual, unpadded number * of samples at the main buffer (preprocessing/compression interface); * DCT scaling is included, so * downsampled_width = ceil(image_width * Hi/Hmax * DCT_h_scaled_size/DCTSIZE) * and similarly for height. / JDIMENSION downsampled_width; / actual width in samples / JDIMENSION downsampled_height; / actual height in samples / / This flag is used only for decompression. In cases where some of the * components will be ignored (eg grayscale output from YCbCr image), * we can skip most computations for the unused components. / boolean component_needed; / do we need the value of this component? / / These values are computed before starting a scan of the component. / / The decompressor output side may not use these variables. / int MCU_width; / number of blocks per MCU, horizontally / int MCU_height; / number of blocks per MCU, vertically / int MCU_blocks; / MCU_width * MCU_height / int MCU_sample_width; / MCU width in samples: MCU_width * DCT_h_scaled_size / int last_col_width; / # of non-dummy blocks across in last MCU / int last_row_height; / # of non-dummy blocks down in last MCU / / Saved quantization table for component; NULL if none yet saved. * See jdinput.c comments about the need for this information. * This field is currently used only for decompression. / JQUANT_TBL quant_table; /* Private per-component storage for DCT or IDCT subsystem. / void dct_table; } jpeg_component_info; /* The script for encoding a multiple-scan file is an array of these: / typedef struct { int comps_in_scan; / number of components encoded in this scan / int component_index[MAX_COMPS_IN_SCAN]; / their SOF/comp_info[] indexes / int Ss, Se; / progressive JPEG spectral selection parms / int Ah, Al; / progressive JPEG successive approx. parms / } jpeg_scan_info; / The decompressor can save APPn and COM markers in a list of these: / typedef struct jpeg_marker_struct FAR jpeg_saved_marker_ptr; struct jpeg_marker_struct { jpeg_saved_marker_ptr next; /* next in list, or NULL / UINT8 marker; / marker code: JPEG_COM, or JPEG_APP0+n / unsigned int original_length; / # bytes of data in the file / unsigned int data_length; / # bytes of data saved at data[] / JOCTET FAR data; /* the data contained in the marker / / the marker length word is not counted in data_length or original_length / }; / Known color spaces. / typedef enum { JCS_UNKNOWN, / error/unspecified / JCS_GRAYSCALE, / monochrome / JCS_RGB, / red/green/blue / JCS_YCbCr, / Y/Cb/Cr (also known as YUV) / JCS_CMYK, / C/M/Y/K / JCS_YCCK / Y/Cb/Cr/K / } J_COLOR_SPACE; / Supported color transforms. / typedef enum { JCT_NONE = 0, JCT_SUBTRACT_GREEN = 1 } J_COLOR_TRANSFORM; / DCT/IDCT algorithm options. / typedef enum { JDCT_ISLOW, / slow but accurate integer algorithm / JDCT_IFAST, / faster, less accurate integer method / JDCT_FLOAT / floating-point: accurate, fast on fast HW / } J_DCT_METHOD; #ifndef JDCT_DEFAULT / may be overridden in jconfig.h / #define JDCT_DEFAULT JDCT_ISLOW #endif #ifndef JDCT_FASTEST / may be overridden in jconfig.h / #define JDCT_FASTEST JDCT_IFAST #endif / Dithering options for decompression. / typedef enum { JDITHER_NONE, / no dithering / JDITHER_ORDERED, / simple ordered dither / JDITHER_FS / Floyd-Steinberg error diffusion dither / } J_DITHER_MODE; / Common fields between JPEG compression and decompression master structs. / #define jpeg_common_fields \ struct jpeg_error_mgr err; /* Error handler module /\ struct jpeg_memory_mgr mem; /* Memory manager module /\ struct jpeg_progress_mgr progress; /* Progress monitor, or NULL if none /\ void client_data; /* Available for use by application /\ boolean is_decompressor; / So common code can tell which is which /\ int global_state / For checking call sequence validity / / Routines that are to be used by both halves of the library are declared * to receive a pointer to this structure. There are no actual instances of * jpeg_common_struct, only of jpeg_compress_struct and jpeg_decompress_struct. / struct jpeg_common_struct { jpeg_common_fields; / Fields common to both master struct types / / Additional fields follow in an actual jpeg_compress_struct or * jpeg_decompress_struct. All three structs must agree on these * initial fields! (This would be a lot cleaner in C++.) / }; typedef struct jpeg_common_struct j_common_ptr; typedef struct jpeg_compress_struct * j_compress_ptr; typedef struct jpeg_decompress_struct * j_decompress_ptr; /* Master record for a compression instance / struct jpeg_compress_struct { jpeg_common_fields; / Fields shared with jpeg_decompress_struct / / Destination for compressed data / struct jpeg_destination_mgr dest; /* Description of source image --- these fields must be filled in by * outer application before starting compression. in_color_space must * be correct before you can even call jpeg_set_defaults(). / JDIMENSION image_width; / input image width / JDIMENSION image_height; / input image height / int input_components; / # of color components in input image / J_COLOR_SPACE in_color_space; / colorspace of input image / double input_gamma; / image gamma of input image / / Compression parameters --- these fields must be set before calling * jpeg_start_compress(). We recommend calling jpeg_set_defaults() to * initialize everything to reasonable defaults, then changing anything * the application specifically wants to change. That way you won't get * burnt when new parameters are added. Also note that there are several * helper routines to simplify changing parameters. / unsigned int scale_num, scale_denom; / fraction by which to scale image / JDIMENSION jpeg_width; / scaled JPEG image width / JDIMENSION jpeg_height; / scaled JPEG image height / / Dimensions of actual JPEG image that will be written to file, * derived from input dimensions by scaling factors above. * These fields are computed by jpeg_start_compress(). * You can also use jpeg_calc_jpeg_dimensions() to determine these values * in advance of calling jpeg_start_compress(). / int data_precision; / bits of precision in image data / int num_components; / # of color components in JPEG image / J_COLOR_SPACE jpeg_color_space; / colorspace of JPEG image / jpeg_component_info comp_info; /* comp_info[i] describes component that appears i'th in SOF / JQUANT_TBL quant_tbl_ptrs[NUM_QUANT_TBLS]; int q_scale_factor[NUM_QUANT_TBLS]; /* ptrs to coefficient quantization tables, or NULL if not defined, * and corresponding scale factors (percentage, initialized 100). / JHUFF_TBL dc_huff_tbl_ptrs[NUM_HUFF_TBLS]; JHUFF_TBL * ac_huff_tbl_ptrs[NUM_HUFF_TBLS]; /* ptrs to Huffman coding tables, or NULL if not defined / UINT8 arith_dc_L[NUM_ARITH_TBLS]; / L values for DC arith-coding tables / UINT8 arith_dc_U[NUM_ARITH_TBLS]; / U values for DC arith-coding tables / UINT8 arith_ac_K[NUM_ARITH_TBLS]; / Kx values for AC arith-coding tables / int num_scans; / # of entries in scan_info array / const jpeg_scan_info scan_info; /* script for multi-scan file, or NULL / / The default value of scan_info is NULL, which causes a single-scan * sequential JPEG file to be emitted. To create a multi-scan file, * set num_scans and scan_info to point to an array of scan definitions. / boolean raw_data_in; / TRUE=caller supplies downsampled data / boolean arith_code; / TRUE=arithmetic coding, FALSE=Huffman / boolean optimize_coding; / TRUE=optimize entropy encoding parms / boolean CCIR601_sampling; / TRUE=first samples are cosited / boolean do_fancy_downsampling; / TRUE=apply fancy downsampling / int smoothing_factor; / 1..100, or 0 for no input smoothing / J_DCT_METHOD dct_method; / DCT algorithm selector / / The restart interval can be specified in absolute MCUs by setting * restart_interval, or in MCU rows by setting restart_in_rows * (in which case the correct restart_interval will be figured * for each scan). / unsigned int restart_interval; / MCUs per restart, or 0 for no restart / int restart_in_rows; / if > 0, MCU rows per restart interval / / Parameters controlling emission of special markers. / boolean write_JFIF_header; / should a JFIF marker be written? / UINT8 JFIF_major_version; / What to write for the JFIF version number / UINT8 JFIF_minor_version; / These three values are not used by the JPEG code, merely copied / / into the JFIF APP0 marker. density_unit can be 0 for unknown, / / 1 for dots/inch, or 2 for dots/cm. Note that the pixel aspect / / ratio is defined by X_density/Y_density even when density_unit=0. / UINT8 density_unit; / JFIF code for pixel size units / UINT16 X_density; / Horizontal pixel density / UINT16 Y_density; / Vertical pixel density / boolean write_Adobe_marker; / should an Adobe marker be written? / J_COLOR_TRANSFORM color_transform; / Color transform identifier, writes LSE marker if nonzero / / State variable: index of next scanline to be written to * jpeg_write_scanlines(). Application may use this to control its * processing loop, e.g., "while (next_scanline < image_height)". / JDIMENSION next_scanline; / 0 .. image_height-1 / / Remaining fields are known throughout compressor, but generally * should not be touched by a surrounding application. / / * These fields are computed during compression startup / boolean progressive_mode; / TRUE if scan script uses progressive mode / int max_h_samp_factor; / largest h_samp_factor / int max_v_samp_factor; / largest v_samp_factor / int min_DCT_h_scaled_size; / smallest DCT_h_scaled_size of any component / int min_DCT_v_scaled_size; / smallest DCT_v_scaled_size of any component / JDIMENSION total_iMCU_rows; / # of iMCU rows to be input to coef ctlr / / The coefficient controller receives data in units of MCU rows as defined * for fully interleaved scans (whether the JPEG file is interleaved or not). * There are v_samp_factor * DCTSIZE sample rows of each component in an * "iMCU" (interleaved MCU) row. / / * These fields are valid during any one scan. * They describe the components and MCUs actually appearing in the scan. / int comps_in_scan; / # of JPEG components in this scan / jpeg_component_info cur_comp_info[MAX_COMPS_IN_SCAN]; /* cur_comp_info[i] describes component that appears i'th in SOS / JDIMENSION MCUs_per_row; /* # of MCUs across the image / JDIMENSION MCU_rows_in_scan; / # of MCU rows in the image / int blocks_in_MCU; / # of DCT blocks per MCU / int MCU_membership[C_MAX_BLOCKS_IN_MCU]; / MCU_membership[i] is index in cur_comp_info of component owning / / i'th block in an MCU / int Ss, Se, Ah, Al; / progressive JPEG parameters for scan / int block_size; / the basic DCT block size: 1..16 / const int natural_order; /* natural-order position array / int lim_Se; / min( Se, DCTSIZE2-1 ) / / * Links to compression subobjects (methods and private variables of modules) / struct jpeg_comp_master master; struct jpeg_c_main_controller * main; struct jpeg_c_prep_controller * prep; struct jpeg_c_coef_controller * coef; struct jpeg_marker_writer * marker; struct jpeg_color_converter * cconvert; struct jpeg_downsampler * downsample; struct jpeg_forward_dct * fdct; struct jpeg_entropy_encoder * entropy; jpeg_scan_info * script_space; /* workspace for jpeg_simple_progression / int script_space_size; }; / Master record for a decompression instance / struct jpeg_decompress_struct { jpeg_common_fields; / Fields shared with jpeg_compress_struct / / Source of compressed data / struct jpeg_source_mgr src; /* Basic description of image --- filled in by jpeg_read_header(). / / Application may inspect these values to decide how to process image. / JDIMENSION image_width; / nominal image width (from SOF marker) / JDIMENSION image_height; / nominal image height / int num_components; / # of color components in JPEG image / J_COLOR_SPACE jpeg_color_space; / colorspace of JPEG image / / Decompression processing parameters --- these fields must be set before * calling jpeg_start_decompress(). Note that jpeg_read_header() initializes * them to default values. / J_COLOR_SPACE out_color_space; / colorspace for output / unsigned int scale_num, scale_denom; / fraction by which to scale image / double output_gamma; / image gamma wanted in output / boolean buffered_image; / TRUE=multiple output passes / boolean raw_data_out; / TRUE=downsampled data wanted / J_DCT_METHOD dct_method; / IDCT algorithm selector / boolean do_fancy_upsampling; / TRUE=apply fancy upsampling / boolean do_block_smoothing; / TRUE=apply interblock smoothing / boolean quantize_colors; / TRUE=colormapped output wanted / / the following are ignored if not quantize_colors: / J_DITHER_MODE dither_mode; / type of color dithering to use / boolean two_pass_quantize; / TRUE=use two-pass color quantization / int desired_number_of_colors; / max # colors to use in created colormap / / these are significant only in buffered-image mode: / boolean enable_1pass_quant; / enable future use of 1-pass quantizer / boolean enable_external_quant;/ enable future use of external colormap / boolean enable_2pass_quant; / enable future use of 2-pass quantizer / / Description of actual output image that will be returned to application. * These fields are computed by jpeg_start_decompress(). * You can also use jpeg_calc_output_dimensions() to determine these values * in advance of calling jpeg_start_decompress(). / JDIMENSION output_width; / scaled image width / JDIMENSION output_height; / scaled image height / int out_color_components; / # of color components in out_color_space / int output_components; / # of color components returned / / output_components is 1 (a colormap index) when quantizing colors; * otherwise it equals out_color_components. / int rec_outbuf_height; / min recommended height of scanline buffer / / If the buffer passed to jpeg_read_scanlines() is less than this many rows * high, space and time will be wasted due to unnecessary data copying. * Usually rec_outbuf_height will be 1 or 2, at most 4. / / When quantizing colors, the output colormap is described by these fields. * The application can supply a colormap by setting colormap non-NULL before * calling jpeg_start_decompress; otherwise a colormap is created during * jpeg_start_decompress or jpeg_start_output. * The map has out_color_components rows and actual_number_of_colors columns. / int actual_number_of_colors; / number of entries in use / JSAMPARRAY colormap; / The color map as a 2-D pixel array / / State variables: these variables indicate the progress of decompression. * The application may examine these but must not modify them. / / Row index of next scanline to be read from jpeg_read_scanlines(). * Application may use this to control its processing loop, e.g., * "while (output_scanline < output_height)". / JDIMENSION output_scanline; / 0 .. output_height-1 / / Current input scan number and number of iMCU rows completed in scan. * These indicate the progress of the decompressor input side. / int input_scan_number; / Number of SOS markers seen so far / JDIMENSION input_iMCU_row; / Number of iMCU rows completed / / The "output scan number" is the notional scan being displayed by the * output side. The decompressor will not allow output scan/row number * to get ahead of input scan/row, but it can fall arbitrarily far behind. / int output_scan_number; / Nominal scan number being displayed / JDIMENSION output_iMCU_row; / Number of iMCU rows read / / Current progression status. coef_bits[c][i] indicates the precision * with which component c's DCT coefficient i (in zigzag order) is known. * It is -1 when no data has yet been received, otherwise it is the point * transform (shift) value for the most recent scan of the coefficient * (thus, 0 at completion of the progression). * This pointer is NULL when reading a non-progressive file. / int (coef_bits)[DCTSIZE2]; /* -1 or current Al value for each coef / / Internal JPEG parameters --- the application usually need not look at * these fields. Note that the decompressor output side may not use * any parameters that can change between scans. / / Quantization and Huffman tables are carried forward across input * datastreams when processing abbreviated JPEG datastreams. / JQUANT_TBL quant_tbl_ptrs[NUM_QUANT_TBLS]; /* ptrs to coefficient quantization tables, or NULL if not defined / JHUFF_TBL dc_huff_tbl_ptrs[NUM_HUFF_TBLS]; JHUFF_TBL * ac_huff_tbl_ptrs[NUM_HUFF_TBLS]; /* ptrs to Huffman coding tables, or NULL if not defined / / These parameters are never carried across datastreams, since they * are given in SOF/SOS markers or defined to be reset by SOI. / int data_precision; / bits of precision in image data / jpeg_component_info comp_info; /* comp_info[i] describes component that appears i'th in SOF / boolean is_baseline; / TRUE if Baseline SOF0 encountered / boolean progressive_mode; / TRUE if SOFn specifies progressive mode / boolean arith_code; / TRUE=arithmetic coding, FALSE=Huffman / UINT8 arith_dc_L[NUM_ARITH_TBLS]; / L values for DC arith-coding tables / UINT8 arith_dc_U[NUM_ARITH_TBLS]; / U values for DC arith-coding tables / UINT8 arith_ac_K[NUM_ARITH_TBLS]; / Kx values for AC arith-coding tables / unsigned int restart_interval; / MCUs per restart interval, or 0 for no restart / / These fields record data obtained from optional markers recognized by * the JPEG library. / boolean saw_JFIF_marker; / TRUE iff a JFIF APP0 marker was found / / Data copied from JFIF marker; only valid if saw_JFIF_marker is TRUE: / UINT8 JFIF_major_version; / JFIF version number / UINT8 JFIF_minor_version; UINT8 density_unit; / JFIF code for pixel size units / UINT16 X_density; / Horizontal pixel density / UINT16 Y_density; / Vertical pixel density / boolean saw_Adobe_marker; / TRUE iff an Adobe APP14 marker was found / UINT8 Adobe_transform; / Color transform code from Adobe marker / J_COLOR_TRANSFORM color_transform; / Color transform identifier derived from LSE marker, otherwise zero / boolean CCIR601_sampling; / TRUE=first samples are cosited / / Aside from the specific data retained from APPn markers known to the * library, the uninterpreted contents of any or all APPn and COM markers * can be saved in a list for examination by the application. / jpeg_saved_marker_ptr marker_list; / Head of list of saved markers / / Remaining fields are known throughout decompressor, but generally * should not be touched by a surrounding application. / / * These fields are computed during decompression startup / int max_h_samp_factor; / largest h_samp_factor / int max_v_samp_factor; / largest v_samp_factor / int min_DCT_h_scaled_size; / smallest DCT_h_scaled_size of any component / int min_DCT_v_scaled_size; / smallest DCT_v_scaled_size of any component / JDIMENSION total_iMCU_rows; / # of iMCU rows in image / / The coefficient controller's input and output progress is measured in * units of "iMCU" (interleaved MCU) rows. These are the same as MCU rows * in fully interleaved JPEG scans, but are used whether the scan is * interleaved or not. We define an iMCU row as v_samp_factor DCT block * rows of each component. Therefore, the IDCT output contains * v_samp_factorDCT_v_scaled_size sample rows of a component per iMCU row. / JSAMPLE * sample_range_limit; /* table for fast range-limiting / / * These fields are valid during any one scan. * They describe the components and MCUs actually appearing in the scan. * Note that the decompressor output side must not use these fields. / int comps_in_scan; / # of JPEG components in this scan / jpeg_component_info cur_comp_info[MAX_COMPS_IN_SCAN]; /* cur_comp_info[i] describes component that appears i'th in SOS / JDIMENSION MCUs_per_row; /* # of MCUs across the image / JDIMENSION MCU_rows_in_scan; / # of MCU rows in the image / int blocks_in_MCU; / # of DCT blocks per MCU / int MCU_membership[D_MAX_BLOCKS_IN_MCU]; / MCU_membership[i] is index in cur_comp_info of component owning / / i'th block in an MCU / int Ss, Se, Ah, Al; / progressive JPEG parameters for scan / / These fields are derived from Se of first SOS marker. / int block_size; / the basic DCT block size: 1..16 / const int natural_order; /* natural-order position array for entropy decode / int lim_Se; / min( Se, DCTSIZE2-1 ) for entropy decode / / This field is shared between entropy decoder and marker parser. * It is either zero or the code of a JPEG marker that has been * read from the data source, but has not yet been processed. / int unread_marker; / * Links to decompression subobjects (methods, private variables of modules) / struct jpeg_decomp_master master; struct jpeg_d_main_controller * main; struct jpeg_d_coef_controller * coef; struct jpeg_d_post_controller * post; struct jpeg_input_controller * inputctl; struct jpeg_marker_reader * marker; struct jpeg_entropy_decoder * entropy; struct jpeg_inverse_dct * idct; struct jpeg_upsampler * upsample; struct jpeg_color_deconverter * cconvert; struct jpeg_color_quantizer * cquantize; }; /* "Object" declarations for JPEG modules that may be supplied or called * directly by the surrounding application. * As with all objects in the JPEG library, these structs only define the * publicly visible methods and state variables of a module. Additional * private fields may exist after the public ones. / / Error handler object / struct jpeg_error_mgr { / Error exit handler: does not return to caller / JMETHOD(noreturn_t, error_exit, (j_common_ptr cinfo)); / Conditionally emit a trace or warning message / JMETHOD(void, emit_message, (j_common_ptr cinfo, int msg_level)); / Routine that actually outputs a trace or error message / JMETHOD(void, output_message, (j_common_ptr cinfo)); / Format a message string for the most recent JPEG error or message / JMETHOD(void, format_message, (j_common_ptr cinfo, char buffer)); #define JMSG_LENGTH_MAX 200 /* recommended size of format_message buffer / / Reset error state variables at start of a new image / JMETHOD(void, reset_error_mgr, (j_common_ptr cinfo)); / The message ID code and any parameters are saved here. * A message can have one string parameter or up to 8 int parameters. / int msg_code; #define JMSG_STR_PARM_MAX 80 union { int i[8]; char s[JMSG_STR_PARM_MAX]; } msg_parm; / Standard state variables for error facility / int trace_level; / max msg_level that will be displayed / / For recoverable corrupt-data errors, we emit a warning message, * but keep going unless emit_message chooses to abort. emit_message * should count warnings in num_warnings. The surrounding application * can check for bad data by seeing if num_warnings is nonzero at the * end of processing. / long num_warnings; / number of corrupt-data warnings / / These fields point to the table(s) of error message strings. * An application can change the table pointer to switch to a different * message list (typically, to change the language in which errors are * reported). Some applications may wish to add additional error codes * that will be handled by the JPEG library error mechanism; the second * table pointer is used for this purpose. * * First table includes all errors generated by JPEG library itself. * Error code 0 is reserved for a "no such error string" message. / const char const * jpeg_message_table; /* Library errors / int last_jpeg_message; / Table contains strings 0..last_jpeg_message / / Second table can be added by application (see cjpeg/djpeg for example). * It contains strings numbered first_addon_message..last_addon_message. / const char const * addon_message_table; /* Non-library errors / int first_addon_message; / code for first string in addon table / int last_addon_message; / code for last string in addon table / }; / Progress monitor object / struct jpeg_progress_mgr { JMETHOD(void, progress_monitor, (j_common_ptr cinfo)); long pass_counter; / work units completed in this pass / long pass_limit; / total number of work units in this pass / int completed_passes; / passes completed so far / int total_passes; / total number of passes expected / }; / Data destination object for compression / struct jpeg_destination_mgr { JOCTET next_output_byte; /* => next byte to write in buffer / size_t free_in_buffer; / # of byte spaces remaining in buffer / JMETHOD(void, init_destination, (j_compress_ptr cinfo)); JMETHOD(boolean, empty_output_buffer, (j_compress_ptr cinfo)); JMETHOD(void, term_destination, (j_compress_ptr cinfo)); }; / Data source object for decompression / struct jpeg_source_mgr { const JOCTET next_input_byte; /* => next byte to read from buffer / size_t bytes_in_buffer; / # of bytes remaining in buffer / JMETHOD(void, init_source, (j_decompress_ptr cinfo)); JMETHOD(boolean, fill_input_buffer, (j_decompress_ptr cinfo)); JMETHOD(void, skip_input_data, (j_decompress_ptr cinfo, long num_bytes)); JMETHOD(boolean, resync_to_restart, (j_decompress_ptr cinfo, int desired)); JMETHOD(void, term_source, (j_decompress_ptr cinfo)); }; / Memory manager object. * Allocates "small" objects (a few K total), "large" objects (tens of K), * and "really big" objects (virtual arrays with backing store if needed). * The memory manager does not allow individual objects to be freed; rather, * each created object is assigned to a pool, and whole pools can be freed * at once. This is faster and more convenient than remembering exactly what * to free, especially where malloc()/free() are not too speedy. * NB: alloc routines never return NULL. They exit to error_exit if not * successful. / #define JPOOL_PERMANENT 0 / lasts until master record is destroyed / #define JPOOL_IMAGE 1 / lasts until done with image/datastream / #define JPOOL_NUMPOOLS 2 typedef struct jvirt_sarray_control jvirt_sarray_ptr; typedef struct jvirt_barray_control * jvirt_barray_ptr; struct jpeg_memory_mgr { /* Method pointers / JMETHOD(void , alloc_small, (j_common_ptr cinfo, int pool_id, size_t sizeofobject)); JMETHOD(void FAR , alloc_large, (j_common_ptr cinfo, int pool_id, size_t sizeofobject)); JMETHOD(JSAMPARRAY, alloc_sarray, (j_common_ptr cinfo, int pool_id, JDIMENSION samplesperrow, JDIMENSION numrows)); JMETHOD(JBLOCKARRAY, alloc_barray, (j_common_ptr cinfo, int pool_id, JDIMENSION blocksperrow, JDIMENSION numrows)); JMETHOD(jvirt_sarray_ptr, request_virt_sarray, (j_common_ptr cinfo, int pool_id, boolean pre_zero, JDIMENSION samplesperrow, JDIMENSION numrows, JDIMENSION maxaccess)); JMETHOD(jvirt_barray_ptr, request_virt_barray, (j_common_ptr cinfo, int pool_id, boolean pre_zero, JDIMENSION blocksperrow, JDIMENSION numrows, JDIMENSION maxaccess)); JMETHOD(void, realize_virt_arrays, (j_common_ptr cinfo)); JMETHOD(JSAMPARRAY, access_virt_sarray, (j_common_ptr cinfo, jvirt_sarray_ptr ptr, JDIMENSION start_row, JDIMENSION num_rows, boolean writable)); JMETHOD(JBLOCKARRAY, access_virt_barray, (j_common_ptr cinfo, jvirt_barray_ptr ptr, JDIMENSION start_row, JDIMENSION num_rows, boolean writable)); JMETHOD(void, free_pool, (j_common_ptr cinfo, int pool_id)); JMETHOD(void, self_destruct, (j_common_ptr cinfo)); / Limit on memory allocation for this JPEG object. (Note that this is * merely advisory, not a guaranteed maximum; it only affects the space * used for virtual-array buffers.) May be changed by outer application * after creating the JPEG object. / long max_memory_to_use; / Maximum allocation request accepted by alloc_large. / long max_alloc_chunk; }; / Routine signature for application-supplied marker processing methods. * Need not pass marker code since it is stored in cinfo->unread_marker. / typedef JMETHOD(boolean, jpeg_marker_parser_method, (j_decompress_ptr cinfo)); / Declarations for routines called by application. * The JPP macro hides prototype parameters from compilers that can't cope. * Note JPP requires double parentheses. / #ifdef HAVE_PROTOTYPES #define JPP(arglist) arglist #else #define JPP(arglist) () #endif / Short forms of external names for systems with brain-damaged linkers. * We shorten external names to be unique in the first six letters, which * is good enough for all known systems. * (If your compiler itself needs names to be unique in less than 15 * characters, you are out of luck. Get a better compiler.) / #ifdef NEED_SHORT_EXTERNAL_NAMES #define jpeg_std_error jStdError #define jpeg_CreateCompress jCreaCompress #define jpeg_CreateDecompress jCreaDecompress #define jpeg_destroy_compress jDestCompress #define jpeg_destroy_decompress jDestDecompress #define jpeg_stdio_dest jStdDest #define jpeg_stdio_src jStdSrc #define jpeg_mem_dest jMemDest #define jpeg_mem_src jMemSrc #define jpeg_set_defaults jSetDefaults #define jpeg_set_colorspace jSetColorspace #define jpeg_default_colorspace jDefColorspace #define jpeg_set_quality jSetQuality #define jpeg_set_linear_quality jSetLQuality #define jpeg_default_qtables jDefQTables #define jpeg_add_quant_table jAddQuantTable #define jpeg_quality_scaling jQualityScaling #define jpeg_simple_progression jSimProgress #define jpeg_suppress_tables jSuppressTables #define jpeg_alloc_quant_table jAlcQTable #define jpeg_alloc_huff_table jAlcHTable #define jpeg_start_compress jStrtCompress #define jpeg_write_scanlines jWrtScanlines #define jpeg_finish_compress jFinCompress #define jpeg_calc_jpeg_dimensions jCjpegDimensions #define jpeg_write_raw_data jWrtRawData #define jpeg_write_marker jWrtMarker #define jpeg_write_m_header jWrtMHeader #define jpeg_write_m_byte jWrtMByte #define jpeg_write_tables jWrtTables #define jpeg_read_header jReadHeader #define jpeg_start_decompress jStrtDecompress #define jpeg_read_scanlines jReadScanlines #define jpeg_finish_decompress jFinDecompress #define jpeg_read_raw_data jReadRawData #define jpeg_has_multiple_scans jHasMultScn #define jpeg_start_output jStrtOutput #define jpeg_finish_output jFinOutput #define jpeg_input_complete jInComplete #define jpeg_new_colormap jNewCMap #define jpeg_consume_input jConsumeInput #define jpeg_core_output_dimensions jCoreDimensions #define jpeg_calc_output_dimensions jCalcDimensions #define jpeg_save_markers jSaveMarkers #define jpeg_set_marker_processor jSetMarker #define jpeg_read_coefficients jReadCoefs #define jpeg_write_coefficients jWrtCoefs #define jpeg_copy_critical_parameters jCopyCrit #define jpeg_abort_compress jAbrtCompress #define jpeg_abort_decompress jAbrtDecompress #define jpeg_abort jAbort #define jpeg_destroy jDestroy #define jpeg_resync_to_restart jResyncRestart #endif / NEED_SHORT_EXTERNAL_NAMES / / Default error-management setup / EXTERN(struct jpeg_error_mgr ) jpeg_std_error JPP((struct jpeg_error_mgr * err)); /* Initialization of JPEG compression objects. * jpeg_create_compress() and jpeg_create_decompress() are the exported * names that applications should call. These expand to calls on * jpeg_CreateCompress and jpeg_CreateDecompress with additional information * passed for version mismatch checking. * NB: you must set up the error-manager BEFORE calling jpeg_create_xxx. / #define jpeg_create_compress(cinfo) \ jpeg_CreateCompress((cinfo), JPEG_LIB_VERSION, \ (size_t) sizeof(struct jpeg_compress_struct)) #define jpeg_create_decompress(cinfo) \ jpeg_CreateDecompress((cinfo), JPEG_LIB_VERSION, \ (size_t) sizeof(struct jpeg_decompress_struct)) EXTERN(void) jpeg_CreateCompress JPP((j_compress_ptr cinfo, int version, size_t structsize)); EXTERN(void) jpeg_CreateDecompress JPP((j_decompress_ptr cinfo, int version, size_t structsize)); / Destruction of JPEG compression objects / EXTERN(void) jpeg_destroy_compress JPP((j_compress_ptr cinfo)); EXTERN(void) jpeg_destroy_decompress JPP((j_decompress_ptr cinfo)); / Standard data source and destination managers: stdio streams. / / Caller is responsible for opening the file before and closing after. / EXTERN(void) jpeg_stdio_dest JPP((j_compress_ptr cinfo, FILE outfile)); EXTERN(void) jpeg_stdio_src JPP((j_decompress_ptr cinfo, FILE * infile)); /* Data source and destination managers: memory buffers. / EXTERN(void) jpeg_mem_dest JPP((j_compress_ptr cinfo, unsigned char * outbuffer, unsigned long * outsize)); EXTERN(void) jpeg_mem_src JPP((j_decompress_ptr cinfo, unsigned char * inbuffer, unsigned long insize)); /* Default parameter setup for compression / EXTERN(void) jpeg_set_defaults JPP((j_compress_ptr cinfo)); / Compression parameter setup aids / EXTERN(void) jpeg_set_colorspace JPP((j_compress_ptr cinfo, J_COLOR_SPACE colorspace)); EXTERN(void) jpeg_default_colorspace JPP((j_compress_ptr cinfo)); EXTERN(void) jpeg_set_quality JPP((j_compress_ptr cinfo, int quality, boolean force_baseline)); EXTERN(void) jpeg_set_linear_quality JPP((j_compress_ptr cinfo, int scale_factor, boolean force_baseline)); EXTERN(void) jpeg_default_qtables JPP((j_compress_ptr cinfo, boolean force_baseline)); EXTERN(void) jpeg_add_quant_table JPP((j_compress_ptr cinfo, int which_tbl, const unsigned int basic_table, int scale_factor, boolean force_baseline)); EXTERN(int) jpeg_quality_scaling JPP((int quality)); EXTERN(void) jpeg_simple_progression JPP((j_compress_ptr cinfo)); EXTERN(void) jpeg_suppress_tables JPP((j_compress_ptr cinfo, boolean suppress)); EXTERN(JQUANT_TBL ) jpeg_alloc_quant_table JPP((j_common_ptr cinfo)); EXTERN(JHUFF_TBL ) jpeg_alloc_huff_table JPP((j_common_ptr cinfo)); /* Main entry points for compression / EXTERN(void) jpeg_start_compress JPP((j_compress_ptr cinfo, boolean write_all_tables)); EXTERN(JDIMENSION) jpeg_write_scanlines JPP((j_compress_ptr cinfo, JSAMPARRAY scanlines, JDIMENSION num_lines)); EXTERN(void) jpeg_finish_compress JPP((j_compress_ptr cinfo)); / Precalculate JPEG dimensions for current compression parameters. / EXTERN(void) jpeg_calc_jpeg_dimensions JPP((j_compress_ptr cinfo)); / Replaces jpeg_write_scanlines when writing raw downsampled data. / EXTERN(JDIMENSION) jpeg_write_raw_data JPP((j_compress_ptr cinfo, JSAMPIMAGE data, JDIMENSION num_lines)); / Write a special marker. See libjpeg.txt concerning safe usage. / EXTERN(void) jpeg_write_marker JPP((j_compress_ptr cinfo, int marker, const JOCTET dataptr, unsigned int datalen)); /* Same, but piecemeal. / EXTERN(void) jpeg_write_m_header JPP((j_compress_ptr cinfo, int marker, unsigned int datalen)); EXTERN(void) jpeg_write_m_byte JPP((j_compress_ptr cinfo, int val)); / Alternate compression function: just write an abbreviated table file / EXTERN(void) jpeg_write_tables JPP((j_compress_ptr cinfo)); / Decompression startup: read start of JPEG datastream to see what's there / EXTERN(int) jpeg_read_header JPP((j_decompress_ptr cinfo, boolean require_image)); / Return value is one of: / #define JPEG_SUSPENDED 0 / Suspended due to lack of input data / #define JPEG_HEADER_OK 1 / Found valid image datastream / #define JPEG_HEADER_TABLES_ONLY 2 / Found valid table-specs-only datastream / / If you pass require_image = TRUE (normal case), you need not check for * a TABLES_ONLY return code; an abbreviated file will cause an error exit. * JPEG_SUSPENDED is only possible if you use a data source module that can * give a suspension return (the stdio source module doesn't). / / Main entry points for decompression / EXTERN(boolean) jpeg_start_decompress JPP((j_decompress_ptr cinfo)); EXTERN(JDIMENSION) jpeg_read_scanlines JPP((j_decompress_ptr cinfo, JSAMPARRAY scanlines, JDIMENSION max_lines)); EXTERN(boolean) jpeg_finish_decompress JPP((j_decompress_ptr cinfo)); / Replaces jpeg_read_scanlines when reading raw downsampled data. / EXTERN(JDIMENSION) jpeg_read_raw_data JPP((j_decompress_ptr cinfo, JSAMPIMAGE data, JDIMENSION max_lines)); / Additional entry points for buffered-image mode. / EXTERN(boolean) jpeg_has_multiple_scans JPP((j_decompress_ptr cinfo)); EXTERN(boolean) jpeg_start_output JPP((j_decompress_ptr cinfo, int scan_number)); EXTERN(boolean) jpeg_finish_output JPP((j_decompress_ptr cinfo)); EXTERN(boolean) jpeg_input_complete JPP((j_decompress_ptr cinfo)); EXTERN(void) jpeg_new_colormap JPP((j_decompress_ptr cinfo)); EXTERN(int) jpeg_consume_input JPP((j_decompress_ptr cinfo)); / Return value is one of: / / #define JPEG_SUSPENDED 0 Suspended due to lack of input data / #define JPEG_REACHED_SOS 1 / Reached start of new scan / #define JPEG_REACHED_EOI 2 / Reached end of image / #define JPEG_ROW_COMPLETED 3 / Completed one iMCU row / #define JPEG_SCAN_COMPLETED 4 / Completed last iMCU row of a scan / / Precalculate output dimensions for current decompression parameters. / EXTERN(void) jpeg_core_output_dimensions JPP((j_decompress_ptr cinfo)); EXTERN(void) jpeg_calc_output_dimensions JPP((j_decompress_ptr cinfo)); / Control saving of COM and APPn markers into marker_list. / EXTERN(void) jpeg_save_markers JPP((j_decompress_ptr cinfo, int marker_code, unsigned int length_limit)); / Install a special processing method for COM or APPn markers. / EXTERN(void) jpeg_set_marker_processor JPP((j_decompress_ptr cinfo, int marker_code, jpeg_marker_parser_method routine)); / Read or write raw DCT coefficients --- useful for lossless transcoding. / EXTERN(jvirt_barray_ptr ) jpeg_read_coefficients JPP((j_decompress_ptr cinfo)); EXTERN(void) jpeg_write_coefficients JPP((j_compress_ptr cinfo, jvirt_barray_ptr * coef_arrays)); EXTERN(void) jpeg_copy_critical_parameters JPP((j_decompress_ptr srcinfo, j_compress_ptr dstinfo)); /* If you choose to abort compression or decompression before completing * jpeg_finish_(de)compress, then you need to clean up to release memory, * temporary files, etc. You can just call jpeg_destroy_(de)compress * if you're done with the JPEG object, but if you want to clean it up and * reuse it, call this: / EXTERN(void) jpeg_abort_compress JPP((j_compress_ptr cinfo)); EXTERN(void) jpeg_abort_decompress JPP((j_decompress_ptr cinfo)); / Generic versions of jpeg_abort and jpeg_destroy that work on either * flavor of JPEG object. These may be more convenient in some places. / EXTERN(void) jpeg_abort JPP((j_common_ptr cinfo)); EXTERN(void) jpeg_destroy JPP((j_common_ptr cinfo)); / Default restart-marker-resync procedure for use by data source modules / EXTERN(boolean) jpeg_resync_to_restart JPP((j_decompress_ptr cinfo, int desired)); / These marker codes are exported since applications and data source modules * are likely to want to use them. / #define JPEG_RST0 0xD0 / RST0 marker code / #define JPEG_EOI 0xD9 / EOI marker code / #define JPEG_APP0 0xE0 / APP0 marker code / #define JPEG_COM 0xFE / COM marker code / / If we have a brain-damaged compiler that emits warnings (or worse, errors) * for structure definitions that are never filled in, keep it quiet by * supplying dummy definitions for the various substructures. / #ifdef INCOMPLETE_TYPES_BROKEN #ifndef JPEG_INTERNALS / will be defined in jpegint.h / struct jvirt_sarray_control { long dummy; }; struct jvirt_barray_control { long dummy; }; struct jpeg_comp_master { long dummy; }; struct jpeg_c_main_controller { long dummy; }; struct jpeg_c_prep_controller { long dummy; }; struct jpeg_c_coef_controller { long dummy; }; struct jpeg_marker_writer { long dummy; }; struct jpeg_color_converter { long dummy; }; struct jpeg_downsampler { long dummy; }; struct jpeg_forward_dct { long dummy; }; struct jpeg_entropy_encoder { long dummy; }; struct jpeg_decomp_master { long dummy; }; struct jpeg_d_main_controller { long dummy; }; struct jpeg_d_coef_controller { long dummy; }; struct jpeg_d_post_controller { long dummy; }; struct jpeg_input_controller { long dummy; }; struct jpeg_marker_reader { long dummy; }; struct jpeg_entropy_decoder { long dummy; }; struct jpeg_inverse_dct { long dummy; }; struct jpeg_upsampler { long dummy; }; struct jpeg_color_deconverter { long dummy; }; struct jpeg_color_quantizer { long dummy; }; #endif / JPEG_INTERNALS / #endif / INCOMPLETE_TYPES_BROKEN / / * The JPEG library modules define JPEG_INTERNALS before including this file. * The internal structure declarations are read only when that is true. * Applications using the library should not include jpegint.h, but may wish * to include jerror.h. / #ifdef JPEG_INTERNALS #include "jpegint.h" / fetch private declarations / #include "jerror.h" / fetch error codes too / #endif #ifdef __cplusplus #ifndef DONT_USE_EXTERN_C } #endif #endif #endif / JPEGLIB_H */	{ "pile_set_name": "Github" }
Genomic Analysis of the Emergence, Evolution, and Spread of Human Respiratory RNA Viruses. The emergence and reemergence of rapidly evolving RNA viruses-particularly those responsible for respiratory diseases, such as influenza viruses and coronaviruses-pose a significant threat to global health, including the potential of major pandemics. Importantly, recent advances in high-throughput genome sequencing enable researchers to reveal the genomic diversity of these viral pathogens at much lower cost and with much greater precision than they could before. In particular, the genome sequence data generated allow inferences to be made on the molecular basis of viral emergence, evolution, and spread in human populations in real time. In this review, we introduce recent computational methods that analyze viral genomic data, particularly in combination with metadata such as sampling time, geographic location, and virulence. We then outline the insights these analyses have provided into the fundamental patterns and processes of evolution and emergence in human respiratory RNA viruses, as well as the major challenges in such genomic analyses.	{ "pile_set_name": "PubMed Abstracts" }
This warning is sent automatically to inform you that your mailbox is approaching the maximum size limit. Your mailbox size is currently 106645 KB. Mailbox size limits: When your mailbox reaches 75000 KB you will receive this message. When your mailbox reaches 100000 KB you will no longer be able to send mail until the size of your mailbox is reduced. To check the size of your mailbox: Right-click the mailbox (Outlook Today), Select Properties and click the Folder Size button. This method can be used on individual folders as well. To make more space available, delete any items that are no longer needed such as Sent Items and Journal entries. You must empty the Deleted Items folder after deleting items or the space will not be freed. To turn Journaling off, click Tools \| Options \| Journaling Options and de-select all items. See client Help for more information.	{ "pile_set_name": "Enron Emails" }
This invention relates mainly to a digital subscriber set, a subscriber terminal for use in a time shared bidirectional digital communication network, such as a time shared two-wire digital communication network. As described in, for example, an article contributed by Jan Meyer, Terje Roste, and Roald Torbergsen to IEEE Transactions on Communications, Vol. COM-27, No. 7 (July 1979), pages 1096-1103, under the title of "A Digital Subscriber Set," with reference to FIGS. 2, 3, 8, and 14 thereof in particular, a time shared two-wire digital communication network comprises a plurality of master terminals, a plurality of subscriber terminals, and a plurality of conventional two-wire communication or subscriber lines between the master and the subscriber terminals. The master terminal may be a line circuit (subscriber circuit) of a digital telecommunication exchange or a like circuit. As will become clear as the description proceeds, a subscriber terminal according to this invention is usable in a more general time shared bidirectional digital communication network. The subscriber terminal may be connected to a master terminal through a more general communication channel. Merely for brevity of description, the network and the master terminal will be restricted in the following to a time shared two-wire digital communication network and to a line circuit in a central office of the network. The communication channel will be called a communication line. Speech and/or data information to be exchanged between a pair of subscriber terminals and consequently between each subscriber terminal and a counterpart master terminal, is bidirectionally transmitted as digital signal bursts through an interconnecting communication line. The data information may be given by facsimile signals. Inasmuch as this invention relates mainly to a subscriber terminal, the signal bursts received thereby from and sent therefrom to the communication line will be referred to as digital "receive" signal bursts and digital "send" signal bursts. In order to separate the two transmission types on the communication line by time division, the receive and the send signal bursts are alternately received from the communication line and sent thereto by a subscriber terminal at a predetermined repetition frequency, herein called a frame frequency. In other words, the communication line transmits successive receive or send signal bursts, one in each frame period. Each signal burst consists of a predetermined number of consecutive signal bits of a bit rate defined by clocks. The information is encoded into the signal bits and decoded therefrom at the subscriber terminal. Such operation of the subscriber terminal must be timed by the frame periods and the clocks. In other words, the operation must be synchronized with phases of the frame periods and the clocks, herein termed a frame phase and a bit phase. On initiating a call from a subscriber terminal, a call originating signal is sent to a master terminal as at least one send signal burst. It has been the practice that the central office always delivers receive signal bursts to all subscriber terminals in the network in order to synchronize the call originating signal with the frame and the bit phases. This is objectionable in view of the power consumption at the central office, which usually remotely feeds the subscriber terminals in the network. An improved subscriber terminal has therefore been proposed to reduce the power consumption. However, the improved subscriber terminal is bulky and heavy and must comprise a hook switch pair as will later be described with reference to one of of the accompanying drawing. However much the subscriber terminal might be improved, the receive and the send signal bursts will still be out of frame and/or clock synchronism at the beginning of call origination. Even during communication, the signal bursts may go out of synchronism. For the best possible performance of a time shared two-wire digital communication network, such loss of synchronism must be corrected within the shortest possible interval of time. Hook switch pairs have been used since very early stages of development of telephones (and are still called by the name of "hook" even in a telephone set where an actual hook is no longer used). Although the hook switch pair is highly reliable, it often causes trouble in the telephone network. The trouble occurs when a handset of the subscriber terminal is misplaced on the "hook." In a telephone set in which a microphone and a loudspeaker are substituted for a conventional handset, the hook switch pair is no longer indispensable.	{ "pile_set_name": "USPTO Backgrounds" }
/* ============================================================================== This file is part of the JUCE library. Copyright (c) 2017 - ROLI Ltd. JUCE is an open source library subject to commercial or open-source licensing. The code included in this file is provided under the terms of the ISC license http://www.isc.org/downloads/software-support-policy/isc-license. Permission To use, copy, modify, and/or distribute this software for any purpose with or without fee is hereby granted provided that the above copyright notice and this permission notice appear in all copies. JUCE IS PROVIDED "AS IS" WITHOUT ANY WARRANTY, AND ALL WARRANTIES, WHETHER EXPRESSED OR IMPLIED, INCLUDING MERCHANTABILITY AND FITNESS FOR PURPOSE, ARE DISCLAIMED. ============================================================================== / namespace juce { //============================================================================== /* An AudioSource that takes a PositionableAudioSource and allows it to be played, stopped, started, etc. This can also be told use a buffer and background thread to read ahead, and if can correct for different sample-rates. You may want to use one of these along with an AudioSourcePlayer and AudioIODevice to control playback of an audio file. @see AudioSource, AudioSourcePlayer @tags{Audio} / class JUCE_API AudioTransportSource : public PositionableAudioSource, public ChangeBroadcaster { public: //============================================================================== /* Creates an AudioTransportSource. After creating one of these, use the setSource() method to select an input source. / AudioTransportSource(); /* Destructor. / ~AudioTransportSource() override; //============================================================================== /* Sets the reader that is being used as the input source. This will stop playback, reset the position to 0 and change to the new reader. The source passed in will not be deleted by this object, so must be managed by the caller. @param newSource the new input source to use. This may be a nullptr @param readAheadBufferSize a size of buffer to use for reading ahead. If this is zero, no reading ahead will be done; if it's greater than zero, a BufferingAudioSource will be used to do the reading-ahead. If you set a non-zero value here, you'll also need to set the readAheadThread parameter. @param readAheadThread if you set readAheadBufferSize to a non-zero value, then you'll also need to supply this TimeSliceThread object for the background reader to use. The thread object must not be deleted while the AudioTransport source is still using it. @param sourceSampleRateToCorrectFor if this is non-zero, it specifies the sample rate of the source, and playback will be sample-rate adjusted to maintain playback at the correct pitch. If this is 0, no sample-rate adjustment will be performed @param maxNumChannels the maximum number of channels that may need to be played / void setSource (PositionableAudioSource newSource, int readAheadBufferSize = 0, TimeSliceThread* readAheadThread = nullptr, double sourceSampleRateToCorrectFor = 0.0, int maxNumChannels = 2); //============================================================================== /** Changes the current playback position in the source stream. The next time the getNextAudioBlock() method is called, this is the time from which it'll read data. @param newPosition the new playback position in seconds @see getCurrentPosition / void setPosition (double newPosition); /* Returns the position that the next data block will be read from This is a time in seconds. / double getCurrentPosition() const; /* Returns the stream's length in seconds. / double getLengthInSeconds() const; /* Returns true if the player has stopped because its input stream ran out of data. / bool hasStreamFinished() const noexcept { return inputStreamEOF; } //============================================================================== /* Starts playing (if a source has been selected). If it starts playing, this will send a message to any ChangeListeners that are registered with this object. / void start(); /* Stops playing. If it's actually playing, this will send a message to any ChangeListeners that are registered with this object. / void stop(); /* Returns true if it's currently playing. / bool isPlaying() const noexcept { return playing; } //============================================================================== /* Changes the gain to apply to the output. @param newGain a factor by which to multiply the outgoing samples, so 1.0 = 0dB, 0.5 = -6dB, 2.0 = 6dB, etc. / void setGain (float newGain) noexcept; /* Returns the current gain setting. @see setGain / float getGain() const noexcept { return gain; } //============================================================================== /* Implementation of the AudioSource method. / void prepareToPlay (int samplesPerBlockExpected, double sampleRate) override; /* Implementation of the AudioSource method. / void releaseResources() override; /* Implementation of the AudioSource method. / void getNextAudioBlock (const AudioSourceChannelInfo&) override; //============================================================================== /* Implements the PositionableAudioSource method. / void setNextReadPosition (int64 newPosition) override; /* Implements the PositionableAudioSource method. / int64 getNextReadPosition() const override; /* Implements the PositionableAudioSource method. / int64 getTotalLength() const override; /* Implements the PositionableAudioSource method. / bool isLooping() const override; private: //============================================================================== PositionableAudioSource source = nullptr; ResamplingAudioSource* resamplerSource = nullptr; BufferingAudioSource* bufferingSource = nullptr; PositionableAudioSource* positionableSource = nullptr; AudioSource* masterSource = nullptr; CriticalSection callbackLock; float gain = 1.0f, lastGain = 1.0f; bool playing = false, stopped = true; double sampleRate = 44100.0, sourceSampleRate = 0; int blockSize = 128, readAheadBufferSize = 0; bool isPrepared = false, inputStreamEOF = false; void releaseMasterResources(); JUCE_DECLARE_NON_COPYABLE_WITH_LEAK_DETECTOR (AudioTransportSource) }; } // namespace juce	{ "pile_set_name": "Github" }
Solar Lamps for 2600 Students in Sundarbans, India Three Lamps for Two Offer this June 12th! By Diti Mookherjee - Project Leader Dear Supporters, You have helped to change the lives of so many young people in the Sundarbans. So many like Kakoli, Hosonara, Pulak and Sheikh Golam who along with their families have a better life today. It is amazing how a solar lamp has transformed lives! Today each student who has been given a solar lamp studies by its steady, powerful light, the family saves over 4% of their annual income from not having to buy kerosene and the fragile ecosystem of the Sundarbans experiences lower carbon emission. A wonderful opportunity comes your way on Bonus Day, June 12, 2013 when for every two solar lamps you donate, GlobalGiving will provide funds for one! Every donation will be matched at 50%. About Project Reports Project Reports on GlobalGiving are posted directly to globalgiving.org by Project Leaders as they are completed, generally every 3-4 months. To protect the integrity of these documents, GlobalGiving does not alter them; therefore you may find some language or formatting issues.	{ "pile_set_name": "Pile-CC" }
The topic of research in this paper, "The future of nationalities and regions in an integrating Europe: The Case of Catalonia", involves all aspects of Catalan life in order to develop and understand their particular and separate nationality. With...	{ "pile_set_name": "Pile-CC" }
NBC is in early development on four new projects it was announced at the Television Critics Association: “a behind-the-scenes look at Hillary Rodham Clinton” titled HILLARY, an “updated retelling” of ROSEMARY’S BABY, STEPHEN KING’S TOMMYKNOCKERS, and PLYMOUTH, which is “based on the epic story of the Mayflower’s landing in America.” Here’s what NBC has to […]	{ "pile_set_name": "Pile-CC" }
Introduction {#S0001} ============ Colon cancer is one of the most common malignant cancers and among the leading causes of cancer-related deaths worldwide.[@CIT0001] The combination therapy of oxaliplatin and fluoropyrimidine has been the standard adjuvant therapy in patients with stage III/IV colon cancer. However, these chemotherapies are toxic and sometimes ineffective. Due to its heterogenicity, multiple genetic mutations were regarded as the underlying causes of this disease, for example, mutations in phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways. Deregulation of MAPK pathway genes have been found, including the amplification and mutation of KRAS, BRAF, and MEK1.[@CIT0002] Therefore, targeting the downstream MEK in the mutated tumors might be a new strategy for colon cancers, especially the patients with KRAS or BRAF mutations. Several MEK inhibitors have entered clinical trial evaluation. However, clinical activity was poor following the treatment with any single MEK inhibitor, and acquired drug resistance appears inevitable.[@CIT0003]--[@CIT0008] Trametinib is a novel oral MEK inhibitor which has been approved by the FDA (Food and Drug Administration) for BRAF-mutated patients alone or in combination with dabrafenib.[@CIT0009]--[@CIT0011] Combination remedies of MEK inhibitors, rather than single medicine therapy, was considered to be more effective in various tumors.[@CIT0012]--[@CIT0014] Therefore, there is an urgent clinical demand for new synergic agents to cooperate with trametinib to enhance the survival of patients with colon cancer. Interferon-Stimulated Gene 15 (ISG15), a ubiquitin-like protein (UBL),[@CIT0015] is an important oncoprotein and has become a potential diagnostic[@CIT0016] and therapeutic[@CIT0017] target for cancer treatment. The function of ISG15 was largely underestimated mainly due to its low expression in most human malignancies.[@CIT0018] Some studies have found that ISG15 expression was elevated and ISG15-conjugates in many malignant tumors, including melanoma[@CIT0019] and oral squamous cell carcinoma[@CIT0020],[@CIT0021] as well as malignancies of the breast,[@CIT0016] endometrium,[@CIT0018] and bladder.[@CIT0022] However, the roles of ISG15 in tumorigenesis and its responses to anticancer treatments in colon cancer remain largely unknown. In a recent study, Roulois et al[@CIT0023] showed that DNA methylation inhibitor 5-aza-2-deoxycytidine (5-AZACdR) could enhance the expression of ISG15 in LIM1215 colon cancer cells, which implied the nature of ISG15 as a tumor suppressor in colorectal cancer. Controversially, Desai et al[@CIT0018] discovered that ISG15 expression and ISG15-conjugated proteins in two colon cancer cases were up-regulated in comparison to normal colon tissues. Whether ISG15 acts as a tumor suppressor or promotor remains controversial. In this study, we explored the function of ISG15 in colon cancer cell lines. Our results showed that high expression of ISG15 was an intrinsic feature for colon cancer, and ISG15 promoted the cell proliferation and metastasis. Trametinib could increase the expression of ISG15 shown by gene expression analysis. After treatment of a synergistic combination of trametinib with ISG15 siRNA, proliferation and colony formation was inhibited in vitro. Thus, combined targeting of ISG15 and MEK might be a promising therapeutic strategy for colon cancer treatment. Materials and Methods {#S0002} ===================== Tissue Samples and Study Cohort {#S0002-S2001} ------------------------------- Sixty-six pairs of tumor samples and matched adjacent non-tumor tissues were obtained from the Shanghai Outdo Biotech Co., Ltd. (Shanghai, China). All the patients signed informed consent forms. This study was approved by the Ethics Committee of Taizhou Hospital of Zhejiang Province. ISG15 expression was detected in all specimens. Two pathologists were appointed to evaluate the specimens separately without prior knowledge of the clinical statuses of the specimens. Immunohistochemistry {#S0002-S2002} -------------------- Immunohistochemistry (IHC) was performed using the biotin-streptavidin HRP detection system according to the manufacturer's instructions. The tissue chips were incubated with ISG15 antibody (1:100; Abcam, Cambridge, UK) in phosphate-buffered saline (PBS) overnight at 4°C in a humidified container. Biotinylated secondary antibodies (Zhongshan Golden Bridge Biotechnology Co. Ltd., China) were applied. The sections were incubated with HRP-streptavidin conjugates appropriate for detecting ISG15. Proper positive and negative controls were included in each IHC assay. Western Blotting Analysis {#S0002-S2003} ------------------------- Total proteins (30 µg) were subjected to fractionation by SDS polyacrylamide gel electrophoresis and immunoblotting assay. Antibodies used in the study included the following: anti-ISG15, anti-PARP, anti-c-Myc, anti-pERK, anti-ERK (all Abcam, Cambridge, UK), and anti-GAPDH (Zhongshan Golden Bridge Biotechnology Co. Ltd., China). Cell Culture and RNA Interference {#S0002-S2004} --------------------------------- Human colon cancer cell lines were obtained from the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, including RKO, HCT116 and SW480. And all the cells were tested and authenticated by an AmpFlSTR Identifiler PCR assays in the year of 2019 in TSINGKE Biological Technology Company. The results showed that RKO and SW480 were 100% exact matched, and HCT116 was 98% matched. All the cell lines were confirmed to be mycoplasma negative via a PCR method and directly thawed from the liquid nitrogen jar. Cells were grown in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum (Gibco, USA), 100mU/mL penicillin, and 100 µg/mL streptomycin in a 5% CO2 atmosphere at 37°C. Cells (1x10 5 cells/well) were seeded into six-well plates and transfected with the indicated constructs using Lipofectamine 2000 (Invitrogen/Life Sciences) according to the manufacturer's instructions. After 72 h, the transfected cells were harvested for further analysis. The sequence of the siRNA sense strand was as follows: si-ISG15\#1: 5-'TCCTGGTGAGGAATAACAA-3ʹ, si-ISG15\#2: 5-'CCAUGUCGGUGUCAGAGCUTT-3ʹ. CCK-8 and Colony Formation Assays {#S0002-S2005} --------------------------------- CCK-8 assay kit was used for colon cancer cell proliferation analysis. Colon cancer cells were seeded in 96-well plate at a density of 5x10^\^3^ cells per well. After incubation, 10 µL CCK8 was added to the wells at different times. The absorbance was measured at 450 nm by a microplate reader (Bio-Rad, Hercules, CA, USA). Colony formation assay was performed to detect the capacity of cell proliferation. RKO, HCT116 and SW480 cells were seeded into 35 mm dishes with 3x10^\^3^ cells per well and cultured for 10 days. Colonies were then fixed with 10% formaldehyde for 30 min and stained for 5 min with 0.5% crystal violet. Wound Healing Assay {#S0002-S2006} ------------------- Colon cancer cells were cultured in 6-well plates and grown until 80--90% confluence. After that, the cell monolayer was scratched with a sterile pipette tip. An Olympus microscope was applied for taking pictures of cell morphology at different time intervals (0,48h). The results were analyzed by ImageJ software. Matrigel Invasion Assays {#S0002-S2007} ------------------------ The capacity invasiveness was determined in a 24-well transwell plate (8 up pore size; Costar). Briefly, 6x10^\^\ 4^ cells were suspended and added to the upper chamber of each insert coated with 200 mg/mL of Matrigel (BD Biosciences, Franklin Lakes, NJ, USA). After 48 h, the cells that traversed the membrane and spread to the lower surface of the filters were stained with haematoxylin and counted.Each experiment was repeated three times independently. RNA Extraction and qRT-PCR {#S0002-S2008} -------------------------- Total RNA was isolated through the guanidinium thiocyanate-phenol-chloroform extraction method using TRIzolsolution (Invitrogen, USA), and cDNA synthesis was done using the Advantage RT-forPCRKit (Takara, Japan). The forward and reverse primers were designed to span two different exons for each gene.The primers for human ISG15 were forward:5ʹ-TGGACAAATGCGACGAACC-3ʹ; reverse: 5ʹ-TTCGTCGTTCACTCGCC-3ʹ.CFX96 Real-Time PCR detectionsystem (Bio-Rad, Hercules, CA, USA) was used to perform qRT-PCR. The threshold cycle number was determinedusing iCycler software version 3.0. Reactions were performed in duplicate and the threshold cycle numbers wereaveraged. The data were analysed using the 2\^^−ΔΔCT^ method. Edu Assay {#S0002-S2009} --------- Quantification of cellular proliferative capacity was determined by 5-Ethynyl-2ʹ-deoxyuridine assay using a Cell-Light TM EdU Apollo^®^488 In Vitro Imaging Kit (Guangzhou RiboBio Co., LTD), according to the manufacturer's instruction. Identification of Differentially Expressed Genes from Public Microarray Data {#S0002-S2010} ---------------------------------------------------------------------------- GSE112282 gene expression profiles were downloaded from the Gene Expression Omnibusdatabase (GEO, [<http://www.ncbi.nlm.nih.gov/geo>]{.ul}). These profiles, deposited by Wyce A et al in 2018, are comprised of two untreated replicates of human colon cells and two replicates of the same cells treated with 25 nM trametinib for 24 h and 96 h. The dataset was analyzed with R BIOCONDUCTOR packages, raw datasets were normalized and DEGs were screened out via the LIMMA package using the cut-off criteria of P-value \< 0.05 and \\|log2(fold change)\\|\>1.5. Functional Enrichment Analysis {#S0002-S2011} ------------------------------ DAVID ([<https://david.ncifcrf.gov/>]{.ul}) was used to perform functional and pathway enrichment analysis. Gene ontology (GO) analysis, including biological process (BP), cellular component (CC) and molecular function (MF)[@CIT0024] enrichment analysis, was carried out for the upregulated genes. P\<0.001 was regarded as indicating statistical significance. Protein-Protein Interaction Network Construction {#S0002-S2012} ------------------------------------------------ In order to interpret the underlying molecular mechanisms, the online Search Tool for the Retrieval of Interacting Genes (STRING) database was utilized to construct a protein-protein interaction (PPI) network of the DEGs. An interaction score of not \< 0.4 (medium confidence score) was deemed statistically significant, and the PPI was visualized. Subsequently, the hub genes were selected based on connection degree by CYTOSCAPE software. Statistical Analysis {#S0002-S2013} -------------------- Assays for characterizing phenotypes of cells were analyzed by Student's test or One-Way ANOVA, presented as the means ± SDs. In the clinical specimen study, the associations of ISG15expression with categorical variables were analyzed using the χ2 test or Fisher's exact test as appropriate. And other variables were analyzed with Spearman correlation test. P values of \<0.05 were deemed statistically significant. Results {#S0003} ======= Up-Regulation of ISG15 Expression in Colon Cancer Samples {#S0003-S2001} --------------------------------------------------------- cBioPortal was applied for cancer genomics datasets analysis. ISG15 was amplified and the mutation frequency was 5% in colon cancers ([Figure 1A](#F0001){ref-type="fig"}). Among them, the ones with high expression of ISG15 mRNA accounted for 4% ([Figure 1B](#F0001){ref-type="fig"}). Moreover, ISG15 mRNA was over-expressed in colon cancer specimens compared to their non-tumor counterparts. ([Figure 1C](#F0001){ref-type="fig"}, P \< 0.05). Kaplan-Meier analysis demonstrated that patients with high ISG15 expression had significantly shorter overall survival (OS) than patients with low ISG15 expression ([Figure 1D](#F0001){ref-type="fig"}, P \< 0.05). Using Western blot, 83.3% (10/12) of the cases showed relatively higher ISG15 expression than their non-tumor counterpart, consistent with the results of mRNA expression analysis ([Figure 1E](#F0001){ref-type="fig"}). To evaluate whether the expression of ISG15 changes as colon cancer progresses, IHC was performed by using an independent formalin-fixed, paraffin-embedded-based (FFPE-based) tissue microarray (TMA) including 66 pairs of colon cancer patients. The results showed that ISG15 expression in colon cancer tissues was obviously higher than that in adjacent noncancerous colon tissues ([Figure 1F](#F0001){ref-type="fig"}). As indicated in [Figure 1G](#F0001){ref-type="fig"}, the mean immunoreactivity scores of the normal and cancer tissues were 1.02 and 5.01, respectively. Samples with scores above 5 were considered as high ISG15 expression ones, leading to the greatest number of tumors classified as having or not having a clinical outcome. In our study, high ISG15 levels were detected in 30/66 (45.5%) of colon cancer patients. The results showed ISG15 expression did not correlate with patient sex, age or lymph node status (P\>0.05). It was, indeed, associated with poor histological classification (P \< 0.01, [Table 1](#T0001){ref-type="table"}). Overall, our data suggested that ISG15 level was higher in colon cancer samples.Table 1Correlation Between ISG15 Expression and Clinicopathological Features of Colon Cancer Patients P-Value=0.0087\: the ISG15 Expression Was Associated with Poor Histological ClassificationStatistical Results of ISG15 Expression in 66 Colon Cancer Cells SpecimensVariablesISG15 ExpressionNLow Expression, nHigh Expression, nP-valueAll cases663630Age≥ 504321220.2997^a^\< 5023158GenderMale3718190.3254^a^Female291811Pathology gradeI (well)12930.0087^\\,b^I-II (moderate)372314II-III (poor)17413Lymph node statusN-4021190.8015^a^N+361511[^1] Figure 1Upregulation of ISG15 expression in colon cancer samples. (A, B) ISG15 status in a colon cancer study obtained from [<http://www.cbioportal.org>]{.ul}. (C) Expression of ISG15 in 286 TCGA cancer and 41 normal samples indicated that ISG15 was obviously upregulated in colon cancer. (D) Kaplan-Meier analysis indicated that high ISG15 expression predicted poorer prognosis in colon cancer. The error bars in all graphs represent SD, and each experiment was repeated three times (\\p\< 0.01 ). (E) The difference in protein expression levels of ISG15 in colon cancer tissues was compared with the corresponding adjacent tissues by Western blot in 12 pairs of human colon cancer specimens. (F, G) The differential expression of ISG15 in colon cancer samples (n = 66) and adjacent normal colon tissues (n =66) is shown by immunohistochemistry. ISG15 staining scores for tumor tissues and normal tissues are represented by a frequency distribution (0--4: low expression; 5--12: high expression). Knockdown of ISG15 Inhibits Cancerous Proliferation and Migration {#S0003-S2002} ----------------------------------------------------------------- We investigated the effect of ISG15 suppression on the malignant phenotypes of colon cancer cells. Results showed that knockdown of ISG15 with si-SG15\#1 and si-SG15\#2 significantly inhibited cell proliferation in the RKO, HCT116 and SW480 cell lines ([Figure 2A](#F0002){ref-type="fig"}). As indicated in [Figure 2B](#F0002){ref-type="fig"}, knockdown by siRNAs resulted in reduced ISG15 protein in colon cancer cell lines. And we concluded that si-SG15\#1 inhibitory effect was stronger than si-SG15\#2. Colony formation assays and Edu assay also indicated that si-ISG15\#1 could significantly inhibited the proliferation and growth of colon cancer cells ([Figure 2C](#F0002){ref-type="fig"} and [D](#F0002){ref-type="fig"}, [[Figure S1A](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul} and [[B](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}). Next, we examined the migratory abilities of HCT116 and SW480 cells by using transwell migration assay. HCT116 and SW480 cells transfected with si-ISG15\#1 displayed lower efficiency of cell migration compared to the vector control ([Figure 2E](#F0002){ref-type="fig"} and [F](#F0002){ref-type="fig"}, P\<0.01). We also performed a wound healing assay by using RKO, HCT116 and SW480 human colon cancer cells. As shown in [Figure 2G](#F0002){ref-type="fig"} and [H](#F0002){ref-type="fig"} and [[Figure S1C](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}, after 48 hrs of silence, si-ISG15\#1 treatment significantly impeded gap closure compared to the vector control. These results indicated that suppression of ISG15 could inhibit the cell growth and migration in colon cancer cells.Figure 2Knockdown ISG15 inhibits cancerous proliferation and migration. (A) Cell proliferation profiling in RKO, HCT116 and SW480 cells infected with si-ISG15\#1 or si-ISG15\#2 continuously for 3 days as analyzed by a CCK8 assay (\p\< 0.05, \\p\< 0.01). (B) Protein levels of ISG15 in the RKO, HCT116 and SW480 cell lines infected with si-ISG15\#1 or si-ISG15\#2. GAPDH was used as an internal control. NC, Negative control; si-ISG15, siRNA of ISG15. (C, D) Colony formation in RKO, HCT116 and SW480 cells infected with si-NC or si-ISG15. The histogram shows the average colony numbers and represents the mean±SEM of three independent experiments (\\\p\< 0.001). (E, F) Transwell invasion assay in si-NC or si-ISG15\#1 transfected HCT116 and SW480 cells. The error bars in all graphs represent the SDs (\\\p\< 0.001). (G, H) Wound-healing assay after transfecting with si-NC or si-ISG15\#1 for 48 h in HCT116 and SW480 cells. Data are shown as the mean ± standard error of the mean (\\\p\< 0.001). Trametinib Treatment Activates the Expression of ISG15 by Identification DEGs {#S0003-S2003} ----------------------------------------------------------------------------- The gene expression profiles of GSE112282 were downloaded from the GEO database, to unravel molecular mechanisms underlying trametinib in the tumors of an experimental mouse model. The GSE112282 dataset contained following four groups: DMSO (control) or 30 nM trametinib for 24 or 96 hrs each in the RKO colon cancer cell line. We found 193 and 304 genes differentially expressed between the control and trametinib groups at 24 and 96 hrs, respectively (\>1.5-fold, p\<0.05, [Figure 3A](#F0003){ref-type="fig"} and [B](#F0003){ref-type="fig"}, [[Figure S2A](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul} and [[2B](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}). Gene ontology analysis were applied to discover the functions of the DEGs for 24 hrs ([[Figure S3](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}) and 96 hrs ([[Figure S4](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}). The DEGs of up-regulated genes were significantly enriched in biological processes related to ossification, transforming growth factor beta receptor signaling pathway (i.e., ISG15, TOB1, ID1) at 24 hrs ([Table 2](#T0002){ref-type="table"}) and type I interferon signaling pathway, cellular response to type I interferon (i.e., ISG15, IRF9, IFITM3, IFI6, IFIT/12/3, and IP6K4) at 96 hrs ([[Table S1](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}). The STRING database and Module analysis via Cytoscape software were constructed to identify gene interactions, the significant hub nodes of the network included IP6K2, ISG15, IFI6, IFI27 and IFITM1 at 24 hrs ([Figure 4](#F0004){ref-type="fig"}) and IFITM3, IRF9, ISG15, IP6K2 and HIST1H2BD at 96 hrs ([[Figure S5](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}). Node degree and betweenness were calculated by the DMNC method to obtain hub nodes. The top 15 candidate hub genes were identified which may play a central role in this network ([[Table S2](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}). And no matter which stage for the trametinib groups (24 hrs or 96 hrs), we found ISG15 always appears as a hub gene and was associated with type I interferon signaling pathway and cellular response to type I interferon. Therefore, the PPI network analysis and hub gene selection and analysis showed that treatment of colon cancer cells with trametinib could induced a dependency on ISG15 signaling especially in terms of type I interferon signaling pathway.Table 2Functional Enrichment Analysis of Up-Regulated Genes Were Significantly Enriched in Biological Process Terms (24h)CategoryIDTerm/gene functionGeneIDGene countpvalueGO_TERM_BPGO:0001503OssificationTOB1/FSTL3/ANO6/FGFR3/ID1/ID3/JUND/SMAD3/TP53INP2/BMPR1A/BMPR2/KLF10/TMSB4X/TUFT1/KAZALD1/CAT/IFITM1/DHRS3/EIF2AK3/ISG15201.28E-07GO_TERM_BPGO:0007179Transforming growth factor beta receptor signaling pathwayCDKN2B/ID1/SMAD3/SMAD7/SMAD9/PTPRK/SKIL/BMPR1A/KLF10/CAV1/CAV2/ADAM9123.58E-06GO_TERM_BPGO:0007178Transmembane receptor protein serine/threonine kinase signaling pathwayTOB1/FSTL3/CDKN2B/HES1/ID1/SMAD3/SMAD7/SMAD9/SKIL/BMPR1A/BMPR2/KLF10/CAV1/CAV2/ADAM9166.40E-06GO_TERM_BPGO:0030282Bone MineralizationANO6/FGFR3/SMAD3/BMPR1A/BMPR2/KLF10/TUFT1/EIF2AK3/ISG1596.56E-06GO_TERM_BPGO:0071560Cellular response to transforming growth factor beta stimulusCDKN2B/ANKRD1/ID1/SMAD3/SMAD7/SMAD9/PTPRK/SKIL/BMPR1A/KLF10/CAV1/CAV2/ADAM9138.08E-06GO_TERM_BPGO:0071559Response to transforming growth factor betaCDKN2B/ANKRD1/ID1/SMAD3/SMAD7/SMAD9/PTPRK/SKIL/BMPR1A/KLF10/CAV1/CAV2/ADAM9139.80E-06GO_TERM_BPGO:0050678Regulating of epithelial cell proliferationCDKN1B/CDKN2B/ANG/HOXA5/HES1/ID1/MIR24-2/SMAD3/PTPRK/PEX2/BMPR1A/BMPR2/CAV1/CAV2/MAGED1151.53E-05GO_TERM_BPGO:0060337Type I interferon signaling pathwayIRF9/IFI6/IFI27/IFIT2/IFIT1/IP6K2/IFITM1/ISG1582.15E-05GO_TERM_BPGO:0071357Cellular response to type I interferonIRF9/IFI6/IFI27/IFIT2/IFIT1/IP6K2/IFITM1/ISG1582.15E-05GO_TERM_BPGO:0050673Epithelial cell proliferationCDKN1B/CDKN2B/ANG/HOXA5/HES1/ID1/ID2/MIR24-2/SMAD3/PTPRK/PEX2/BMPR1A/BMPR2/CAV1/CAV2/MAGED1162.63E-05GO_TERM_BPGO:0034340Repose to type I interferonIRF9/IFI6/IFI27/IFIT2/IFIT1/IP6K2/IFITM1/ISG1583.22E-05GO_TERM_BPGO:0030278Regulation of ossificationTBO1/ANO6/ID1/ID3/JUND/SMAD3/BMPR1A/BMPR2/IFITM1/DHRS3/ISG15113.49E-05 Figure 3Trametinib treatment activates the expression of ISG15 as shown by the identification of DEGs. (A) Volcanoplot of the 193 identified DEGs at 24 hrs. Red indicates DEGs with a \\|log2FC\\|\>1.5. DEG, differentially expressed gene; FC, fold change. (B) Heat map showing the 193 differentially expressed genes betweenthe trametinib (n=2) and control groups at 24 hrs. (n=2; \>1.5-fold, p\<0.05). The most highly upregulated (red) and downregulated (green) genes in the trametinib group are listed.Figure 4Functional enrichment analysis of upregulated DEGs in trametinib treatment for 24h. Using the STRING online database and Cytoscape, upregulated genes in the trametinib groups were filtered into the DEG PPI network complex. (IP6K2, ISG15, IFI6, IFI27, IFITM1, MIS18A and so on are hub genes in red or orange; other linked genes in blue). Inhibition of ISG15 Enhances the Anti-Cancer Effect of Trametinib in Colon Cancer Cells {#S0003-S2004} --------------------------------------------------------------------------------------- We next tested whether combined therapeutic strategies with trametinib and ISG15 inhibition could be effective in treating colon cancer cells. As shown in [Figure 5B](#F0005){ref-type="fig"}, trametinib decreased the expression of c-Myc, a cell proliferation related protein, and improved the expression of Bax, an apoptosis inducing protein. Furthermore, trametinib increased the mRNA and protein expression of ISG15 ([Figure 5A](#F0005){ref-type="fig"} and [B](#F0005){ref-type="fig"}). Therefore, we treated cancer cells with ISG15 siRNA and trametinib and found that this combination had a synergistic effect that inhibited cell proliferation ([Figure 5C](#F0005){ref-type="fig"}, [[Figure S1D](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}) and colony formation ([Figures 5D](#F0005){ref-type="fig"}, [[S1E and F](https://www.dovepress.com/get_supplementary_file.php?f=226395.zip)]{.ul}). Next, we also examined the expression of c-Myc and Bax by Western blot following the knockdown of ISG15, and found that suppression of ISG15 had no effect on c-Myc, but promoted the upregulation of Bax ([Figure 5E](#F0005){ref-type="fig"}). Finally, we combined trametinib with si-ISG15 to investigate whether ISG15 inhibition enhances the cytotoxicity of trametinib against colon cancer at the protein levels. Our results showed that si-ISG15 synergized with trametinib to dramatically reduce the expression of ISG15 and increase the pro-apoptotic genes PARP and Bax ([Figure 5F](#F0005){ref-type="fig"}). Together, ISG15 inhibition combined with trametinib displayed synergistic inhibitory effects in colon cancer cells.Figure 5ISG15 inhibition enhances the anti-cancer effect of trametinib in colon cancer cells. (A) The mRNA expression of ISG15 following treatment with the indicated concentrations of trametinib (0--50 nM) in colon cancer cells for 2 d by qPCR assay (\p\< 0.05, \\p\< 0.01, \\\p\< 0.001). (B) WB for ISG15, c-Myc, Bax, pERK and ERK following treatment with the indicated concentrations of trametinib (0--50 nM) in colon cancer cells for 2 d. (C) Histograms shows the percentage of cell proliferation in colon cancer cells after transfection with si-ISG15 and/or 25 nM trametinib by CCK8 assays at day 3 (\\\p\< 0.001). (D) Colony formation assays show that knockdown of ISG15 combined with 25 nM trametinib inhibited colon cancer cell proliferation at day 7. (E) The levels of ISG15, c-Myc and Bax following ISG15 silencing in colon cancer cells for 3 d as determined via Western blot. NC, Negative control; si-ISG15, siRNA of ISG15. (F) The levels of ISG15, cleaved PARP and Bax following treatment with si-ISG15 (and/or 25 nM trametinib) in RKO and HCT116 cells for 3 d. NC, Negative control; si-ISG15, siRNA of ISG15. Discussion {#S0004} ========== ISG15, a 15 KDa protein, belongs to the ubiquitin-like (UBL) superfamily[@CIT0025] which is synthesized by several cells in response to various stimuli such as type-I IFNs, virus and genotoxicity.[@CIT0026] In addition, the function of ISG15 involves in diverse cellular pathways, including translation, RNA splicing, chromatin remodeling, polymerase II transcription, cytoskeleton organization, stress responses,[@CIT0027] autophagy[@CIT0028] and metabolism.[@CIT0029] Previous studies have discovered that ISG15 expression is associated with tumor responses to chemotherapy, radiotherapy and IFN-α treatment.[@CIT0030],[@CIT0031],[@CIT0032] Recently researchers have identified ISG15-deficient patients and suggested the underlying process of ISG15 regulation, these might cast some light on the intricacy of this protein. Also, there has been voices demanding a re-evaluation of ISG15.[@CIT0033] Several investigations has demonstrated the carcinogenicity of ISG15, which played an important role in cancer-associated inflammation.[@CIT0018],[@CIT0020],[@CIT0021],[@CIT0023] ISG15 is also associated with cytoskeleton disruption, cancer cell migration and poor prognosis.[@CIT0034] Recently, ISG15 is thought to function both as an oncogene and a tumor-suppressor gene in different tumors.[@CIT0035] For example, knockdown of ISG15 expression reduced breast cancer cell motility compared to the control in cell migration assays.[@CIT0036] In another study, Jeon et al[@CIT0037] reported that ISG15, as a possible tumor suppressor, provoked anchorage-dependent cell growth after doxorubicin treatment in mouse breast cancer model. Adam R.Brown[@CIT0038] purposed a process through which those select IFN-stimulated genes, especially ISG15, may facilitate colon cancer cell survival and growth by suppressing apoptosis, which was consistent with our findings. In addition, protein ISGylation could exacerbate experimental colitis and colitis-associated cancer. Jun-Bao Fana[@CIT0039] discovered an elevation of inflammation-related cytokines as well as the p38 MAP kinase activation induced by LPS in mouse. Above all, ISG15 plays an important role in the progression of various tumors. However, the pathological or physiological functions of ISG15 and their implications for targeted therapy have not been clearly elucidated in colon cancer. In our study, immunohistochemical analysis and Western blot analysis were used to detect ISG15 expression in colon tumor tissues and pericancerous tissues. The results demonstrated that the expression of ISG15 protein was significantly higher in tumors than that in adjacent control tissues. Additionally, inhibition of ISG15 with siRNA could suppress tumor growth and migration in colon cancer. Using bioinformatics, it was also predicted that the ISG15 mRNA level of colon cancer patients was higher than that of normal patients, and the expression level of ISG15 was inversely proportional to the overall survival (OS) in colon cancer patients. Further investigation in gene expression indicated that trametinib treatment could induce the expression of ISG15. While suppression of ISG15 by siRNA could enhance the cytotoxicity of trametinib against colon cancer. In summary, we have identified ISG15 as an oncogene in colon cancer, with a mechanism that mainly dealt with the proliferation and metastasis of colon cancer cells. Notably, our data point out the possibility that inhibition of ISG15 with small molecules which do not currently exist combined with trametinib treatment would be a novel therapeutic strategy for colon cancer. Ethics Approval and Consent to Participate {#S0005} ========================================== The human colon cancer tissues as provided by the Ethics Committee of Taizhou Hospital of Zhejiang Province. Funding {#S0006} ======= This work was supported by the National Natural Science Foundation of China (Grant No.81572850). Disclosure {#S0007} ========== No potential conflict of interest was reported by the authors. [^1]: Notes: \\p\<0.01, The ISG15 expression was associated with poor histological classification. ^a^Fisher's exact test was used for statistical analyses. ^b^Pearson's χ2 test was used for statistical analyses.	{ "pile_set_name": "PubMed Central" }
305 F.3d 456 Lloyd D. ALKIRE, Plaintiff-Appellant,v.Judge Jane IRVING, et al., Defendants-Appellees. No. 00-4567. United States Court of Appeals, Sixth Circuit. Argued: March 6, 2002. Decided and Filed: September 18, 2002. COPYRIGHT MATERIAL OMITTED COPYRIGHT MATERIAL OMITTED COPYRIGHT MATERIAL OMITTED COPYRIGHT MATERIAL OMITTED COPYRIGHT MATERIAL OMITTED Gary M. Smith (argued and briefed), Equal Justice Foundation, Columbus, OH, Edward A. Icove (briefed), Smith & Condeni, Cleveland, OH, for Appellant. 1 Timothy T. Reid (argued and briefed), Reid, Berry, Marshall & Wargo, Cleveland, OH, for Appellees. 2 Before MOORE and COLE, Circuit Judges; TARNOW, District Judge.* OPINION 3 TARNOW, District Judge. I. INTRODUCTION 4 Plaintiff Lloyd D. Alkire was arrested for drunk driving and held almost seventy-two hours without a probable cause hearing. He was subsequently incarcerated for failure to appear for show cause hearings and failure to pay fines and court costs. Alkire sued defendants Holmes County, Judge Jane Irving, Holmes County Court, and Sheriff Timothy Zimmerly under 42 U.S.C. § 1983, arguing that his constitutional rights were violated by his warrantless detention and civil debt-related incarceration. After a partial settlement disposed of several issues in the case, the district court denied Alkire's summary judgment motion and granted defendant's summary judgment motion on the remaining constitutional issues raised. The district court also denied Alkire's class certification motion. This appeal followed. 5 Alkire raises five issues in his appeal. The first four ask whether the district court properly denied Alkire's summary judgment motion and granted defendant's summary judgment motion as to the liability of Holmes County and Sheriff Zimmerly for violating Alkire's: (1) Fourth Amendment right not to be held on a warrantless arrest without arraignment for forty-eight hours; (2) Thirteenth Amendment right not to be imprisoned for a civil debt; (3) Fourteenth Amendment right to due process and equal protection for failing to allow credit toward fines and costs for time served; and (4) Fourteenth Amendment right not to lose his liberty due to indigency. The fifth issue on appeal is whether the district court properly denied Alkire's motion for class certification. For the reasons stated below, we REVERSE the district court on the first issue and REMAND to the district court for further proceedings. We AFFIRM the district court on the second, third, fourth, and fifth issues. II. FACTUAL HISTORY 6 On Saturday, August 19, 1995 at 9:40 a.m., plaintiff Lloyd Alkire was arrested for driving while intoxicated ("DWI"). Alkire was taken to the Holmes County Jail where he remained all weekend. There was a warrant for Alkire from another jurisdiction. The parties dispute whether Alkire was held on the DWI arrest or the warrant. Alkire was arraigned in Holmes County Court before Judge Jane Irving on Tuesday morning, August 22, 1995—almost seventy-two hours after his arrest. No probable cause hearing was held prior to the August 22nd hearing. 7 At a subsequent hearing on September 1, 1995, Alkire pleaded no contest to the DWI charges. He was sentenced to fifteen days in jail and fined $575 and court costs of $45, for a total of $620. Alkire signed a payment contract agreeing to pay $50 monthly installments starting September 11, 1995. No inquiry was made into Alkire's ability to pay, but it appears from the record that he signed the contract voluntarily. 8 Alkire did not make any payments toward the money owed. Due to Alkire's failure to pay, on November 15, 1995, Judge Irving signed a show cause letter ordering him to appear at a hearing on December 13, 1995 at 11:00 a.m. The letter advised that failure to appear or to pay the amount owed ($635.00)1 in full would result in the issuance of a bench warrant for Alkire's arrest. Alkire responded with a letter dated November 22, 1995, which informed Judge Irving that he was disabled and explained his financial difficulties.2 9 Alkire did not appear for the December 13, 1995 hearing. Judge Irving issued a bench warrant for his arrest. Alkire sent a second letter, dated December 15, 1995, explaining his failure to appear at the hearing. The letter stated that he was in the hospital on the hearing date, further explained his financial difficulties, and outlined his inability to find employment. 10 On May 20, 1996, Alkire was arrested on the outstanding bench warrant. At a hearing on May 21, 1996, Judge Irving found Alkire in contempt and sentenced him to thirty days in jail for "failing to pay any fine or costs." The Judge further stated that Alkire could work off the fine and costs. There was no inquiry at the hearing into Alkire's ability to pay. 11 Alkire served the thirty day sentence from May 21, 1996, to June 20, 1996. During that time, he worked at a recycling center, receiving the current minimum wage rate of $4.25 per hour, which was credited toward his fine. As a result, according to Alkire, he was able to work off his entire fine. In fact, he says that he worked 4.75 more hours than his fine, but he received no compensation for that extra work. The county's policy does not allow defendants to work off their court costs, so Alkire calculates that after the thirty days in jail, he still owed court costs in the amount of $173.30. However, Holmes County Court records indicate he owed $295.22. 12 Five days after his release, on June 25, 1996, another show cause letter was sent to Alkire for failure to pay the $295.22 amount. The letter set a hearing date of July 24, 1996, and stated that he was required to either pay in full before the date or appear. Alkire again failed to appear. Judge Irving found him in contempt for "failure to obey a previous order" and issued another bench warrant. Alkire was arrested on July 29, 1996, and released on his own recognizance on July 31, 1996. The bond notice set a hearing date of August 28, 1996, to answer the charges of "contempt of court-non-payment of costs." The bond also noted that Alkire must pay the court costs in the amount of $156.603 by the next court date. 13 Alkire sent a letter dated August 27, 1996, which explained that he lost his job as a result of his last stay in jail. He also stated he had just started a new job on August 27th. He said that, since he cannot pay the fines without a job, it would make no sense to arrest him and cause him to lose the new job. Alkire proposed a payment schedule based on his anticipated earnings from the new job. 14 Alkire again failed to appear at the August 28, 1996, hearing. Judge Irving again held Alkire in contempt and issued a third bench warrant for "failure to obey a previous order of this court." He was arrested on October 22, 1996, on the third warrant. At a hearing on the same day, he was found guilty of contempt and ordered to serve thirty days in the Holmes County Jail. There was no inquiry at the hearing regarding his ability to pay. Also, no credit was given toward the money owed during this period of incarceration. 15 On October 24, 1996, while Alkire was still serving the thirty day sentence, a third show cause letter was issued demanding payment of $173.30 or an appearance on November 20, 1996. The hearing was continued to December 18, 1996. After the present action was filed, the final show cause hearing date was postponed indefinitely. III. PROCEDURAL HISTORY 16 Plaintiff Alkire filed a complaint and a motion for class certification on December 16, 1996, in the U.S. District Court for the Northern District of Ohio, alleging violations of his constitutional rights for the extended warrantless detention and debt-related imprisonment. Alkire filed an amended complaint on January 7, 1997. Alkire filed summary judgment motions against all the defendants on December 1, 1998. Defendants Holmes County, Holmes County Court, and Sheriff Zimmerly filed summary judgment motions on December 1, 1998. Judge Irving filed her summary judgment motion on December 3, 1998. 17 The parties agreed to a stipulation of settlement, but it did not resolve all the issues between the parties; it only purported to settle the declaratory and injunctive portions of the suit. Thus, in a June 30, 2000, order accepting the stipulation of settlement, the district court dismissed all the pending motions without prejudice to their being resubmitted to reflect the settlement between the parties. The class certification and summary judgment motions were resubmitted, but the parties merely re-filed their initial motions, so they do not reflect the settlement as ordered by the district court.4 18 The district court denied the motion for class certification on September 26, 2000. On November 9, 2000, the court denied Alkire's summary judgment motions and granted defendants' summary judgment motions. Alkire timely appealed the district court's judgment on December 4, 2000. IV. STANDARD OF REVIEW 19 We review the district court's order granting defendants' and denying Alkire's motions for summary judgment de novo using the same summary judgment test as the district court. See Crawford v. Roane, 53 F.3d 750, 753 (6th Cir.1995).5 Summary judgment is proper where there are no genuine issues of material fact and the moving party is entitled to judgment as a matter of law. Fed.R.Civ.P. 56(c); see also Celotex Corp. v. Catrett, 477 U.S. 317, 322-23, 106 S.Ct. 2548, 91 L.Ed.2d 265 (1986). All facts and inferences must be construed in a light most favorable to the party opposing the motion. Matsushita Elec. Indus. Co. v. Zenith Radio Corp., 475 U.S. 574, 587, 106 S.Ct. 1348, 89 L.Ed.2d 538 (1986). 20 We review a class certification decision for abuse of discretion. Sprague v. Gen. Motors Corp., 133 F.3d 388, 397 (6th Cir.1998) (en banc). An abuse of discretion is present when the district court "applies the wrong legal standard, misapplies the correct legal standard, or relies on clearly erroneous findings of fact." Schachner v. Blue Cross & Blue Shield, 77 F.3d 889, 895 (6th Cir.1996). V. DISCUSSION 21 There are five issues for our consideration as framed by Alkire. The first four ask whether the trial court erred in failing to find Holmes County and Sheriff Zimmerly in his official capacity liable: (1) under the Fourth Amendment for the policies and customs that resulted in Alkire's warrantless detention for nearly seventy-two hours; (2) under the Thirteenth Amendment for the policies and customs that resulted in Alkire being arrested three times and jailed for 60 days for failing to pay civil debts owed the county; (3) under due process and equal protection for the policy and custom of not allowing credit toward fines and costs for time served, so that Alkire was incarcerated 16 days in excess of the maximum otherwise permitted under state law; and (4) under due process and equal protection for the policies and customs that resulted in Alkire being arrested three times and jailed for 60 days in connection with non-payment of fines and court costs without any inquiry into his ability to pay. The fifth issue asks whether the trial court abused its discretion by refusing to certify a class action. 22 A. Whether the district court erred in finding no violation of Alkire's Fourth Amendment rights not to be held for seventy-two hours on a warrantless arrest. 23 Alkire argues that the district court erred as a matter of law by not granting his summary judgment motion that Holmes County and Sheriff Zimmerly were liable under § 1983 for violating his Fourth Amendment right against being detained without a prompt probable cause determination. Section 1983 provides that: 24 Every person who, under color of any statute, ordinance, regulation, custom, or usage ... subjects, or causes to be subjected, any citizen of the United States... to the deprivation of any rights ... secured by the Constitution and laws, shall be liable to the party injured in an action at law ... [or] suit in equity. 25 42 U.S.C. § 1983. To state a § 1983 claim, Alkire must establish (a) deprivation of a right secured under the Constitution or federal law; and (b) that deprivation was caused by a person acting under color of state law. Brock v. McWherter, 94 F.3d 242, 244 (6th Cir.1996). 26 As for the first prong of this test, since Alkire has alleged he was held in violation of the Fourth Amendment, we must ask what the Fourth Amendment requires. It requires a "fair and reliable determination of probable cause," which must be made promptly after a warrantless arrest. Gerstein v. Pugh, 420 U.S. 103, 125, 95 S.Ct. 854, 43 L.Ed.2d 54 (1975). A judicial determination of probable cause within forty-eight hours of arrest, "will, as a general matter, comply with the promptness requirement of Gerstein." County of Riverside v. McLaughlin, 500 U.S. 44, 56, 111 S.Ct. 1661, 114 L.Ed.2d 49 (1991). If the probable cause hearing is not held within forty-eight hours, the burden shifts to the government "to demonstrate the existence of a bona fide emergency or other extraordinary circumstance." Id. The Supreme Court specifically mentioned that intervening weekends do not count as an `extraordinary circumstance." Id. On the other hand, if the defendant is held on a valid warrant, he "is not constitutionally entitled to a separate judicial determination that there is probable cause to detain him pending trial." Baker v. McCollan, 443 U.S. 137, 143, 99 S.Ct. 2689, 61 L.Ed.2d 433 (1979). 27 Alkire argues he was being held on the warrantless DWI arrest. Defendants argue he was being held on the warrant from another jurisdiction. If Alkire is correct, then his Fourth Amendment rights were violated, since he was entitled to a probable cause hearing within forty-eight hours. However, if defendants are correct, then holding Alkire nearly seventy-two hours, while questionable, does not automatically violate his Fourth Amendment rights. 28 Even after careful review of the record, it is unclear as to which party is correct. Alkire states in his brief that the Holmes County records demonstrate that he was held on the DWI arrest.6 The defendants counter by citing Sheriff Zimmerly's affidavit, where he states that the State Highway Patrol discovered the outstanding warrant from another jurisdiction at the time of Alkire's arrest. However, Sheriff Zimmerly's statement falls short of stating that the warrant, rather than the DWI arrest, was the reason Alkire was detained seventy-two hours. This dispute between the parties constitutes a material factual dispute, which is inappropriate for resolution on summary judgment. 29 Applying the second part of the test for a § 1983 claim, we must also examine whether the possible deprivation of Alkire's Fourth Amendment rights was caused by a person acting under color of state law. Brock, 94 F.3d at 244. Local governments, counties, and municipalities are considered under this definition of person, and "may be sued for constitutional deprivations." Monell v. Dep't of Social Servs. City of New York, 436 U.S. 658, 690-91, 98 S.Ct. 2018, 56 L.Ed.2d 611 (1978). State governments, and their "arms, officers, and instrumentalities," however, are immune from suits for money damages under the Eleventh Amendment. Mumford v. Basinski, 105 F.3d 264, 267 (6th Cir.1997) (citing Mt. Healthy City Sch. Dist. v. Doyle, 429 U.S. 274, 280, 97 S.Ct. 568, 50 L.Ed.2d 471 (1977)). In Ohio, a county common pleas court "is not a segment of county government, but an arm of the state for purposes of section 1983 liability and Eleventh Amendment immunity analysis." Mumford, 105 F.3d at 269. 30 As for those actors not immune under the Eleventh Amendment, § 1983 claims cannot be premised on a theory of respondeat superior. Monell, 436 U.S. at 691, 98 S.Ct. 2018. Instead, the plaintiff must "identify a municipal `policy' or `custom' that caused the plaintiff's injury," and the municipality through this policy must have been the "`moving force' behind the injury alleged." Bd. of County Comm'rs v. Brown, 520 U.S. 397, 403, 404, 117 S.Ct. 1382, 137 L.Ed.2d 626 (1997). Where a government "custom has not received formal approval through the body's official decisionmaking channels," such a custom may still be the subject of a § 1983 suit. Monell, 436 U.S. at 690-91, 98 S.Ct. 2018. 31 Applying this test, Judge Irving and the Holmes County Court are protected by Eleventh Amendment immunity, since Ohio law considers county courts arms of the state for this purpose. However, neither Sheriff Zimmerly nor Holmes County have Eleventh Amendment immunity, since Sheriff Zimmerly is a county employee and Holmes County can be liable for constitutional deprivations where a county policy or custom was the moving force behind the deprivation. 32 According to Alkire, in 1994, after a new Holmes County jail opened, Sheriff Zimmerly established the policy of detaining persons in the county jail until their initial appearance, since they now had adequate jail space. The record reflects that, because the Holmes County Court is a part-time court, the first available court date was often not until Tuesday mornings; court was never held on weekends or holidays. As a result, any warrantless arrest from late afternoon Friday through Sunday morning would very likely run afoul of the forty-eight hour requirement mandated by Riverside. This is the very sort of `policy or custom' that was envisioned in Brown. Liability extends to Holmes County because any policy of county employee Sheriff Zimmerly on holding detainees until trial was also a county policy, and this policy was the `moving force' behind the injury alleged. It is not necessary that Holmes County officially endorsed this policy through legislative action for it to carry its imprimatur. 33 In addition, neither Sheriff Zimmerly nor Holmes County can claim absolute, quasi-judicial, or qualified immunity for their policy that resulted in the detention of prisoners beyond the forty-eight hour threshold. As for absolute immunity, the proponent seeking such immunity bears the burden of establishing the justification for it. Antoine v. Byers & Anderson, Inc., 508 U.S. 429, 432, 433 n. 4, 113 S.Ct. 2167, 124 L.Ed.2d 391 (1993) ("The presumption is that qualified rather than absolute immunity is sufficient to protect government officials in the exercise of their duties. We have been quite sparing in our recognition of absolute immunity, and have refused to extend it any further than its justification would warrant."). One type of absolute immunity is judicial immunity. Mireles v. Waco, 502 U.S. 9, 9, 112 S.Ct. 286, 116 L.Ed.2d 9 (1991) ("A long line of this Court's precedents acknowledges that, generally, a judge is immune from a suit for money damages.") (collecting cases). However, neither Judge Irving nor the Clerk's Office appears to have played any role in the decision to detain prisoners beyond forty-eight hours. Nor was Sheriff Zimmerly acting under the official orders of Judge Irving in carrying out the policy. 34 As for quasi-judicial immunity, which is extended to those persons performing tasks so intertwined with the judicial process that they are considered an arm of the judicial officer, Bush v. Rauch, 38 F.3d 842, 847 (6th Cir.1994), it does not apply here. According to Bush: 35 The Supreme Court has endorsed a "functional" approach in determining whether an official is entitled to absolute immunity. Under this approach, a court "looks to `the nature of the function performed, not the identity of the actor who performed it.'" For example, a prosecutor who undertakes acts in the preparation or initiation of judicial proceedings is entitled to absolute immunity. On the other hand, when a prosecutor performs administrative acts unrelated to judicial proceedings, qualified immunity is all that is available. 36 Id. (citations omitted). Again, Sheriff Zimmerly's policy was not dictated by Judge Irving, and it can be described as administrative in nature. The record demonstrates that it was his decision, beginning in 1994, to keep those arrested in jail until their initial appearance. Judge Irving often does not discover that someone has been arrested until they arrive for a hearing before her. 37 Finally, we conclude that neither Holmes County nor Sheriff Zimmerly enjoy qualified immunity from this claim. According to the doctrine of qualified immunity, "government officials performing discretionary functions generally are shielded from liability for civil damages insofar as their conduct does not violate clearly established statutory or constitutional rights of which a reasonable person would have known." Harlow v. Fitzgerald, 457 U.S. 800, 818, 102 S.Ct. 2727, 73 L.Ed.2d 396 (1982). Qualified immunity involves a two-step inquiry. First, the court must determine whether, based upon the applicable law, the facts viewed in the light most favorable to the plaintiff show that the defendants violated his constitutional rights. Saucier v. Katz, 533 U.S. 194, 201, 121 S.Ct. 2151, 150 L.Ed.2d 272 (2001). If a favorable view of the facts does demonstrate a constitutional violation, the next step is to ask whether the right was clearly established at the time of the defendants' actions. Id. 38 Qualified immunity, of course, offers no protection for Holmes County. It is well established that municipalities are not entitled to qualified immunity. Russo v. City of Cincinnati, 953 F.2d 1036, 1046 (6th Cir.1992). We also conclude that Sheriff Zimmerly is not entitled to qualified immunity as to the plaintiff's Fourth Amendment claim. We have already determined that, if plaintiff's version of the facts is believed, a constitutional violation has occurred. There is little doubt, moreover, that the relevant law was clearly established at the time of defendants' actions. The constitutional violation in the instant case follows directly from the Supreme Court's 1991 decision in McLaughlin. Since the events at issue in the instant case occurred more than four years after McLaughlin was decided, it seems apparent that the plaintiff's constitutional right to receive a probable cause determination within forty-eight hours of his arrest was clearly established at the time of his arrest. 39 Therefore, the district court's dismissal on this issue is reversed. Because there are genuine issues of material fact concerning Alkire's Fourth Amendment claim, however, the district court's denial of Alkire's motion for summary judgment is affirmed. This case is remanded for further proceedings to determine whether Alkire was being held on the arrest warrant or the DWI arrest. 40 B. Whether the district court erred in finding no violation of Alkire's Thirteenth Amendment right not to be imprisoned for a civil debt. 41 Alkire argues that the district court erred as a matter of law in not granting his summary judgment motion that Holmes County and Sheriff Zimmerly were liable under § 1983 for violating his Thirteenth Amendment right not to be imprisoned for civil debt. As stated above, to state a § 1983 claim, Alkire must establish (a) deprivation of a right secured under the Constitution or federal law; and (b) that deprivation was caused by a person acting under color of state law. Brock, 94 F.3d at 244. 42 The constitutional right against imprisonment for civil debt is well established. The State may not "`impos[e] a fine as a sentence and then automatically conver[t] it into a jail term solely because the defendant is indigent and cannot forthwith pay the fine in full.'" Bearden v. Georgia, 461 U.S. 660, 667, 103 S.Ct. 2064, 76 L.Ed.2d 221 (1983) (quoting Tate v. Short, 401 U.S. 395, 91 S.Ct. 668, 28 L.Ed.2d 130 (1971)). Ohio law is even more stringent: 43 no member of a class of judges can, under the Ohio law, impose a fine in a criminal case until he has assured himself that the defendant has made a knowing and intelligent waiver of his right to have his ability to pay the fine determined. 44 Karr v. Blay, 413 F.Supp. 579, 583 (N.D.Ohio 1976). This rule does not apply to willful refusal to pay a fine, only inability to pay or indigency. Bearden, 461 U.S. at 668, 103 S.Ct. 2064 (citing Williams v. Illinois, 399 U.S. 235, 242 n. 19, 90 S.Ct. 2018, 26 L.Ed.2d 586 (1970)). Criminal contempt, though, is a separate crime from the punishment on the underlying offense; it is designed to be punitive and "vindicate the authority of the court." Int'l Union, United Mine Workers of Am. v. Bagwell, 512 U.S. 821, 827-28, 114 S.Ct. 2552, 129 L.Ed.2d 642 (1994). 45 Applying the law to these facts, first, the lack of a judicial determination of Alkire's ability to pay appears to be a violation of Ohio law. Second, even though it is appropriate to impose a jail term for criminal contempt, it is unconstitutional to impose a jail term when an indigent person is unable to pay a fine. Judge Irving's orders give conflicting rationales for her bench warrants and contempt orders. For example, the first bench warrant was issued for Alkire's "failure to obey a previous order of this court" and "fail[ure] to appear." However, her first contempt order sentenced him to thirty days for "failing to pay any fine or costs." 46 Despite the conflicting rationales given for the orders, Judge Irving is shielded from suit by absolute judicial immunity. Judicial immunity is immunity from suit, and is only overcome for non-judicial acts, or where the judge acted in complete absence of jurisdiction. Mireles, 502 U.S. at 11-12, 112 S.Ct. 286. This immunity extends to the Clerk's Office, which processed her orders and bench warrants. Foster v. Walsh, 864 F.2d 416, 417 (6th Cir.1988) ("a clerk who issues a warrant at the direction of a judge is performing a function to which absolute immunity attaches."). Sheriff Zimmerly, who executed the judge's orders, and Holmes County, as his employer, also enjoy this immunity. Bush, 38 F.3d at 847 ("enforcing or executing a court order is intrinsically associated with a judicial proceeding"). Thus, Alkire's § 1983 suit is unable to reach Holmes County and Sheriff Zimmerly for monetary damages. 47 Accordingly, the district court's denial of Alkire's summary judgment motion and grant of defendants' summary judgment motion with regard to the Thirteenth Amendment claim survive de novo review. While there appear to be possible constitutional violations, the district court recognized the problem and encouraged a settlement agreement to resolve these practices. The resulting stipulated settlement appears to end the questionable practices and obviates the need for injunctive relief. Damages are clearly barred due to Judge Irving's absolute judicial immunity, and the immunity extends to the other defendants who were executing her orders. 48 C. Whether the district court erred in finding no violation of Alkire's due process and equal protection rights where defendants failed to allow credit toward fines and costs for time served. 49 Alkire asserts that the district court erred as a matter of law in not granting summary judgment against Holmes County and Sheriff Zimmerly for violation of his rights to due process and equal protection by not crediting his time served in jail toward his fines and court costs. Once again, to state a § 1983 claim, Alkire must establish (a) deprivation of a right secured under the Constitution or federal law; and (b) that deprivation was caused by a person acting under color of state law. Brock, 94 F.3d at 244. 50 Section 2947.14(D) of the Ohio Revised Code states: 51 No person shall be ordered to be committed to a jail or workhouse or otherwise be held in custody in satisfaction of a fine imposed as the whole or a part of a sentence except as provided in this section. Any person imprisoned pursuant to this section shall receive credit upon the fine at the rate of thirty dollars per day or fraction of a day. If the unpaid fine is less than thirty dollars, the person shall be imprisoned one day. 52 OHIO REV.CODE ANN. § 2947.14(D) (amount raised from thirty to fifty dollars per day effective September 6, 2002, see 2002 Ohio Laws 149). 53 Applying thirty dollars per day to his fine, Alkire argues he was held sixteen days longer than he should have been during his first incarceration. Then, in addition, he was arrested two more times and incarcerated another thirty days. The Ohio Supreme Court has held that, as applied to an indigent, imprisonment for non-payment of a fine, crediting only three dollars per day toward the fine, is unconstitutional. Strattman v. Studt, 20 Ohio St.2d 95, 253 N.E.2d 749, 753 (1969). Alkire argues that, "[a.]fortiori, Holmes County's custom of no credit is as fundamentally unfair and discriminatory" as three dollars per day. Defendants reply that Alkire was jailed for criminal contempt rather than failure to pay the fine. As noted above, criminal contempt is a separate crime from punishment for the underlying offense. Bagwell, 512 U.S. at 827-28, 114 S.Ct. 2552. 54 The district court's denial of Alkire's summary judgment motion and grant of defendants' summary judgment motion survive de novo review. Even assuming that Alkire was imprisoned for non-payment of his debts, he is unable to reach the responsible parties in a § 1983 suit. The Clerk's office is the defendant responsible for accounting, crediting, and collecting the fines and costs. The Clerk's office operates in close conjunction with Judge Irving, and as such, is cloaked in her absolute judicial immunity, its own Eleventh Amendment immunity, and its own quasi-judicial immunity. Mireles, 502 U.S. at 11, 112 S.Ct. 286; Mumford, 105 F.3d at 267. While Sheriff Zimmerly and Holmes County are not protected from § 1983 suits by the Eleventh Amendment, they played no role in the accounting and crediting of Alkire's debt in relation to his time served. Notably, when Judge Irving's order specifically mentioned that Alkire was allowed to work off his fines, he was allowed to do so. In the absence of such an order, he was not allowed to do so. Sheriff Zimmerly was acting on a valid bench warrant that ordered Alkire to be arrested and incarcerated for thirty days. Consequently, he and Holmes County are protected by quasi-judicial immunity and qualified immunity. Bush, 38 F.3d at 847; Hunter, 502 U.S. at 227, 112 S.Ct. 534. 55 Accordingly, the district court's denial of Alkire's summary judgment motion and grant of defendant's summary judgment motion as to Holmes County and Sheriff Zimmerly survive de novo review. If Alkire were incarcerated for criminal contempt, he is not entitled to monetary credit for his time served. If he were incarcerated for non-payment of fines, neither Sheriff Zimmerly nor Holmes County are liable under § 1983. 56 D. Whether the district court erred in finding no violation of Alkire's Fourteenth Amendment right not to lose his liberty due to indigency. 57 Alkire argues that the district court erred as a matter of law by not granting summary judgment against Holmes County and Sheriff Zimmerly for violating Alkire's right not to suffer incarceration due to indigency. This is basically a restatement of the argument in Section B, supra. As discussed in Section B, both the United States Constitution and Ohio statute prohibit a loss of liberty for those who are unable to pay their civil debts. Bearden, 461 U.S. at 674, 103 S.Ct. 2064; Karr, 413 F.Supp. at 583. Alkire's appellate brief documents the policies of the Clerk's Office, including requiring payment of fines and costs within two years, making no inquiry into financial ability to pay, and never having found an inability to pay in the past six years. He also points to the practices and customs of Sheriff Zimmerly, who "never" questions the legality of arrest or incarceration in connection with failure to pay. Alkire argues that these practices and customs further the violation of his right not to suffer incarceration due to indigency. 58 Unlike the unlawful detention of prisoners after a warrantless arrest for longer than forty-eight hours before a probable cause hearing is held, Sheriff Zimmerly and Holmes County are acting at the direction of Judge Irving and the County Court in enforcing bench warrants and incarcerating prisoners for the term of their criminal contempt sentence. The Clerk's Office may be complicit in blurring the line between failure to appear and failure to pay, but it is ultimately Judge Irving who decides to issue criminal contempt sanctions. 59 Sheriff Zimmerly, Holmes County, and the Clerk's Office all derive their authority and orders from the actions of Judge Irving. Judge Irving enjoys absolute judicial immunity, Pierson v. Ray, 386 U.S. 547, 553-54, 87 S.Ct. 1213, 18 L.Ed.2d 288 (1967), and Sheriff Zimmerly, Holmes County, and the Clerk's Office have quasi-judicial immunity and qualified immunity because they are performing quasi-judicial duties under the direction of a judicial officer. Bush, 38 F.3d at 847; Hunter, 502 U.S. at 227, 112 S.Ct. 534. These duties are intimately "intertwined with the judicial process" to the degree that "these persons are considered an arm of the judicial officer who is immune." Bush, 38 F.3d at 847 (citing Scruggs v. Moellering, 870 F.2d 376 (7th Cir.1989)). 60 Accordingly, the district court's denial of Alkire's summary judgment motion and grant of defendants' summary judgment motion on this issue survive de novo review. The Clerk's Office merely refers cases of non-payment to Judge Irving who makes her own determination about how to proceed. Sheriff Zimmerly and Holmes County merely execute the orders issued by Judge Irving when incarcerating individuals. The defendants are not exceeding the § 1983 immunity afforded to them. 61 E. Whether the district court abused its discretion in refusing to certify a class. 62 Alkire argues that the district court abused its discretion by denying his motion for class certification on damages and restitution. There are four prerequisites to a class action, found in Fed.R.Civ.P. 23(a): 63 One or more members of a class may sue or be sued as representative parties on behalf of all only if: (1) the class is so numerous that joinder of all members is impracticable, (2) there are questions of law or fact common to the class, (3) the claims or defenses of the representative parties are typical of the claims or defenses of the class, and (4) the representative parties will fairly and adequately protect the interests of the class. 64 Although Rule 23(a)(2) refers to common questions of law or fact, in the plural, there need only be one question common to the class-though that question must be a "common issue the resolution of which will advance the litigation." Sprague, 133 F.3d at 397. See also Amchem Prods., Inc. v. Windsor, 521 U.S. 591, 623, 117 S.Ct. 2231, 138 L.Ed.2d 689 (1997). Ultimately, the class may only be certified if, "after rigorous analysis," the district court is satisfied that these prerequisites have been met. Gen. Tel. Co. v. Falcon, 457 U.S. 147, 161, 102 S.Ct. 2364, 72 L.Ed.2d 740 (1982). The burden is on the plaintiff "to establish his right" for class certification. Senter v. Gen. Motors Corp., 532 F.2d 511, 522 (6th Cir.1976). 65 If Alkire can satisfy the four prerequisites for class certification found in Rule 23(a), then he must show that, in addition, he satisfies one the three types of class actions found in Fed.R.Civ.P. 23(b). Only two of the three types found in Rule 23(b) are relevant here, types II and III. A type II class action requires that the plaintiff seek primarily injunctive or declaratory relief. Fed.R.Civ.P. 23(b)(2). Type III requires that "the court find[] that the questions of law or fact common to the members of the class predominate over any questions affecting only individual members, and that a class action is superior to other available methods for the fair and efficient adjudication of the controversy." Fed.R.Civ.P. 23(b)(3). 66 The district court's denial of Alkire's motion for class certification survives abuse of discretion review. On the first prerequisite, numerosity, the district court found it was "highly improbable" that the Alkire could make such a showing. While Alkire postulates that there are hundreds of potential plaintiffs, defendants' search of jail records produced only nine potential class members who were incarcerated due to failure to pay a civil debt or court costs. The district court did not abuse its discretion by believing defendants' asserted number of class members over Alkire's speculative one. 67 The second prerequisite of Rule 23(a) requires common questions of law and fact among the class, and the third prerequisite looks to the typicality of the claims or defenses of the representative party. The district court found that the potential class members are too diverse to warrant class treatment, that the "varying reasons for the arrests, varying lengths of stay in jail, varying financial situations, vary reasons for contempt adjudications... would impact on the amount of damages any individual class member might be entitled to." The district court expressly found that Alkire's proposed class lacks the "common questions of fact" required under the second prong and the "typicality" required under the third prong of Rule 23(a).7 68 Alkire argues that the district court abused its discretion because only one common question of law or fact is required. He points to a common question of fact, "the existence and routine application of the illegal policies ultimately proven by the [defendants' own] depositions," and common questions of law, including issues one through four presented in this appeal. 69 Our review is for abuse of discretion, and the district court did not abuse its discretion in applying the class action prerequisites. There are enormous variations in the factual and legal backgrounds surrounding the hundreds of cases Alkire asserts might qualify for class membership. A class action cannot be certified unless the resolution of the common issues "will advance the litigation." Sprague, 133 F.3d at 397. The district court neither applied the wrong legal standard in examining these two elements, nor did it misapply the correct legal standard. The court correctly placed the burden of demonstrating his right to class certification and concluded that Alkire did not meet his burden. Such a conclusion was not an abuse of discretion. 70 Even if we agreed with Alkire that the district court abused its discretion in applying the prerequisites, we would still not find in his favor because he has not satisfied either the type II or III requirements for maintaining a class action. Alkire, in his initial motion for class certification, asserted his right to class certification under a type II class action only. As the district court noted, though, the stipulated settlement regarding declaratory and injunctive relief demonstrates that Alkire has "obtained all the relief future potential plaintiffs would want or need." Alkire even agrees with the district court's conclusion on this point, stating the he does not dispute the district court's holding "as to a class of future members.... The stipulations do provide sufficient protection for their interests." Thus, Alkire cannot maintain a type II class action. 71 Alkire's quarrel with the district court, then, is its failure to certify a type III class action, where monetary damages predominate. However, he ignores the requirements of a type III class action, which include a showing that the common questions predominate over the individual ones and that the class action is a superior method for adjudication. Consequently, Alkire's argument that only one common question is necessary for class certification does not apply under the type III analysis. The district court's finding that numerous factual issues, such as varying reasons for arrest, varying lengths of stay, and varying financial situations "do not warrant class treatment" is even stronger when reviewed under the type III requirements. Accordingly, we affirm the district court's denial of Alkire's motion for class certification. VI. CONCLUSION 72 For the foregoing reasons, we REVERSE the district court with respect to its grant of defendant's summary judgment motion as to the liability of Sheriff Zimmerly and Holmes County for potentially violating Alkire's Fourth Amendment right not to be detained more than forty-eight hours without a probable cause hearing and REMAND for further proceedings. We AFFIRM the district court on its grant of defendants' summary judgment motions on the other three constitutional issues. We also AFFIRM the district court's denial of Alkire's motion for class certification. Notes: * The Honorable Arthur J. Tarnow, United States District Judge for the Eastern District of Michigan, sitting by designation 1 There is no explanation in the record for the discrepancy between $620 and $635 2 The date stamp indicates that the letter was filed on September 26, 1995, which would be before the court sent the first show cause letter. Alkire argues that this demonstrates he was being proactive about his inability to meet the payment schedule. However, the letter itself is dated November 22, 1995. In addition, the letter refers to "your letter last week," apparently referencing the Judge's show cause letter, which was signed on November 15, 1995. Thus, we will assume that the date stamp was inaccurate and the correct date is November 22, 1995, as listed in the letter 3 Again there is no explanation in the record for the discrepancy between this amount and the $295.22 amount 4 Consequently, it is not clear whether the settlement regarding prospective relief is in effect, or whether Alkire is still seeking declaratory and injunctive relief. Since the District Court assumed he was not, and the parties did not address declaratory and injunctive relief, we will assume that the settlement resolved the prospective portions of the case 5 Alkire is appealing both the grant of defendants' summary judgment motions and the denial of his summary judgment. Normally, the denial of a summary judgment motion indicates that there is a genuine issue of material fact for trial. As such, denials are considered interlocutory appeals from which no appeal is available until the entry of a final judgment after a trial on the meritsUnited States v. Florian, 312 U.S. 656, 61 S.Ct. 713, 85 L.Ed. 1105 (1941). "However, when the appeal from a denial of summary judgment is presented together with an appeal from a grant of summary judgment, we have jurisdiction to review the appropriateness of the district court's denial." Thomas v. U.S., 166 F.3d 825, 828 (6th Cir.1999). The denial of summary judgment based purely on legal grounds is reviewed de novo. Id. 6 In support, Appellant cites three documents from an evidentiary appendix, which was filed in the district court with his motion for class certification. While Appellant included some of the evidentiary appendix in the joint appendix provided to this Court, he did not provide the specific pages he cites for this point 7 The fourth element of Rule 23(a), whether the representative parties will fairly and protect the interests of the class, is not addressed by the district court or in the briefs. Therefore, we will also not address it	{ "pile_set_name": "FreeLaw" }
Last night, the all too convenient screenshot (below) began to circulate throughout the blogosphere. It aims to confirm that Kanye West will be releasing a new album called Paris due out November 24th. It has almost unbelievable... It’s that time of the year. Where XXL Magazine gives us their yearly picks in hip-hop/rap (and R&B now). Many factors go into landing on this list, but as always there’s some common sense entries, as well as a... Lil Durk‘s mixtape Signed To The Streets dropped a few weeks ago. It confirmed the hype that he’s one of the next rappers out of Chicago that’s going to keep it hip-hop and bring some real music to the genre....	{ "pile_set_name": "Pile-CC" }
The experience was also enhanced by the fact that, upon our arrival, we were welcomed by a Host wearing an all-white dress -- like you'd see welcoming guests to the park on the show. She was standing behind a shelf full of western-style guns and knives, though we weren't actually able to choose a weapon of our choice. They did have cowboy hats for the visitors, though, so that gave it a more realistic feel. Then, after you go to through the train that takes you to Westworld (this one was just a prop, as we actually got there in themed shuttle bus), our first stop was the Sweetwater post office. Weirdly enough, both Jessica and I had letters waiting for us. Mine was from someone I didn't know, who warned me that the people in the town were acting strange and I needed to be on the lookout. Hers was about women suffrage and said that the revolution was imminent. Thankfully, we both managed to make it out alive after two hours. Is it wrong that we both wish we could go back? Catch up on the latest news from SXSW 2018 right here.	{ "pile_set_name": "OpenWebText2" }
Photodegradable plastic films have also been known are known and more recently so-called biodegradable plastic films. The photodegradable plastic films are are obtained by introducing photoactive additives into a basic material which can be a polyolefin, for example. Generally, these additives are form by molecules containing oxygen and/or heavy metals the role of which is to initiate the formation of free radicals under the action of ultraviolet (UV) radiation; these radicals cause a rupture of the chains of the polymer and therefore make the polymer fragile, by making it weak and therefore mechanically degradable. However, the use of certain additives which are strongly oxidizing causes the degradation to start immediately after the manufacture of the films, which has for consequence to reduce the storage capacity either of the master mixtures or of the films. It should be noted that in agricultural uses of photodegradable films, portions of the films which are buried in the ground are protected from UV radiation and therefore not altered and not mechanically degradable, which has for its consequence to increase the scraps. With respect to the biodegradable plastic films, they are obtained by the introduction of a so-called biodegradable organic filler such as starch which, consumed by the microorganisms, will make in turn the film fragile and therefore more easily degradable under the influence of the UV radiation. The addition of starch as a consumable filler for microorganisms has consequences both concerning the fabrication of the film and in its mechanical properties; actually: starch is partially decomposed as soon as a temperature of 180.degree. C. is reached during the extrusion operation used in making the film; starch is not compatible with the polymers and therefore embrittles the films. Finally, the granulometry of the industrially available starch does not permit making films of small thickness. Yet, the thickness is an element of the cost price of the film, but also a parameter which governs the degradation speed of the film.	{ "pile_set_name": "USPTO Backgrounds" }
Q: Line bundles and Cyclic Covers of Curves Let $X \to Y$ be a cyclic etale cover of smooth projective geometrically connected curves over some field $k$. Then the map is classified by an element of the cohomology group $H^1_{et}(Y_{k_s}, \mu_n)$; in other words the data of the covering is equivalent to giving a line bundle on $Y$ together with a trivialization of its $n$-th power. It follows that the induced map on Picard schemes given by pullback is not injective. My question is: what can be said about the kernel? I am especially interested in the special case of a degree $2$ cover; i.e are there are any other elements in the kernel besides the trivial bundle and the bundle classified by the covering. This one is given explicitly by pushing forward the structure sheaf on $X$ and modding out by the structure sheaf on $Y$. I tried asking this on MSE but got no answer. A: Let me give an answer when $\mathrm{char} \, k=0$. In this situation the double cover $f \colon X \to Y$ is defined by a line bundle $\mathcal{L}$ such that $\mathcal{L}^{\otimes 2} = \mathcal{O}_Y$ and the trace map provides a splitting $$f _* \mathcal{O}_X = \mathcal{O}_Y \oplus \mathcal{L}^{-1}.$$ Assume now that $\mathcal{M}$ belongs to the kernel of $$f^* \colon \mathrm{Pic} \, Y \to \mathrm{Pic} \, X.$$ Then $f^* \mathcal{M} = \mathcal{O}_X$ so, by applying the functor $f_$ and the projection formula, we obtain $$f_ \mathcal{O}_X = f_* f^* \mathcal{M} = \mathcal{M} \otimes f_* \mathcal{O}_X = \mathcal{M} \oplus (\mathcal{M} \otimes \mathcal{L}^{-1}).$$ By the Krull-Schmidt theorem the decomposition of a vector bundle in a direct sum of indecomposable ones is unique up to permutation of the summands, so we get either $\mathcal{M} = \mathcal{O}_Y$ or $\mathcal{M}=\mathcal{L}$. Summing up, $\ker \, f^$ is the subgroup of order $2$ generated by $\mathcal{L}$. Exactly the same argument shows that if the étale cover is cyclic of degree $n$, then $\ker f^$ is cyclic of the same order. A: Theorem. Let $X \to Y$ be an étale Galois cover with group $G$ of proper geometrically integral schemes over any field $k$. Then we have an exact sequence $$0 \to \operatorname{Hom}(G,k^\times) \to \operatorname{Pic}(Y) \to \operatorname{Pic}(X)^G.$$ In particular, the kernel has size at most $n = \|G^{\operatorname{ab}}\|$, with equality if and only if $n$ is invertible in $k$ and $\mu_r \subseteq k$, where $r$ is the exponent of $G^{\operatorname{ab}}$. Proof. An étale Galois cover with group $G$ is the same thing as a $G$-torsor, and we have a Hochschild–Serre spectral sequence (see e.g. Milne's Étale cohomology notes, Thm 14.9) $$E_2^{pq} = H^p(G,H^q(X,\mathbb G_m)) \Rightarrow H^{p+q}(Y,\mathbb G_m).$$ The exact sequence of low degree terms is $$0 \to H^1(G,\mathbb G_m(X)) \to H^1(Y,\mathbb G_m) \to H^1(X,\mathbb G_m)^G \to H^2(G,\mathbb G_m(X)) \to \ldots .$$ Since $X$ is proper and geometrically integral, the global sections of $\mathcal O_X$ are just the constants $k$, hence the global sections of $\mathbb G_m$ are just $k^\times$. This clearly has the trivial $G$-action, so $$H^1(G,\mathbb G_m(X)) = \operatorname{Hom}(G,k^\times).$$ This proves the first statement. The second statement follows since $$\operatorname{Hom}(G,k^\times) = \operatorname{Hom}(G^{\operatorname{ab}},k^\times),$$ and for any finite abelian group $G$ there is a noncanonical isomorphism $G^{(p')} \cong \operatorname{Hom}(G,\bar k^\times)$, where $(-)^{(p')}$ denotes the prime to $p$-part if $\operatorname{char} k = p > 0$ (and the entire group if $\operatorname{char} k = 0$). Since the group generated by the images of homomorphisms $G \to \bar k^\times$ is the subgroup $\mu_r$ for $r$ the exponent of $G$, we conclude that they are all realised over $k$ if and only if $\mu_r \subseteq k$. $\square$	{ "pile_set_name": "StackExchange" }
Accelerating Vaccine Development During the 2013-2016 West African Ebola Virus Disease Outbreak. The Ebola virus disease outbreak that began in Western Africa in December 2013 was unprecedented in both scope and spread, and the global response was slower and less coherent than was optimal given the scale and pace of the epidemic. Past experience with limited localized outbreaks, lack of licensed medical countermeasures, reluctance by first responders to direct scarce resources to clinical research, community resistance to outside interventions, and lack of local infrastructure were among the factors delaying clinical research during the outbreak. Despite these hurdles, the global health community succeeded in accelerating Ebola virus vaccine development, in a 5-month interval initiating phase I trials in humans in September 2014 and initiating phase II/III trails in February 2015. Each of the three Ebola virus disease-affected countries, Sierra Leone, Guinea, and Liberia, conducted a phase II/III Ebola virus vaccine trial. Only one of these trials evaluating recombinant vesicular stomatitis virus expressing Ebola virus glycoprotein demonstrated vaccine efficacy using an innovative mobile ring vaccination trial design based on a ring vaccination strategy responsible for eradicating smallpox that reached areas of new outbreaks. Thoughtful and intensive community engagement in each country enabled the critical community partnership and acceptance of the phase II/III in each country. Due to the delayed clinical trial initiation, relative to the epidemiologic peak of the outbreak in the three countries, vaccine interventions may or may not have played a major role in bringing the epidemic under control. Having demonstrated that clinical trials can be performed during a large outbreak, the global research community can now build on the experience to implement trials more rapidly and efficiently in future outbreaks. Incorporating clinical research needs into planning for future health emergencies and understanding what kind of trial designs is needed for reliable results in an epidemic of limited duration should improve global response to future infectious disease outbreaks.	{ "pile_set_name": "PubMed Abstracts" }
Just a brief business update before I get going on today’s company profile. Things are good at Alluvial Capital Management, LLC. Assets under management will soon reach $6 million, and performance since inception has been solid. Thanks again to the many blog readers who have become clients. New clients are always welcome! I’ve revamped my firm’s website a bit, if anyone would like to check it out. For a guy with zero experience with design, I don’t think it looks half bad. My readers ask me how I discover the stocks I write about. There’s no single answer, and in fact I find many by reading other blogs, online forums, and Twitter. But the majority I stumble upon through simple screening and follow-up research. I start with a particular geography or industry and go through the small companies I find one by one. I’m not mechanical about it; if I find a particularly interesting company or an unusual investing theme comes to mind, I’ll follow that path to see where it goes. For example, this week I decided to generate a list of Swiss companies with high share prices. Switzerland is full of very old companies and many have multiple business lines, which often leads to disguised assets. Additionally, many micro-cap companies with high share prices are inefficiently priced due to miniscule trading volumes. Anyway, one of the first companies I happened across was BVZ Holding AG, which operates a railway that provides the only access to Zermatt, a Swiss resort community in the Alps. Immediately, I thought of another Alpine railway company and a favorite investment of mine, Jungfraubahn Holding AG. My reasoning remains simple: companies like these are virtually immune to competition because of the astonishing cost (financial, environmental, and aesthetic) that creating additional railways in the pristine mountains would require. BVZ appears cheap at just 9x earnings and half of book value. But as I continued my analysis, I discovered some serious drawbacks. Chiefly, the company has low margins, low returns on capital and extremely high leverage. Returns on assets and equity languish in the low single digits and net debt is 6.6x EBITDA. Try as I might, I can find no convincing reason why these factors might change, so BVZ Holding was out. I was sad to see an interesting company turn out to be unattractive, but I then found myself wondering if there were any other Swiss Alps railroad operators I’d yet to examine. Sure enough, there are a handful! And the best of these is quite a mouthful: Bergbahnen Engelberg-Truebsee-Titlis AG. “BETT,” as I’ll call it, operates a railway that carries recreationers up the Titlis Mountain in central Switzerland, as well as gondolas and cable cars between the various slopes and lodging areas. Among many other attractions including hotels and restaurants, the company operates the spectacular Glacier Cave and the Titlis Cliff Walk, Europe’s highest suspension bridge. In 2013, transport made up two-thirds of revenues, while hotels, restaurants and other accommodations made up the rest. It’s a straightforward business model, and it’s a profitable one. BETT’s revenues have grown at an annual pace averaging 4.5% over the last twenty years, while operating income growth has averaged 10.4%. The effect of such superior long-term growth is impressive: from 1993 to 2013, the company’s operating income rose 600%. Today, BETT is earning better EBITDA and EBIT margins than ever before. For the twelve trailing months, the EBITDA margin reached an exceptional 47.2%, while operating margins reached 36.6%. Here’s a look at the company’s results for the last few years expressed in Swiss Francs. Doubling operating margins and quadrupling earnings since 2007 is no small feat, and investors should examine how this was accomplished. The main driver behind the increase has been increasing visitorship. Per the company, recent years have seen an influx of new visitors from Asia. Switzerland has become a very fashionable place for a vacation among newly wealthy citizens of China and other rapidly growing Asian nations. Revenue growth in excess of operating cost growth creates operating leverage, resulting in rapid earnings growth. BETT has also been a smart investor in its own growth. The company has used its consistently strong cash flow to upgrade and expand facilities, further increasing its capacity and attractiveness as a destination. Sharp-eyed investors may notice an earnings anomaly in 2010, where net income declined 75% despite a sharp increase in EBIT. That year, the company suffered an unfortunate setback when over 10 million CHF in Asian market investments made by a company executive turned out to be wholly fraudulent. Naturally, the executive was fired and prosecuted, but the funds were essentially gone. Following the fraud discovery, BETT made big reforms to its corporate governance designed to prevent future losses. One might think that a recreation business sporting operating margins in the mid-30s would quickly attract competitors, yet it doesn’t appear to be so for BETT. The uniquely challenging geography of the Swiss Alps, as well as a strong desire on the part of the local government and populace to conserve the region’s beauty severely limits competitors’ ability to construct competing hotels or transportation routes. (Compare this to what happens in locations without such limitations. The American Niagara Falls, anyone?) Because of this limited competition, I expect BETT to continue to earn above-average margins nearly indefinitely, or for at least as long as the winter sports and vistas of the Swiss Alps remain popular. For such a unique asset with a strong history of high returns and growth, one might expect to pay a premium price. Turns out that’s far from the truth. BETT shares can be had for just 7.2x EBIT or 7.5x earnings. Net debt is very reasonable at less than trailing operating income. Just try buying a similar-quality asset virtually anywhere in the world for 7x operating income. I believe the primary cause of BETT’s low valuation is its liquidity. The company’s free float is only about CHF 137 million, uninvestable for many large funds. And daily trailing volume averages only about CHF 50,000, making building a large position quite the challenge for those same funds and institutions. But perhaps not for you! The other significant factor that may influence BETT’s valuation is its increased reliance on tourists from Asia. Should the Chinese economy experience a sharp downturn, the ability of wealthy Chinese to afford expensive Swiss vacations will be curtailed. In that event, BETT’s operating margins would drop. While any Chinese slowdown would have a harmful short-term effect, I think the long-term outlook for BETT is positive as Asian consumers continue to grow in number and in wealth. Alluvial Capital Managment, LLC does not hold shares of Bergbahnen Engelberg-Truebsee-Titlis AG for client accounts. Alluvial does hold shares of Jungfraubahn Holding AG for client accounts. OTCAdventures.com is an Alluvial Capital Management, LLC publication. For information on Alluvial’s managed accounts, please see alluvialcapital.com. Alluvial Capital Management, LLC may buy or sell securities mentioned on this blog for client accounts or for the accounts of principals. For a full accounting of Alluvial’s and Alluvial personnel’s holdings in any securities mentioned, contact Alluvial Capital Management, LLC at info@alluvialcapital.com.	{ "pile_set_name": "OpenWebText2" }
Indictment handed up in Somerset kidnap case The man accused of kidnapping a Bernardsville woman at gunpoint last month and stashing her in a nearby barn while demanding a $1 million ransom was indicted yesterday in Somerset County on multiple charges. Edgar Rene del Cid-Perez, 34, of Bernardsville, faces charges of first-degree kidnapping, second-degree possession of a weapon for an unlawful purpose, second-degree burglary, and third-degree unlawful possession of a weapon. Del Cid-Perez entered the home of Karen Maffucci, 44, through an unlocked garage door on Nov. 30 after keeping surveillance on the house overnight from a shed on the property, police said. Del Cid-Perez had previously worked for Unique Landscaping, the company owned by Maffucci's husband, David. Armed with a handgun and knife, del Cid-Perez bound Karen Maffucci with duct tape and forced her into her SUV, police said. He took her to a barn at a horse farm about two miles away and left her there, police said. Maffucci, however, was able to maneuver to a piece of wood and used the edge to saw through the tape binding her hands, police said. Once free, she flagged down a motorist on Hardscrabble Road and went the police. Del Cid-Perez contacted David Maffucci about two hours later, unaware that his captor had freed herself, and demanded $1 million for her safe return, police said. Through cell phone records, investigators quickly tracked the case to del Cid-Perez and arrested him.	{ "pile_set_name": "Pile-CC" }
While I was working on my research project, I stumbled on this three year old question on stackoverflow , and I got inspired by it to do an ...	{ "pile_set_name": "OpenWebText2" }
Q: What's correct way to use default constructor for XmlSerializer? Could you help me to find an error please? I'm trying to use XmlSerialize: public static void ProcessLines(List<string> allLines, out pfm pfm) { ... pfm = newPfm; pfm forseril = new pfm(""); XmlSerializer mySerializer = new XmlSerializer(typeof(pfm)); StreamWriter myWriter = new StreamWriter("myFileName.xml"); mySerializer.Serialize(myWriter, forseril); myWriter.Close(); } And here is that thing that I think should be a default constructor: [Serializable] [XmlRoot(ElementName = "Pfm", Namespace = null)] public class pfm { public pfm(string data) { this.data = data; } public string data; public Ctl ctl { get; set; } [XmlAttribute(AttributeName = "Name")] public string Name { get; set; } } I used an istruction from Microsoft site: instruction A: What XmlSerializer requires is a parameterless constructor -- a constructor with no arguments. Thus your pfm needs a constructor as follows: public class pfm { pfm() : this("") { } public pfm(string data) { this.data = data; } } It doesn't need to be public. Sample fiddle.	{ "pile_set_name": "StackExchange" }
The Struggle Against Carbon Ash is the Struggle Against Capital “The struggle we are carrying out in Peñuelas is against very powerful people.” This is how Janette Albino, one of the community leaders, described the fight against the depositing of toxic ashes en the community of Tallaboa. The capitalist, who is owner of the means of production, uses these same means to generate profits which are appropriated through the exploitation of workers and the destruction of the environment. Energy production is part of this cycle of capitalist exploitation. The capitalist owners of the coal-fired energy plants are responsible for the debacle unleashed in Peñuelas. Over the past years the US has seen a reduction in the production of energy from coal. According to the Environmental Information Agency, coal based energy had been reduced by 10%. This is due to the development of technology to extract natural gas more efficiently and cheaply. Federal regulations to protect the environment and surrounding communities also contributed to this reduction. For this reason, companies that generate coal-fired energy, the dirtiest and most contaminating, have decided to move their operations outside of the US. The struggle against coal ash in Peñuelas is the struggle against the burning of carbon in Guayama by the Virginia-based AES Energy. It is the struggle against “very powerful people”; against a billion dollar industry. AES Energy has 29 coal-fired plants in the US. Of these, 12 produce over 100 megavolts of energy. The AES plant in Guayama produces 454 megavolts of energy burning 1.5 million tons of carbon annually and producing 300 thousand tons of toxic ash each year. AES not only produces the dirty energy that is unwanted in the US in Guayama, they also export the production of coal-fired energy to South Africa and India with financing from the US Import and Export Bank. Because the producers of polluting carbon-based energy have seen a reduction in domestic production they are now pursing profits by exporting. Burning coal in Guayama by AES over the next 20 years is part of the battle between capitalists to maintain the energy monopoly. Health and the wellbeing of the people are now part of the capitalist’s agenda for accumulating profits. And as if this scenario were not sufficiently complex, the Wall Street Junta has entered the scene. It was imposed on the colonial government through the PROMESA Law to ensure the payment debt to bondholders. This law was pushed forward by Bob Bishop, a republican congressman who is one of the biggest defenders of mining interests and the burning of coal for energy production. In order to ensure the debt payment, the Wall Street Junta demands that PREPA reduce its budget. The so-called ‘revitalization’ attempts to reduce dependence on petroleum (51% of production) and shift to natural gas (31% of production) without touching coal-based energy at 16%. Prepa’s savings will be redirected to debt payments and not to consumers as they have gone around trying to deceive people. The working class should clearly understand these moves carried out by capitalists in the colony. In this way we can see the whole panorama in order to organize against those that oppress us.	{ "pile_set_name": "Pile-CC" }
PROJECT SUMMARY Breathing is a remarkable behavior fundamental to life that mediates gas exchange to support metabolism and regulate pH. A reliable, non-stop, robust rhythmic pattern of respiratory muscle activity is essential for breathing in mammals. Failure to maintain a normal breathing pattern in humans suffering from sleep apnea, apnea of prematurity, congenital central hypoventilation syndrome, hyperventilation syndrome, Rett syndrome, and perhaps Sudden Infant Death Syndrome, leads to serious adverse health consequences, even death. Various neurodegenerative diseases, such as Parkinson's disease, multiple systems atrophy, and amyotrophic lateral sclerosis, are associated with sleep disordered breathing that we hypothesize results from the loss of neurons in brain areas controlling respiration. If breathing is to be understood in normal and in pathological conditions, the mechanisms for respiratory central pattern generation must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preBtzinger Complex and the retrotrapezoid nucleus/parafacial respiratory group. We propose a broad series of experiments both in vivo and in vitro in rodents using advanced techniques including: viral delivery to express genetically encoded opsins or DREADDs in key subpopulations of neurons in these regions; advanced optical techniques to determine the contributions of the preBtzinger Complex microcircuit to rhythm generation; state-of-the-art neuroanatomical techniques to establish, in appropriate and necessary detail, the interconnectivity of the brainstem respiratory pattern generator. The data from these experiments will provide an extraordinary window into the mechanisms underlying respiratory rhythm and pattern generation.	{ "pile_set_name": "NIH ExPorter" }
Who Is Responsible for America's Security? The Declaration of Independence announced the sovereignty of the United States and, with it, the “full Power to levy War.” Accordingly, the Constitution’s Framers viewed the security of the nation to be the foremost responsibility of the federal government. That security, history showed, could neither be maintained by committee against pressing and agile threats, nor placed in a single hand. Their solution, as elsewhere, was careful checks and balances involving all three branches of government—but with just one at the fore. Who is responsible for ensuring America’s national security? With the memory of the War for Independence still fresh and the fledging nation facing constant threat from foreign powers and Indian tribes, the Framers saw national security as the highest calling of the federal government that they would create.[1] The Articles of Confederation had proved inadequate as they created a weak and ineffectual government. The world’s naval powers were fearsome but despotic, unworthy examples for this great experiment in freedom and democratic self-rule. So the Framers turned to the lessons of history and reason. The balance they struck remains, like our Constitution, unique. The Constitution vests the President of the United States with the full “executive power” of the federal government. He is named the “commander in chief of the Army and Navy of the United States, and of the militia of the several states, when called into the actual service of the United States.” So does the Constitution place paramount authority for national security in a single executive. The unbounded delegation of the full executive power stands in sharp relief to the limited and carefully enumerated powers accorded the Congress. In Article I of the Constitution, its reach is limited to the “legislative powers herein granted.” Among them are the powers “to declare war, grant letters of marque and reprisal, and make rules concerning captures on land and water”; “To raise and support armies, but no appropriation of money to that use shall be for a longer term than two years”; “To provide and maintain a navy;” “To make rules for the … regulation of the land and naval forces”; and to call forth state militias in service of the nation. In theory, these delegations give rise to a tension between the President and the Congress. The former has ultimate discretion over the deployment of soldiers and nearly all aspects of the conduct of war. The latter holds the power of the purse, by which it may stymie executive initiative. Yet in practice, rather than stand in opposition, the two branches’ respective powers over national security have proved complementary, and rare disputes have been settled in compromise, not duel. That control of the greatest force ever known to mankind should be governed by compromise for over two centuries would be a miracle if it were not by design. "The President is the sole organ of the nation in its external relations, and its sole representative with foreign nations."- John Marshall March 7, 1800 American Presidents have deployed military force several hundred times in the nation’s history. Yet, Congress has declared war only five times, first against the British in 1812 and most recently against the Axis powers in 1941. There is no inconsistency in this. To “declare war,” as it was understood at the time of the framing of the Constitution and as it has been practiced, is to realign the legal rights and obligations of nations. A declaration of war renders subjects of the enemy power enemies of the United States, who may be forced to choose between departure or capture; it renders enemy property subject to confiscation or seizure; it provides a measure of damages to be paid in any post-war reparations; and it requires American citizens to treat the enemy as such in their affairs. But to declare war is not to wage war. Placing that power in the legislative branch was an idea that the Framers soundly rejected. Under the Articles of Confederation, the United States lacked a formal executive, and all war power was vested in the Congress, delegated in some respects to a Department of Foreign Affairs. This arrangement was unworkable. Lacking any unitary executive, America’s foreign policy and defense floundered, as the legislators squabbled and proved unable to reach agreement on equipping a federal army to protect U.S. outposts or to commit the nation to any diplomatic course. The need for an executive was apparent by the time of the Constitutional Convention in 1787, but the delegates clashed over the necessary powers of the office. James Madison, in particular, turned to the works of political philosophers John Locke and Montesquieu and jurist William Blackstone. All three had, for pragmatic reasons, placed the power to make war and peace, to enter into foreign alliances, and to conduct all other diplomacy, in a single executive. Alexander Hamilton looked to ancient history and the experiences of those states which had attempted to divide the executive power, usually with unfortunate results. Madison’s and Hamilton’s views largely prevailed, with but little dissention. One late draft vested in Congress the power to “make war.” Madison feared the language too inflexible for the needs of a nation under constant threat of foreign attack to which Congress had proved itself unequal. At his insistence, Congress’s power was limited to declaring war; the remainder of the war power would reside in the executive. This alteration proved contentious in several ratification debates. Patrick Henry accused the Constitution’s Framers of all but reinstating a monarchy in America through the centralization of war power in the presidency. George Nicholas, a supporter of the Constitution, explained the fallacy of Henry’s claim: [N]o appropriation of money, to the use of raising or supporting an army, shall be for a longer term than two years. The President is to command. But the regulation of the army and navy is given to Congress. Our Representatives will be a powerful check here. The President would be nothing less than the full commander in chief of the nation’s military, but would be tempered by Congress’s exercise of its own powers. As far back as Marbury v. Madison, the Supreme Court recognized that questions of foreign affairs fall within the discretion of the President. Consequently, the only appropriate check on the president’s foreign affairs discretion is political and therefore questions of this sort are not to be resolved in the courts. Accordingly, for more than 200 years, the courts properly rebuffed all attempts to seek judgment on the use of force abroad and other overseas operations. In recent years, however, the Supreme Court has overstepped its constitutional bounds in a series of cases involving detainees in the war on terrorism. The Court’s decisions in these cases find support neither in precedent nor in the Constitution. “That unity is conducive to energy will not be disputed,” Alexander Hamilton observed. “Decision, activity, secrecy, and dispatch will generally characterize the proceedings of one man in a much more eminent degree than the proceedings of any greater number.” What was true during the founding has proven true in the modern era. At the command of President Ronald Reagan, the first of 7,000 U.S. troops landed on the shores of Grenada on October 25, 1983, to put down a violent coup that threatened to put the country in the Communist bloc and give the Soviet Union a second forward base, after Cuba, in the American vicinity. The invasion was unexpected, and American victory was swift and decisive. It also likely prevented a humanitarian catastrophe, based on reports of mass killing by Communist forces. "The Founders intended that the President have primary responsibility- along with the necessary power-to protect the national security and to conduct the Nation's foreign relations."- Justice Clarence Thomas June 28, 2004 Could a deliberative body have acted to protect the nation with similar decision, activity, secrecy, and dispatch? The evidence suggests not. After allowing time for deliberations and debate, the United Nations General Assembly held a vote on the situation in Grenada on November 2, a full week after U.S. forces had landed and days after all resistance had been subdued. By an overwhelming majority, the U.N. expressed its disapproval of the U.S. invasion. Asked his opinion on the vote, President Reagan said, “It didn’t upset my breakfast at all.” The reasons for the President’s calm resolve were obvious. He acted, as he should have, in support of the United States’ interests and to enforce treaty obligations at the request of other party nations. Though the Framers could never have imagined the events of September 11, 2001, or the terrorist forces that have made America their enemy, they built a republic that could endure and defeat all external threats and prosper. The war on terrorism, being fought against an enemy with few assets and dead aim on soft targets, has only increased the importance of swiftness and secrecy. The President has the power, and bears the responsibility, to make tough decisions at a moment’s notice—whether to trust fresh but uncertain intelligence, bomb an al-Qaeda safe house, target a terrorist for drone attack, or arrest a terror suspect. These decisions are not subject to legislative check or veto. Nor, in an age where a rogue state or stateless terrorist group may threaten the lives of million of Americans, could they be, if the safety of the nation is to be maintained. National security comes first; without it, life and liberty are threatened and happiness is an impossibility. Therefore, as James Madison wrote: “Security against foreign danger is one of the primitive objects of civil society. It is an avowed and essential object of the American Union.” Protecting the nation requires a unity of purpose and faculty, and it cannot be devolved to a committee or Congress. The Framers recognized as much, and their wisdom is our strength. The President, first and foremost, is responsible for ensuring America’s national security. Edwin Meese III is the Ronald Reagan Distinguished Fellow in Public Policy and Chairman of the Center for Legal & Judicial Studies at The Heritage Foundation. Enduring Truths Alexander Hamilton, The Federalist Papers, Essay No. 70, "The Executive Power Further Considered" Alexander Hamilton explains the necessity for an energetic, unitary executive to secure republican safety, particularly against foreign aggressors. Vesting the responsibility for America's national security in a single executive rather than a legislative body best ensures the goals of "decision, activity, security, and dispatch." Alexander Hamilton, Pacificus-Helvidius Debates, Pacificus Number 1, 1793 The first in a series of debates between Alexander Hamilton and James Madison that discuss the scope of executive power in foreign policy relations. Hamilton argues that while Congress has the right to formally declare war, it is "the duty of the Executive to preserve peace till war is declared." The President can further the interests of the United States abroad without prior congressional approval. John Yoo, "Energy in the Executive," April 24, 2006 American Presidents have deployed military force several hundred times in the nation's history, yet Congress has declared war on only five occasions. Yoo explains why there is no inconsistency in this. The Framers of the Constitution carefully distinguished a declaration of war from the act of waging war. Congress cannot tell the President how to deploy the military forces it raises and funds, but its control of the purse strings constitutes a powerful check on the President. Current Issues WAR POWERS. James Jay Carafano, "Libya: How Congress Should Speak to the White House," June 2, 2011. Prior to intervening in Libya, the President did not consult Congress, and his military strategy has since failed to advance U.S. interests. Although the President acted imprudently, he did not violate the Constitution and acted within the powers accorded to him as commander in chief. In responding, Congress should remain mindful of its obligations to act in America's interest within constitutional bounds. NATIONAL DEFENSE. Senator Jim Talent, "A Constitutional Basis for Defense," June 1, 2010. National defense is one of the paramount responsibilities of the federal government. Former Senator Jim Talent discusses the state of America's defenses and the actions that Congress and the President must take in order to adequately protect America against the ongoing dangers that it faces abroad. SUPREME COURT. Charles D. "Cully" Stimson, "Elena Kagan: Justice Stevens Redux?" May 18, 2010. In recent years, the Supreme Court has played an ever increasing role in shaping national security. But it has failed to give proper deference to the commander in chief and has found a constitutionally guaranteed right of habeas corpus for terrorists who are under the custody of the United States. Stimson outlines these instances of judicial activism and warns of the threats that such activism poses both to national security and the proper role of the courts. The Senate must be mindful of these concerns when questioning and confirming a President's appointment to the Supreme Court. INTELLIGENCE. Brian W. Walsh and Todd Gaziano, "Modernize FISA, But Don't Hobble American Intelligence Operations," October 16, 2007. The highly regarded, bipartisan 9/11 Commission concluded that the failure to detect or prevent the September 11 terrorist attacks was caused in part by major gaps in U.S. intelligence gathering. President George W. Bush exercised the constitutional authority exercised by every American commander in chief and improved intelligence gathering on the activities of foreign terrorists. Congress's attempts to micromanage and thus undermine the commander in chief's constitutional authority to engage in traditional military intelligence gathering activities should be resisted. Download the Report: ENDNOTES [1]See, for example, The Federalist Papers, Essay No. 3, in which John Jay writes, “Among the many objects to which a wise and free people find it necessary to direct their attention, that of providing for their SAFETY seems to be the first.” Rep. Peter Roskam (R-IL) says it's "a great way to start the day for any conservative who wants to get America back on track." Sign up to start your free subscription today! Sorry! Your form had errors: First name is not validLast name is not validEmail Id is not validZip code is not valid About The Heritage Foundation The Heritage Foundation is the nation’s most broadly supported public policy research institute, with hundreds of thousands of individual, foundation and corporate donors. Heritage, founded in February 1973, has a staff of 275 and an annual expense budget of $82.4 million. Our mission is to formulate and promote conservative public policies based on the principles of free enterprise, limited government, individual freedom, traditional American values, and a strong national defense. Read More	{ "pile_set_name": "Pile-CC" }
After months of preparation and waiting, it’s finally fight night as Miguel Cotto and Saul “Canelo” Alvarez meet Saturday night in a highly anticipated middleweight bout headlining the HBO pay-per-view card form Mandalay Bay in Las Vegas. While coverage begins at 9 p.m. ET, the fight should probably should start at about 11:45 p.m. ET or later. Cotto (40-4, 33 KO) and Alvarez (45-1-1, 32 KO) meet at a catch-weight of 155 points in what some expect to be "the fight of the year" after some casual boxing fans were disappointed by Mayweather-Pacquiao in May. Both boxers are fairly well-known, bring an aggressive brand of fighting to the ring, and are legends of sport in their respective countries. These two squaring off represents the latest chapter in a long rivalry of Puerto Rican and Mexican boxers. When it comes to honoring those countries before the fight, actor and singer Jaime Camil will sing Mexico’s national anthem while Latin Grammy-nominee Pedro Capo will sing Puerto Rico’s national anthem. Here are a 10 interesting facts about the fight set to take place at Mandalay Bay: 1) The judges selected for the bout are Burt Clements, Dave Moretti and Kohn McKaie. Clements has worked two of Canelo’s fights but none of Cotto’s. Morretti has judged four of Cotto’s bouts, including losses to Mayweather (2012) and Pacquiao (2009) and three of Canelo’s fights, including his last two wins over Erislandy Lara (2014) and Alfredo Angulo (2014). McKaie has never worked any of Alvarez’s fights but has judged two of Cotto’s, including his TKO of Zab Judah (2007). 3) Four days before the fight, Cotto was stripped of his WBC World Middleweight Championship belt. Sources told ESPN's Dan Rafael the action was taken as a result of Cotto refusing to pay a $300,000 sanctioning fee to have the belt on the line. Cotto reportedly felt the fee was "akin to extortion." With a win over the lineal champion, Alvarez can leave Las Vegas the champion and holder of the now-vacated belt. 4) In his last fight, Cotto won via fourth-round TKO over Australian Daniel Gael in June, bringing his knockout total to 33. 5) Alvarez's last bout ended in a third-round knockout of James Kirkland at Minute Maid Park in Houston. It was Alvarez's 32nd knockout. 6) Alvarez has won his last three fights after losing to Floyd Mayweather Jr. in 2013. He beat Angulo (TKO) and Lara (split decision) before knocking out Kirkland. 7) Cotto has a three-fight win streak of his own following losses to Mayweather Jr. and Austin Trout. Cotto, who credits new trainer Freddie Roach for much of his success, has beaten Delvin Rodriguez (TKO) and Sergio Gabriel Martinez via referee's stoppage before the latest TKO victory over Gaele. 8) Most fans are expected to be pulling for Alvarez with a heavy pro-Mexican crowd expected to fill the seats in Las Vegas. 9) Alvarez turned pro at age 15 and has fought 47 times, two more than Cotto, who is 10 years his senior. 10) Cotto became the first Puerto Rican boxer to hold titles in four different weight classes when he defeated Martinez in 2014.	{ "pile_set_name": "Pile-CC" }
Slávka Frniaková Slávka Frniaková (born 9 March 1979 in Žilina) is a Slovak former basketball player who competed in the 2000 Summer Olympics. References Category:1979 births Category:Living people Category:Slovak women's basketball players Category:Olympic basketball players of Slovakia Category:Basketball players at the 2000 Summer Olympics Category:Sportspeople from Žilina	{ "pile_set_name": "Wikipedia (en)" }
Orthopedic Surgery for Knees. The limitations and chronic pain of damaged knees and joints need expert care. At St Pete Hip and Knee, we restore the normal functioning of knees and joints that have been damaged and we help patients get back to their lives and normal activity levels. We see many patients who suffer from arthritis and trauma initiated joint pain and can benefit significantly from orthopedic surgery. Orthopedic Surgical Procedures St Pete Hip and Knee offers a wide range of services and performs thousands of joint and knee surgical procedures annually. From partial knee replacement and total knee replacement to bilateral joint replacement, we are committed to patient-friendly, safe and effective treatments. Patients from the St Petersburg area give high marks for our surgical center, making it the number one joint correction center both in the number and quality of procedures performed. A Commitment to Care Physicians in St Petersburg, Florida, and beyond refer their patients to our clinic, especially for the more complex procedures for correcting total joint dysfunction. As we endeavor to maintain the highest standards in every regional referral center, we enlist surgeons who are thoroughly trained in the joint preservation operations which are essential for preventing the progress of congenital knee arthritic conditions in young adults. Adopting up-to-date techniques and technology, we guarantee success in every operation and remain committed to health education and continuous research.	{ "pile_set_name": "Pile-CC" }
Early application of Global Subjective Evaluation Produced by the Patient and survival in patients with cancer. Introduction: malnutrition is a frequent event in cancer, and unless identified early, it can lead to progressive functional impairment of the organism. Objective: to associate the early application of the Global Subjective Evaluation Produced by the Patient (GSEPP) to the time of hospitalization and death in cancer patients. Methods: a cross-sectional, analytical study carried out between July and September 2014 in patient records (> 20 years) with cancer, with hospitalization for more than three days in a reference cancer hospital. Age, sex, origin, disease location, antineoplastic treatment, length of stay and application of GSEPP, type of discharge, weight loss in one and six months, body mass index (BMI) and GSEPP score were collected. Results: three hundred and sixty-six patients were evaluated: 51.6% women, 54.9% adults, 27.6% tumors of the digestive tract, 11.5% with metastasis, 21.9% of deaths and 40.4% with hospitalization time greater than or equal to ten days. The length of hospital stay was statistically lower in the early application of GSEPP (11.4 ± 1.5 vs 23.3 ± 1.3 days). The delay in the application of GSEPP was positively correlated with the increase in length of hospital stay, the GSEPP score, as well as malnutrition by BMI and weight loss in one and six months. Conclusion: early application of GSEPP was associated with improvements in the parameters of malnutrition, shorter hospitalization time, but not mortality. Measures that abbreviate its application should be taken to awaken the importance and the impact of this instrument in the health of the evaluated patient.	{ "pile_set_name": "PubMed Abstracts" }
At latest weekend's Anime Central event, North American publisher Vertical announced release plans for NISIOISIN's Nekomonogatari, the fourth part of the Monogatari series - the sixth and seventh books overall. Its "Black" is the final book of the first season and "White" is the first book of the second. Along with this, they also announced new plans for a Flowers of Evil omnibus collection of Shūzō Oshimi's 2009-2014 manga. New announcement: Nekomonogatari (black) and Nekomonogatari (white) coming later this year/early next year. pic.twitter.com/DThByUitOD — Kunal @ ACen (@kunaldes) May 21, 2017 Flowers of Evil Complete (omnibus) coming. Trying to get new art for the covers and color inserts from the magazines Image is a placeholder pic.twitter.com/HmjmgcRwpK — Kunal @ ACen (@kunaldes) May 21, 2017 Novels/light novels Currently on sale - Seven Deadly Sins Light novel Coming soon - Your Lie In April light novel September - Anime Supremacy novel Manga Ajin 9 was released in March, catching up with the Japanese release. There will be a wait for the next June Mysterious Girlfriend X 12 (final volume) Nichijou 8 (of 10) July BLAME! 4 (of 6) Devils' Line 7 Gundam Wing Mobile Suit Gundam: WING volume 1 in July Cover just recently finalized pic.twitter.com/eFSMoo8lpG — Kunal @ ACen (@kunaldes) May 21, 2017 August She and Her Cat October Helvetica Standard (large size and full color) November Arakawa Under the Bridge (coming in 7 2-volume omnibuses) Late 2017 Imperfect Shojo by NISIOISIN Early 2018 Voices of a Distant Star via @kunaldes ----- Scott Green is editor and reporter for anime and manga at geek entertainment site Ain't It Cool News. Follow him on Twitter at @aicnanime.	{ "pile_set_name": "OpenWebText2" }
MS-8209, an amphotericin B analogue, delays the appearance of spongiosis, astrogliosis and PrPres accumulation in the brain of scrapie-infected hamsters. The histopathological response of scrapie-infected hamsters treated at the late stage of the infection with an "anti-scrapie" drug, a polyene macrolide antibiotic designated MS-8209, was evaluated in the brain. The results showed that (1) MS-8209 prolonged significantly the incubation time of the experimental disease, (2) MS-8209 delayed the appearance of spongiosis and astrogliosis in the brain, (3) immunodetection of abnormal prion protein and glial fibrillary acidic protein was significantly reduced in the central nervous system. In addition, this report indicates that polyene antibiotics markedly delay the development of the classical brain lesions that result from scrapie infection.	{ "pile_set_name": "PubMed Abstracts" }
Q: How to solve $n^2-n<\lfloor\frac{n^2}{4}\rfloor$ ,$n \in \mathbb{N}$? How to solve this inequality? $$n^2-n<\lfloor\frac{n^2}{4}\rfloor \\ n \in \mathbb{N}$$ I can solve normal inequalities but this includes floor function with which I am not familiar. and because of that I could do nothing from the beginning. A: HINT: It's always true that $\left\lfloor\frac{n^2}4\right\rfloor\le\frac{n^2}4$, so if $n^2-n<\left\lfloor\frac{n^2}4\right\rfloor$, then certainly $n^2-n<\frac{n^2}4$. What solutions does this inequality have in $\Bbb N$? Are any of them solutions to the original inequality?	{ "pile_set_name": "StackExchange" }
BALENCIAGA / Women's Sunglasses Very contemporary and glamorous, eyewear from Balenciaga is the preferred choice for folks who understand true luxury wear. A boutique brand, Balenciaga does not follow the typical, assembly-line manufacturing approach. Expect more limited editions and a small, handpicked selection every season. The inventory at Balenciaga is progressive, always managing to surprise its patrons. Every season, Balenciaga surprises its critics with its unique ability to fuse retro-influences with sporty, futuristic shapes. Balenciaga initially gained fame with its Lariat range of motorcycle-inspired handbags. Global bestsellers, these bags continue to trend but are not easily accessible. You have to be at one of Balenciaga’s stores or visit a retailer who specializes in refined, upmarket lifestyle merchandise. Balenciaga caters to discerning buyers, men and women, who like the idea of indulgence—a sophisticated alternative to regular, branded eyeglasses and sunglasses out there. Balenciaga’s approach to eyewear is reflected across its versatile portfolio. From handbags to shoes, jewelry and belts, the brand chooses to update its offerings with the best. Nothing usual or mainstream makes it to Balenciaga’s line of products. The exclusivity factor is essential here, including elegant frames and eyeglasses. From cat eye to oversized and geometric frames, expect Balenciaga to deliver designer sunglasses and even prescription sunglasses with an emphasis on elegance. Designs at Balenciaga are never outright blingy, they don't shout for attention. The approach is in fine detailing that can be appreciated only by a handful of folks who understand avant-garde creations. From ready-to-wear apparels to accessories, workplace ensembles or evening wear, Balenciaga’s design philosophy has always managed to create an impression, flaunted by Hollywood fraternity, making it to many red carpet events. Fashion editors agree that Balenciaga brings the type of exclusivity that very few brands deliver. Balenciaga’s range of sunglasses underline this approach. Each eyewear is futuristic without being bizarre. That typical French influence of subtle styling is clearly palpable. Our collection of Balenciaga should induce a feeling of buying the best in luxury brands. You get the assurance of finding the latest from Balenciaga under one roof—a smartly categorized online interface that helps you browse and shop the best Balenciaga has to offer. How do we manage this? Our dedicated team of fashion curators and trend-spotters are always in harmony with what is creating noise in the niche of fashion wear that stands apart from the crowd. Balenciaga resonates with our approach. It is passionate and Parisian—traits that we associate with pioneering designs, innovative contours and clean lines. Explore the most holistic online collection of Balenciaga designer eyewear, including high-tech aviators and marbled, round or oversized frames…	{ "pile_set_name": "Pile-CC" }
Bladder afferent pathway and spinal cord injury: possible mechanisms inducing hyperreflexia of the urinary bladder. Lower urinary tract dysfunction is a common problem in patients with spinal cord injury (SCI). Since the coordination of the urinary bladder and urethra is controlled by the complex mechanisms in spinal and supraspinal neural pathways, SCI rostral to the lumbosacral level disrupts voluntary and supraspinal control of voiding and induces a considerable reorganization of the micturition reflex pathway. Following SCI, the urinary bladder is initially areflexic. but then becomes hyperreflexic because of the emergence of a spinal micturition reflex pathway. Recent electrophysiologic and histologic studies in rats have revealed that chronic SCI induces various phenotypic changes in bladder afferent neurons such as: (1) somal hypertrophy along with increased expression of neurofilament protein; and (2) increased excitability due to the plasticity of Na+ and K+ ion channels. These results have now provided detailed information to support the previous notion that capsaicin-sensitive, unmyelinated C-fiber afferents innervating the urinary bladder change their properties after SCI and are responsible for inducing bladder hyperreflexia in both humans and animals. It is also suggested that the changes in bladder reflex pathways following SCI are influenced by neural-target organ interactions probably mediated by neurotrophic signals originating in the hypertrophied bladder. Thus, increased knowledge of the plasticity in bladder afferent pathways may help to explain the pathogenesis of lower urinary tract dysfunctions after SCI and may provide valuable insights into new therapeutic strategies for urinary symptoms in spinal cord-injured patients.	{ "pile_set_name": "PubMed Abstracts" }
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After a poll showed that Turkish Twitter users believe that Turkey gets oil from Erdogan-ISIL ties and the Russian Embassy reposted the results for discussion, the Erdogan-linked pundit who made the poll panicked, disabling his account and blaming Russia for 'sabotage' a day later. Pro Erdogan Islamist writer conducts a poll. Who buys ISIS oil? 1.Russia 2.Syria 3.Turkey @RT_com pic.twitter.com/XHornaRwSJ — #Kobane #Kurdistan (@whoRtheKurds) December 2, 2015 A columnist at Turkey's Akit newspaper, Abdurrahman Dilipak, known for close connections to the country's president, deleted a poll on his Twitter account after it was found that respondents overwhelmingly answered that Turkey, not Russia or Syria, buys oil from Daesh. After seeing the initial results, Dilipak argued that Turkey's ruling AKP party "insufficiently informs Turkey's population on the question of buying oil from Daesh," adding that the results confirm this. However, the repost of the poll on the Russian Embassy's Twitter led Dilipak to accuse the embassy of "sabotage" and shut down his twitter account. İlginç bir anket! 1 saatin bilançosu ortada… pic.twitter.com/4TMw19ske1 — RusEmbTurkey (@RusEmbTurkey) December 2, 2015 "Interesting Poll! Results collected in one hour…" The poll showed that 78% of respondents believed that Daesh sells its oil to Erdogan's Turkey. The pundit then shut down his twitter account and brought it back a day later, writing an angry response, claiming that he was sabotaged by the Russian Embassy. Dilipak is a fierce critic of Turkey's founder, Mustafa Kemal Ataturk, and has called for Turkey's President Recep Tayyip Erdogan to be a new "Caliph" after a return of the Caliphate, which Ataturk abolished in 1924. On Novebmer 10, the 77th anniversary of Ataturk's death, the newspaper Dilipak writes for published an article called "Tyranny Ended in 1938," the year Ataturk died, which led to outrage in Turkish society.	{ "pile_set_name": "OpenWebText2" }
When you're married to a girl that looks and has the sex drive of Tori Black, going to work seems pretty inconvenient. Lucky for you, Tori's willing to do a private little show so you can jerk it at the office and know exactly what awaits for you when you get home. Watch the very sexy Tori in virtual reality as she dirty talks her way into one of the hottest JOI scenes you'll ever see. It's going to be a great night for you!	{ "pile_set_name": "OpenWebText2" }
Q: animateKeyframes with repeat and delay does not work as expected I'm creating a simple left to right animation for a label using key frames but when the animation repeats, the delay is ignored. The first time it executes, the delay of 3 seconds has an effect, but when the animation repeats, the delay is ignored. This causes the animation to re-start immediately after it ends. UIView.animateKeyframes(withDuration: 10, delay: 3, options: [.calculationModePaced, .repeat], animations: { let xDist = self.Label_ArtistAlbum2.frame.origin.x UIView.addKeyframe(withRelativeStartTime: 0.0, relativeDuration: 0.1, animations: { self.Label_ArtistAlbum2.frame.origin.x = self.Label_ArtistAlbum2.frame.origin.x - (xDist * 0.1) }) UIView.addKeyframe(withRelativeStartTime: 0.9, relativeDuration: 0.1, animations: { self.Label_ArtistAlbum2.frame.origin.x = 0 }) }, completion: nil) I've tried adding an extra keyframe at the end however this has no effect even with the altered times: UIView.animateKeyframes(withDuration: 10, delay: 3, options: [.calculationModePaced, .repeat], animations: { let xDist = self.Label_ArtistAlbum2.frame.origin.x UIView.addKeyframe(withRelativeStartTime: 0.0, relativeDuration: 0.1, animations: { self.Label_ArtistAlbum2.frame.origin.x = self.Label_ArtistAlbum2.frame.origin.x - (xDist * 0.1) }) UIView.addKeyframe(withRelativeStartTime: 0.1, relativeDuration: 0.7, animations: { self.Label_ArtistAlbum2.frame.origin.x = 0 }) //attempted pause - does not appear to work perhaps since the position is unchanged? UIView.addKeyframe(withRelativeStartTime: 0.8, relativeDuration: 0.2, animations: { self.Label_ArtistAlbum2.frame.origin.x = 0 }) }, completion: nil) If the delay will not be repeated along with the rest of the animation, how can I create a pause before the entire animation repeats? A: I've done a lot of testing on this issue and have found what I believe is the problem. I think that the animation option for the Curve is my issue. In my case choosing calculationModePaced has the effect of recalculating my keyframe parameters and not guaranteeing to hit any of them except the beginning and end. All intermediate keyframes become 'suggestions'. You can't create a pause at the end because the keyframe is 'consumed' when recalculating and does not stand on it's own. I changed to calculationModeLinear and got the keyframes I expected, and the pause too. However, it is as smooth as I would like so I'll have to keep tinkering... Apple's docs are here - they're descriptive but could really use some graphics and/or examples: https://developer.apple.com/reference/uikit/uiview?language=swift A good graph of the curves can be found here: https://www.shinobicontrols.com/blog/ios7-day-by-day-day-11-uiview-key-frame-animations	{ "pile_set_name": "StackExchange" }
Hood Canal News Ready to start filling your 2019 calendar with fun things to do? Start by planning your getaway to Hood Canal! Spring, Summer, Fall or Winter, check out our seasonal recommendations below. And take advantage of our spring and summer specials: for stays prior to May 15th get 3 nights for the price of 2; for stays between June 1st – September 1st get 7 nights for the price of 5 (excluding 4th of July week). Give us a call 888-796-3450, or request a reservation using our online form. Spring Spring means our mountain hikes are more accessible as the snow melts. Check out the Washington Trail Association website for Hood Canal trails and trail reports here. Spring also means the return of Daytime low tides, time to gather Hood Canal oysters and clams. Click here for the handiest daytime low tide chart for 2019. Here is a link to local beaches. And the popular, Hama Hama Oysterrama returns in April. Shrimpfest is also back! Memorial Day weekend attend the Brinnon Shrimpfest. Celebrating Hood Canal Spot Shrimp and other local seafood. It lures hungry shrimpers from all over the Northwest to fish Hood Canal’s rich waters. Shrimpfest features craft booths, food booths, belt sander races, exhibits, live music, kids activities and so much more. View from Mt Walker Hama Hama Oysterrama in April Brinnon Shrimpfest Memorial Day Weekend Summer Crab Season opens! Check out WDFW website for crabbing dates and regulations. Hiking the summits of Mt Ellinor, Mt Townsend and other lofty Olympic Mountain vistas. Visit the WTA.org website for Trip Reports. Take advantage of warmer summer weather and low tides for shellfish gathering and beachcombing. Or try your hand at Kayak and Kayak crabbing with Hood Canal Adventures. Summer crabbing on Hood Canal Digging for Manila clams Bring your Kayak or call Kayak Brinnon Fall A fun fall weekend starts with the Jefferson County Farm Tour. Fall hiking adventures include spectacular colors, less people and more wildlife. Dosewallips State Park has a variety of hikes and wildlife viewing areas in the forest and on the beach. Winter Start your holiday tradition by choosing an Olympic National Forest christmas tree, and take advantage of winter rates. Have the trails to yourself-There are plenty of stunning lowland trails with rivers, waterfalls and moss covered trees to start the new year off on the right foot. Then celebrate by Wine tasting at Olympic Peninsula wineries. Cheers! Tips for finding a Perfect Christmas Tree An excellent family tradition: Stay the weekend and score the perfect Christmas Tree! For just $5 each pick up your U-cut tree permit for the Olympic National Forest. Its available at the Quilcene Ranger Station. Click Here for directions and hours. And take advantage of our 3 for 2 special. Stay 3 nights for the price of 2. Call us for details 888-796-3450. Time to Visit Hood Canal Here on the west side of Hood Canal, we greet fall as a time to relax and welcome the cooler weather which makes for stunning fall colors, mountain trails with less people, more mushrooms, and migrating wildlife. Fall may be the best time to hike Hood Canal before the snow hits the summits Autumn color makes for nice photography, not to mention the eastern views from the Olympic mountain vistas toward the Puget Sound waterways. The crowds are gone. To choose your Hood Canal hike, Wta.org has the most comprehensive database of hikes in Washington state. Choose the Olympic Peninsula Region and the Sub region Hood Canal. The website gives you a Hike Finder, Hiking Guides and Trip Reports. Be sure to check NOAA weather and snow levels before you go. Mushrooms Fall mushrooming has begun! In the Olympic National Forest, no permit is required for incidental gathering of mushrooms for personal use. For a single species, the daily limit for personal use is one (1) gallon. For multiple species, the daily limit is three (3) species, (1) gallon each. Harvested chanterelle mushrooms must have a cap diameter of one inch or greater. Here is link to the National Forest Mushroom information handout. And, here is a link to #PNW Mushroom experts, the Puget Sound Mycological Society. A great resource for Harvesting rules, Recipes and more! Wildlife While looking for mushrooms, watch for wildlife. Its the time of the season for Salmon, Migrating birds and Roosevelt Elk. For viewing wildlife and safety tips we recommend the Dept of Fish and Wildlife, Wildlife Viewing section. #WineDDown your Summer at Hood Canal with Farms, Oysters and Wine! If you’re not ready to say goodbye to summer, why not toast its finale with farm, food, wine? Join us! September 15 & 16th Every year the Jefferson County Farm Tour draws thousands of visitors eager to experience a working farm and connect with local farmers. A self-guided Tour! Want to participate? Hop on your bike or load up your car with friends and family. Here is a list and map of farms for the day-of events. Farm Tour Central is at the Chimacum Corner Farmstand which is open daily and features a Sunday Farmers Market from 10-2. The Farm Tour is Open to the public with a $10 Suggested Donation per carload. No one turned away! You can make this donation at any stop including Center Valley Animal Rescue. Sunday, September 16th Quilcene Oyster Races No, Oysters are not racing, but YOU can. The course covers 13.11 miles and features views overlooking Hood Canal and Quilcene Bay, plus a peek at the Olympic Mountains (weather permitting). The Half Marathon is hilly and challenging, but totally worth it! There is also a free concert from 1-3 pm . Details Here. Speaking of oysters, the last of this year’s daytime low tides are Sept 20 – 26th. Here is a list of beach seasons. However, you can still get your Hood Canal seafood fix at the Hama Hama Oyster Bar Thursdays-Mondays. Their farm store is open daily. Or, visit the Taylor Shellfish Market in Shelton also open daily. Shelton is also home to the annual Oysterfest. This year’s event takes place October 6 & 7th. Oysters, wines, microbrews, live music and more. Attended by thousands, OysterFest is home to the West Coast Oyster Shucking Championships and is Washington State’s official seafood festival. More information can be found here. Olympic Peninsula has its own region of wineries. The Olympic Peninsula Wineries are a group of hands-on owners/winemakers committed to handcrafting excellent, award-winning Washington wines. Each of our Olympic Peninsula Wineries offer visitors friendly hospitality and a unique, memorable experiences. Owners/winemakers are often available to personally pour for the visitors in their tasting rooms and to answer questions. And the Fall Harvest usually provides for special events and tastings. Stay tuned for details. If you need one more reason to #WineDDown to Hood Canal, it’s because it is the beginning of our non-peak season. That means lower prices for our vacation rentals (starting September 16th), and less people on hiking trails, beaches and wineries. Enjoy! Windermere Hood Canal Vacation Rentals is proud to announce a new partnership with Northwest Stays, a regional listing platform featuring the best professionally managed vacation rentals in the Pacific Northwest. From lovely urban area vacation rentals to charming and cozy cabins, you’ll find everything you want in a vacation at Northwest Stays. Vacation Homes on Hood Canal, managed by Windermere Hood Canal can be found in the Hood Canal, Brinnon, Hoodsport, Lilliwaup, Port Ludlow and Quilcene sections where you can search all of our inventory and visit our website (where you are now) to book the ideal rental property for you. Northwest Stays also features professional managers from nearby areas: you can trust the rentals you’ll find on the website are vetted, trusted properties that are ideal for your next getaway. Instead of clicking around and not being sure that you’re finding a trusted vacation rental company, you can choose from the best at Northwest Stays. In addition to the benefits of searching from trusted professional vacation rental managers, NWVRP.org, you’ll also pay no booking fees or any guest traveler fees on Northwest Stays. Each listing page brings you directly to the rental managers website where you can book direct to save money the same exact rental property. We’re excited to share the new marketplace with you, our guests, and look forward to seeing you explore the platform to find new places to travel in the beautiful PNW. 6 Reasons to Escape The City – To Hood Canal If you need a break from the rat race this summer, escape to the quiet, and wild, west side of Hood Canal. Only 2 hours from Seattle and 3 hours from Portland, but a world apart from the hubbub. Here in Brinnon we are 45 minutes from the nearest traffic signal! Besides pure relaxation, vacationers come here in the summer for the crab, shellfish, hiking, kayaking, boating and wildlife. We have 8 vacation rental homes on the water for the perfect beach vacation experience. The peak season is here, so check our availability calendar and book directly with us to avoid the booking fees charged by the big online travel sites. 2. Go Shellfishing Hood Canal is known for its oysters and clams. Are there low tides during your stay? Gathering clams and oysters is only practical on most beaches during the daytime on tides lower than 2 feet, although minus tides are better. If you’d like to try shellfishing, bring old tennis shoes, rubber boots, or aqua socks to wear on the beach. Our beaches are full of oysters, the shells are razor sharp and can easily cut, so be careful. Bring a bucket and a rake to get clams. On most beaches you can just rake down to the clams since they are close to the surface. Be sure to fill in your holes. Bring an oyster shucking knife and a pair of gloves. Oysters shells are very sharp so you will want to wear gloves when you open them with a knife. An oyster knife is much different than a regular knife so if you love to eat oysters be sure to bring one along. Bring beach towels or old towels. The towels in the houses are for bathing and not the beach. Don’t forget your shellfish license. You can buy them at the Brinnon store. You can buy an annual license or a 1-3 day license. Everyone has to have one even if you are on private property.List of BeachesRules and LimitsClam and Oyster season at Public BeachesDaytime low tidesAbout our local oysters and clams If you’d rather just buy some shellfish, you can get them at Taylor Shellfish in Shelton or Hama Hama in Lilliwaup. They often have oysters and clams in Quilcene at Twana Roadhouse or Quilcene Village store. The vacation home kitchens are stocked with cookware and utensils for preparing your meals. Some kitchens will have seasonings, but you should bring your favorites with you. Prepare your dinner then sit outside with your bounty and a beverage and take in the waterfront view, seals, eagles, and the changing tide. 3.Go Hiking Experience Forest fresh air, vista views from the olympic mountain trails overlooking Hood Canal. Its a hikers paradise with easy to difficult trails to explore for all ages. Bring your camera and check out these local classic waterfall hikes: Rocky Brook Falls, Falls View, and Murhut Falls or check out the Hood Canal Hiking guide from Washington Trails Association. 4. Go Kayaking Popular launch sites include Pt Whitney, Pleasant Harbor, Seal Rock Campground, Yelviks Boat ramp, Dosewallips State Park, and Triton Cove. Kayak Brinnon provides kayak rentals and tours from Yelviks beach in Brinnon and will deliver kayaks to locations between Quilcene and Potlatch. There is plenty of sealife to view. And, often our local elk herd are present near Dosewallips State Park. 6. View Wildlife There are plenty of birds that frequent the tidelands around Hood Canal and along the way on your hikes in Olympic National Forest. Stop off at one of the visitor centers in Quilcene, Brinnon, or Hoodsport to pick up a bird guide. They are an excellent stop for hiking maps and area information. Deer are numerous and Elk can be seen around the Dosewallips State Park. Wildlife information from the Department of Fish and Wildlife can be found Here. Shrimp Hood Canal If you want to experience the best tasting shrimp of the Pacific Northwest, the spot shrimp from Hood Canal, you have two options. You can be adventurous and catch it yourself, or you can buy it. Where to Buy Hood Canal Shrimp Normally the best place to get Hood Canal Shrimp is at the Brinnon Shrimpfest on Memorial Day weekend. Unfortunately, the Shrimpfest was called off this year due to lack of volunteers. Luckily YOU CAN BUY SPOT SHRIMP ON MEMORIAL DAY WEEKEND – 10 am to 4 pm Saturday, Sunday and Monday at the Brinnon Community Center located at 306144 Highway 101 in Brinnon, WA. Meanwhile, if you’d like to try shrimping yourself, here are some tips: How to Catch Hood Canal Shrimp Basically you need a boat, shrimp pots (see special pot requirements), weighted line and buoys, shellfish license, bait (usually fish flavored cat food), warm clothes, a sense of adventure and a bit of gold rush mentality. There are only four days of shrimping: May 5, 9, 12 and 23rd, 4 hours each day. See all the rules at the Washington Fish and Wildlife website here. You can’t put your pots in the water until 9 am and must have them out by 1 pm. People usually do two “pulls”. This prevents getting totally skunked if your first location is bad. It takes some skill to drop your pots and pull them. Why? With only a few hours of shrimp season, there are literally a hundred boats all crowded around the prime shrimping spots. Add windy weather, and tide movement and you have mayhem, tangled line, capsizes, lost pots and stinky boats with plenty of shrimp guts all around. The brave will do it. The adventurers. For the rest of us, thank goodness for the sale of shrimp. To get an idea of why shrimping is not for the faint of heart, we took a recent poll of the shrimping experts from Hood Canal who revealed their sage advice. And admittedly, things they had learned from experience… Timing Don’t show up at the boat launch at 8:30 am on shrimp day and expect to get out on the water before 9. There will be people lined up at “zero dark thirty” to get their boat in the water and it will be backed up to Canada. All of the greats spots will be taken and you will then be a jerk trying to drop your line next to theirs especially if its windy or a fast moving tide. Then, expect a repeat shortly after 1 pm as the flotilla returns to the boat launch. Many of them having consumed their own personal “anti-freeze” making backing up a trailer a real spectacle. Location Location Location The shrimp like to hang out near the bottom – usually 200 to 300 feet deep! That is a lot of line to pull up. Either have a “pot puller” or Arnold Schwarzeneger in your boat to make it happen. If you have a gas powered pot puller, don’t forget to put gas in it. Its best to invest in a depth-finder so that you don’t exceed the length of your line. See Pot Problems below. Clothing and Hygiene You will get wet and stinky. Even if it is not foggy or misty, there will likely be some current and wind and some splashing as you drop and pick up pots. So its nice to wear extra waterproof layers to keep dry and warm. Also there is the “head popping blow back.” Shrimp guts sometimes squirt all over as you extract their heads. Some clothing never gets the smell out. So don’t wear your good stuff. A thermos of nice hot coffee to keep you warm you say? Just remember, if you don’t have a bathroom on board your boat, you might want to curtail your coffee intake or make it dependent on the amount of time you can make it back to the harbor and the bathroom. Too many Skippers, Not enough Deck Hands Usually pick the person that knows how to drive a boat in wind and current. This can change several times during the morning due to wind, currents, waves, boats and pots. And remember that Arnold is busy. You get my drift? and other pot problems You put your name and address on your buoy and made sure it is a yellow buoy (as required), but you can’t find your pot. Many attach unique markers to their buoys like helium balloons, styrofoam objects, skull and crossbones, shiny streamers, underwear and other creative ideas. Oh, and don’t forget to attach the buoy to your pot as you expertly fling the pot into the water. If you remembered to bring a depth-finder you could have set a GPS waypoint to where you dropped your pot. If you still can’t find your pot by 1 pm, you’ll have to wait until the next low tide AND you have to call Fish and Wildlife and report a lost pot. This may help if they find it first, or if they find someone else who found it first. See WDFW rules “Do not attempt to salvage lost gear without getting a permit” website link. Pots have been recovered with a grappling hook. And no, you can’t keep the shrimp that’s still in there. Don’t get out of line Don’t miss out on most of the shrimp because your line wasn’t properly stored from last time you went shrimping. Untangling line in full sight of all the other shrimpers is a shattering shameful experience and will cost you precious time. Or your line gets caught in someones boat propeller because you did not use weighted line. This also costs the other person precious time and you don’t want to go there. Yay Shrimp! You pull your pot and have a million shrimp! Make sure to bring a separate bucket for each person with a license. Put a maximum of 80 per bucket. Also bring an extra bucket for popping their heads (the shrimp). Its ok to pop heads before you get back to the harbor. Most do and then dump the heads on their way back. Just make sure its NOT THE TAILS YOU ARE DUMPING OUT (looks of horror). Fishing reports May 5th reports say most people got their limits, but there were more people shrimping than ever before. May 9th was very stormy and much less people went out in the 12+ mph wind. Many of those that did go out gave up due to problems pulling pots and tangles due to weather. May 12th was great weather and lots of shrimp. May 23rd the weather is looking good. Stay tuned for more information. Shellfishing Hood Canal Spring sun, Hood Canal and daytime low tides. A recipe for a fine getaway to Hood Canal with the main course being Shellfish, of course. The warmer temperatures mean the snow levels go up, providing access to Hood Canal’s finest mountain trails with outstanding vista views. The melting snow rushes down rivers and supercharges the waterfall hikes. The Washington state flower, the rhododendron, provides a rosey pink background and a feast for your eyes. But more about Hood Canal Shellfish. Washington shellfish are sought by consumers around the world and are a well-deserved source of pride for local growers. Shellfish are also a key part of our marine ecosystems, providing habitat and helping filter and cleanse water. For all of these reasons, shellfish are an extraordinary resource for Washington state to exclaim. Hood Canal is famous for its oysters and manilla clams which are easy to get at low tide. Most years we start on Easter with our traditional Easter egg and clam hunt. This year, daytime low tides continue through April 6th, then again 16th-22nd. Coinciding with Washington Shellfish week April 15th – 21st and culminating with the Hood Canal Hama Hama Oyster rama on the 21st. Buy your shellfish license, check out the Public Beaches or stay at a waterfront vacation rental with your own beach. If shellfish hunting isn’t your thing, you can always buy your seafood at Hama Hama or Taylor Shellfish farm. Or dine your way around the Olympic Peninsula following the OlympicCulinaryLoop which includes Olympic Peninsula Wineries, Breweries and Distilleries. There will be some low tides on Hood Canal in late March. Low enough to gather oysters and clams!Here is a link to public beaches. And take advantage of our 3 for 2 special! Stay 2 nights and get the 3rd night free for stays thru March 31st.	{ "pile_set_name": "Pile-CC" }
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[Dynamic investigation of tibial biomechanical property endured persistent intensive stress]. For investigating the changes in continuous biomechanical nature of bone bearing intensive stress in vivo, we adopted the animal model of persistent intensive stress. Thirty-seven rabbits were involved in the experiment; they were randomly divided into control group (5 rabbits) and trained group (32 rabbits). All animals were forced to jump and run about 300 times everyday in the electric stimulation cage so as to simulate the persistent intensive stress on tibias for different periods. Subsequently, all animals were sacrificed at different times (1-11 weeks), and all tibias of them were collected for biochemical investigation. By torsion destroy test, the experiment showed that the changes of biomechanical nature appeared obviously in a period of 6 weeks or so in the experiment. Furthermore, during the 2nd-3rd week of each period, the biomechanical indexes decreased strikingly; the abilities of deformation resistant dropped, the twisting rigidity decreased (69.7% lower than control, P< 0.01), the flexible index inereased (203.2% higher than control, P<0.05), the angle of twisting destroy increased (102.9% greater than control, P< 0.05). And the tibial mechanical strength declined too; the destroy torsion, energy absorption and energy absorb density decreased (most of them being 50% lower than control, even accounting for 34.5% of control; P< 0.05 or P< 0.01). We noticed that the biomechanical properties of bone endured persistent intensive stress presented periodicity and the period of change in bone biomechanical nature covered about 6 weeks in the experiment. Therefore, we have ground to conclude that a weakness period did exist when rabbit tibias endured 2-3 weeks persistent intensive stress, and such weakness did exist at the 2nd-3rd week of each training period.	{ "pile_set_name": "PubMed Abstracts" }
[An analysis of regional ventilation in pulmonary sarcoidosis by inspired 133Xe washout test]. Xenon-133 ventilation study were used to measure regional ventilation in seven patients with pulmonary sarcoidosis and in four normal subjects. For the purpose of analyzing the washout curves on the whole lungs, two ventilation indexes were calculated, which were TA/H and T1/2. TA/H is that the area under the curve divided by the difference in mean count rate during equilibrium and at 120 s after washout started. T1/2 value represents the time required to 50% of the mean count rate during equilibrium. The average time of TA/H on the whole lung was 13.5 +/- 1.1 s in normal subjects (n = 4), 13.0 +/- 4.3 s in stage I (bilateral hilar lymphadenopathy without lung involvement on chest X-ray) sarcoidosis (n = 3), 21.3 +/- 1.8 s in stages I, II (lung involvement) sarcoidosis (n = 4). The average time of T1/2 on the whole lung was 43.7 +/- 4.7 s in normal subjects, 42.3 +/- 16.0 s in stagel sarcoidosis, 72.5 +/- 28.6 s stages II, III sarcoidosis. The ventilation indexes on the regional lungs showed almost a similar tendency to that on the whole lung. The ventilation indexes in patients with stage II, III sarcoidosis were significantly longer than in normal subjects and in patients with stage I sarcoidosis. It was suggested that 133Xe washout test might detect regional ventilation abnormalities which were not recognized on chest X-ray in pulmonary sarcoidosis.	{ "pile_set_name": "PubMed Abstracts" }
System Management It is essential that SAT systems be operated with an application and a drying period. The drying period is critical to effective treatment, restoration of aerobic conditions, and maintenance of infiltration rates. The length of time required to dry each basin of visible water should be recorded, and any increasing trend in required drying time should be noted. An increase in the necessary drying time can signal the need for basin surface maintenance. Such maintenance can include disking, scarifying (tilling or breaking up the surface), or scraping off surface solids.	{ "pile_set_name": "Pile-CC" }
Philadelphia is urging residents not to swim in dumpsters after a rented trash bin was filled with fire hydrant water and transformed into a pool. The online news site Billy Penn first reported the shenanigans at a weekend block party. The party's organizers told the site they power-washed the dumpster, lined the bottom with plywood and tarps and cushioned the corners with pool noodles. However, filling it with hydrant water caused the biggest issue with city officials. The Department of Licenses and Inspections issued a statement saying the city won't issue permits for block party dumpster pools. Agency spokeswoman Karen Guss said, "you would think this decision would not require an explanation." Among the reasons: It takes water that should be available in the event of a fire; the strong water pressure could push someone into harm's way; and the huge amount of water released could cause a main break. "We are not screwing around, Philly," Guss' statement reads. "The city strongly recommends that residents opt for recreational options that are safer, more sanitary and less likely to deplete the resources firefighters need in an emergency."	{ "pile_set_name": "OpenWebText2" }
Immunological responses of Eurasian badgers (Meles meles) vaccinated with Mycobacterium bovis BCG (bacillus calmette guerin). Wildlife species, such as the badger (Meles meles), may act as maintenance hosts for Mycobacterium bovis and contribute to the spread and persistence of tuberculosis in associated cattle populations. Targeted vaccination of badgers against tuberculosis is an option that, if successfully employed, could directly facilitate the advancement of bovine tuberculosis eradication in affected areas. In this study, the immunological responses of a group of badgers vaccinated subcutaneously with low doses of Mycobacterium bovis bacillus calmette guerin (BCG) were measured in vitro and compared with non-vaccinated control animals over a period of 42 weeks. Peripheral blood mononuclear cells (PBMC) from badgers which had received repeated booster injections of BCG proliferated in response to culture with PPD-bovine (purified protein derivative of tuberculin). The proliferation was significantly greater than that seen in the non-vaccinated control group. In contrast, the proliferative response of PBMC from vaccinated badgers to PPD-avian declined relative to the control group. These results demonstrate that repeated vaccination of badgers with M. bovis BCG induced a population of T-lymphocytes responsive to specific antigens in PPD-bovine. Throughout the course of the study, the sera from all animals were tested (BrockTest) by an enzyme-linked immunosorbent assay (ELISA) system for the presence of antibodies to MPB83, a serodominant antigen whose expression is high in M. bovis, but very low in BCG (Pasteur). No animals at any stage showed seroconversion to the antigen, consistent with the tuberculosis-free status of the badgers under study.	{ "pile_set_name": "PubMed Abstracts" }
Abra Amedomé Abra Amedomé was a Togolese politician woman. Trained as a pharmacist in France, Montpellier, Abra Julie Amedome returned to Togo and became a highly successful businesswoman. She was the first pharmatian woman in Togo. She was married to professor Antoine Afantchao Amedome (professor of médecine).She took a leading role in the national ruling party, and in 1975 became president of the Union National des Femmes Togolaise. In 1979 she became minister of social affairs and women's production, continuing in this role until 1983. She was one of six women elected to the Parliament of Togo in 1979; the others were Cheffi Meatchi, Kossiwa Monsila, Essohana Péré, Zinabou Touré, and Adjoavi Trenou. References Category:Living people Category:20th-century women politicians Category:Government ministers of Togo Category:Social affairs ministers Category:Members of the National Assembly (Togo) Category:Togolese women in business Category:20th-century businesswomen Category:Togolese pharmacists Category:Women government ministers of Togo Category:Year of birth missing (living people) Category:Place of birth missing (living people) Category:Women pharmacists	{ "pile_set_name": "Wikipedia (en)" }
This past week was a crazy one for fans of the popular comic book, cartoon and movie characters, the Teenage Mutant Ninja Turtles, when Michael Bay, producer of the upcoming reboot told press at the Nickelodeon Upfront that they plan on introducing a new element to the characters by making them an “alien race,” something that he and others involved with the characters began to backtrack on when the internet exploded in an uproar. Bay’s exact words were: “When you see this movie, kids are going to believe, one day, that these turtles actually do exist when we are done with this movie. These turtles are from an alien race and they are going to be tough, edgy, funny and completely lovable.” It just so happens ComingSoon.net/SuperHeroHype was talking to the project’s director Jonathan Liebesman (Battle: Los Angeles) this morning for his upcoming Greek myth epic Wrath of the Titans and we asked him if he had been hearing about any of this backlash and what he thought of it. He was suitably diplomatic. “I heard about it, and I’m glad there’s such a passionate fanbase–I think that was good news for everyone–but literally, I’ve just been locked in a room with Kevin Eastman. I think what we’re developing, the fans will love. I’m a fan, and I love what we’re doing. It’s a lot of stuff Kevin’s been thinking about for a long time and just hasn’t done. Anything we expand will tie right into the mythology, so I think fans will go apesht when they see it.” Since they are still developing the movie, he wouldn’t really address whether this movie was going to be bigger in scale–something we’d assume from Liebesman’s previous two movies and the involvement of Bay–whether it would break away from the family audience leanings of the previous movies or whether the Turtles would be men in costumes or done via performance capture. (Who knows? Maybe they’ll get Andy Serkis to play all four Turtles. That would be something, right?) Incidentally, later on, we attended a press conference for the movie and Liebesman mentioned having walked by posters of his new movie while walking around New York City and what that meant to him. While he was referring to Wrath of the Titans, he may as well have been referring to Teenage Mutant Ninja Turtles, because he’s clearly not on board the project to make a movie the fans are going to hate. “That’s why we worked so hard on this. You just don’t want to fck it up and you don’t want to disappoint people who pay money,” he said, before paraphrasing something his star Sam Worthington told him about having a chance to do a second movie as being “out of respect for the people who are paying money to see the movie–you feel those people are the reason why we have these jobs.” Look for our full interview with Jonathan Liebesman next week before Wrath of the Titans opens on Friday, March 30.	{ "pile_set_name": "Pile-CC" }
import ApiService from './ApiService' const ImageService = { /** * Search for images by keyword. / search(params) { return ApiService.query('images', params) }, getProviderCollection(params) { return ApiService.query('images', params) }, /* * Retreive image details by Id number. * SSR-called */ getImageDetail(params) { if (!params.id) { throw new Error( '[RWV] ImageService.getImageDetail() id parameter required to retreive image details.' ) } return ApiService.get('images', params.id) }, getRelatedImages(params) { if (!params.id) { throw new Error( '[RWV] ImageService.getRelatedImages() id parameter required to retreive related images.' ) } return ApiService.get('recommendations/images', params.id) }, } export default ImageService	{ "pile_set_name": "Github" }
If you don’t own a Kindle, you can download this free application which will allow you to read Kindle books on your PC. You can read this ebook on an assortment of other devices as well. Just download the appropriate application from the Amazon site. If you don’t own a Kindle, you can download this free application which will allow you to read Kindle books on your PC. You can read this ebook on an assortment of other devices as well. Just download the appropriate application from the Amazon site. This week’s BundleoftheWeek.com collection includes five amazing resources to help you run your home more efficiently! Covering everything from organizing your schedule and household records to meal planning, cleaning and budgeting, this bundle is the perfect collection to help you keep your home resolutions. Get all 5 ebooks for only $7.40 (a savings of over 80%) for one week only. Organizing Life as MOM by Jessica Fisher Designed to equip you and inspire you to get your act together, Organizing Life as MOM includes inspiration to simplify and focus on the most important things in your life. You’ll find real life help in organizing your different roles and responsibilities, 130 printable pages to help you keep track of all the comings and goings of your household, fillable forms you can tailor to your needs and your home, and tips for putting together a household notebook. Easy. Homemade. by Mandi Ehman Easy Homemade: Homemade Pantry Staples for the Busy Modern Family features more than 60 tried-and-true recipes for homemade kitchen staples that can be made with basic ingredients and don’t require a lot of time. In addition, Mandi offers kitchen tips, information about choosing various ingredients, and more to empower your busy family to make your favorite pantry staples from scratch! Plan It, Don’t Panic by Stephanie LangfordIn Plan It, Don’t Panic: Everything You Need to Successfully Create and Use a Meal Plan, Stephanie helps you: find a meal planning method that suits your family best, work with special dietary needs, become a grocery-shopping ninja, make the most of leftovers, organize and store your recipes, and more. She also shares tips and strategies to help you perfect your meal planning style plus printable planning pages and 4 weeks of real, whole food meal plans. 28 Days to Hope for Your Home by Dana White In 28 Days to Hope for Your Home {Not for the Mildly Disorganized}, Dana draws on her own experiences as a former slob, offering a practical guide to help you discover hope for a real change in your home. Broken down into 28 baby steps, this ebook will help you develop four basic but essential home management habits. You’ll also find practical tips to keep you from giving up, bonus sections with realistic strategies for laundry management, meal prep, and decluttering, and insights into why these habits are a struggle for so many of us! Hybrid Homemaker by Melissa Gorzelanczyk The Hybrid Homemaker: A Guide to Personal and Financial Freedom is full of tips and strategies to show you — step-by-step — how to get out of debt, stick to a budget, make money doing what you love, shrug off the world’s burden of doing it all, figure out what matters to you and create a home where beauty and happiness appear through your actions. The Homemaking bundle is only available through 8am EST on Monday. Get yours today: If you don’t own a Kindle, you can download this free application which will allow you to read Kindle books on your PC. You can read this ebook on an assortment of other devices as well. Just download the appropriate application from the Amazon site. If you don’t own a Kindle, you can download this free application which will allow you to read Kindle books on your PC. You can read this ebook on an assortment of other devices as well. Just download the appropriate application from the Amazon site. If you don’t own a Kindle, you can download this free application which will allow you to read Kindle books on your PC. You can read this ebook on an assortment of other devices as well. Just download the appropriate application from the Amazon site. If you don’t own a Kindle, you can download this free application which will allow you to read Kindle books on your PC. You can read this ebook on an assortment of other devices as well. Just download the appropriate application from the Amazon site.	{ "pile_set_name": "Pile-CC" }
Correction to: Exploration of selected electronic characteristics of half-sandwich organoruthenium(II) β-diketonate complexes. We would like to apologize for a wrong conclusion on the fourth page where the correlation of the Ru-P bond length and possible anticancer activity is discussed.	{ "pile_set_name": "PubMed Abstracts" }
The remains of Grenfell tower. Photo: Carl Court/Getty Images There is no such thing as an accident when a high-rise building fails. If gas leaks, wires spark, or a wall crumbles, those are not acts of fate, but the preventable consequence of people not doing their jobs. Terminology matters; if it turned out that the fire that consumed Grenfell Tower in London, killing at least 30 people (and probably many more), had been set by a radicalized Muslim immigrant or an anti-Muslim white supremacist, those facts would shape the U.K.’s foreign and security policies. If it’s just an instance of faulty construction, politicians can wring their hands on television, appropriate some emergency funds, and then move on. It’s too soon to be sure exactly what caused the Grenfell Tower to burn. A thick plume of accusations suggests a lot of possible culprits: a faulty refrigerator; the recently installed cladding of cheap aluminum panels with a flammable core; the gap between the wall and the rain screen, which could have created a chimney effect and sped flames and smoke up the building’s exterior; ineffectual fire alarms; a lack of sprinklers; the presence of just a single fire stair. Behind the technical factors is another layer of social issues. Residents have accused building management and authorities of ignoring their chillingly specific complaints, perhaps because of a generalized disinterest in the building’s poor and largely Muslim population, or because of the pressures of gentrification from the neighborhood all around. Grenfell Tower, up close. Photo: Carl Court/Getty Images New Yorkers might be tempted to react complacently to some items on this list. Aluminum panels are common, but the slightly less expensive version with the flammable polyethylene core is not legal here. All buildings higher than 50 feet must have automatic sprinklers and two fire stairs, not one. And yet to argue those points is to miss the larger awfulness of the situation. Whether the proximate causes turn out to be corruption, venality, racism, or some combination of all three, the underlying sin is contempt for the people who must live in conditions they cannot control. If residents of subsidized housing had truly mattered, then more questions would have been asked during the building’s recent renovation, fire codes updated, circumstances foreseen. The plastic-and-aluminum panels on Grenfell Tower’s skin were also involved in three catastrophic fires in Dubai — and yet somehow the global community of architects, engineers, regulators, façade consultants, and construction firms continues to permit their use. Contempt also shapes official attitudes to public housing in the United States. It explains why President Trump appointed Ben Carson, a doctor with no expertise or avowed interest in housing issues, to run the nation’s Department of Housing and Urban Development. Contempt explains why he named an amateur, Lynne Patton, a family loyalist who plans weddings and golf tournaments, to run the New York/New Jersey section of HUD. These are not casual appointments: They send a clear signal that people in public housing shouldn’t be there and deserve no better. NYCHA, an agency responsible for the living conditions of more than half a million New Yorkers, is in such deep financial distress that its buildings are allowed to decline into lethal states of disrepair. Last year, a malfunctioning elevator killed 84-year-old Olegario Pabon. A fire in another apartment killed two toddler sisters, Amanda and Jannubi Jabie, after a maintenance worker noticed a malfunctioning smoke detector and did nothing. A panicked cop in a stairwell darkened by burned-out bulbs accidentally shot and killed Akai Gurley. The fact that these deaths occur one or two at a time, instead of in one catastrophic blaze, does not excuse their horror. NYCHA Polo Grounds Houses complex of apartments in Harlem. Photo: Richard B. Levine/Corbis via Getty Images No government agency even builds public housing much any more; instead all three levels of government subsidize private developers or mission-driven nonprofit organizations. In New York, many of these apartments are “affordable” in only the loosest sense of the word. Still, they are usually adequately designed, robust, and managed by owners who have an incentive to keep their properties from falling apart. Alexander Gorlin is one of many architects who could devote all their time to satisfying the caprices of the wealthy, but choose to work at the low end of the market, too, because that’s where their talents truly matter. It’s always easy to malign the architecture of public housing projects as inherently inhumane. Many Americans see public housing as a machine for converting public funds into pathologies. Yet hundreds of thousands of New Yorkers continue to live in these buildings from another era, many more dwell in privately managed squalor, and 60,000 have no home at all. Even thousands of miles away, the Grenfell Tower blaze casts a ghoulish light on the importance of government’s least glamorous task: to fix what is broken for those who need it most. Because neglect is the moral equivalent of murder. *A version of this article appears in the June 26, 2017, issue of New York Magazine.	{ "pile_set_name": "OpenWebText2" }
Q: Problem adding image to UIView I'm making an app with a piano and each key will be it's own subclass. I tried making the keys a subclass of UIButton, but after having some problems getting the methods to be called, I checked online and found out that others were also having problems subclassing UIButtons. So then I tried subclassing a UIView. The problem was that I tried adding an image to it, but it showed up as a black box. Here is the code from the CustomView @implementation Keys - (id)initWithFrame:(CGRect)frame { self = [super initWithFrame:frame]; if (self) { self.backgroundColor = [UIColor colorWithPatternImage:[UIImage imageNamed:@"whitekey.gif"]]; } return self; (I've confirmed that the problem isn't whitekey.gif) Here is the code from the viewController - (void)viewDidLoad { [super viewDidLoad]; Keys *whiteKey = [[Keys alloc] initWithFrame:CGRectMake(0, 0, 100, 300)]; [self.view addSubview:whiteKey]; } Is it better if I subclass UIImageView? A: You should be using UIImageView. An image view object provides a view-based container for displaying either a single image or for animating a series of images. http://developer.apple.com/library/ios/#documentation/uikit/reference/UIImageView_Class/Reference/Reference.html Maybe a UIView as a container, with a UIImageView with the piano key image, with additional UIViews on top of that, depending on what you need to do?	{ "pile_set_name": "StackExchange" }
[Consequences for the intrauterine development of the offspring of the irradiation of male germinal cells at different stages of spermatogenesis]. Single whole-body exposure of adult male rats Wistar in different stages of spermatogenesis to gamma-rays (doses from 0.25 to 5.00 Gy) resulted in violations of antenatal development of the first generation offsprings. The pronouncement of these violations depends on the spermatogenesis stage in the moment of irradiation and exposure dose.	{ "pile_set_name": "PubMed Abstracts" }
Case: 16-11174 Document: 00513946985 Page: 1 Date Filed: 04/10/2017 IN THE UNITED STATES COURT OF APPEALS FOR THE FIFTH CIRCUIT United States Court of Appeals Fif h Circuit No. 16-11174 FILED April 10, 2017 Lyle W. Cayce LONNY ACKER, Clerk Plaintiff - Appellant v. GENERAL MOTORS, L.L.C., Defendant - Appellee Appeal from the United States District Court for the Northern District of Texas Before STEWART, Chief Judge, and JONES and OWEN, Circuit Judges. EDITH H. JONES, Circuit Judge: Appellant Lonny Acker is a General Motors, L.L.C. (“GM”) employee who was approved for intermittent Family and Medical Leave Act (“FMLA”) leave but on several occasions was absent from work and did not follow company protocol for requesting FMLA leave. He suffered several weeks of disciplinary unpaid layoff. He sued GM for FMLA interference and retaliation and for disability discrimination under the Americans with Disabilities Act (“ADA”) and the Texas Commission on Human Rights Act (“TCHRA”). The district court entered summary judgment for GM. We AFFIRM, principally because the FMLA and accompanying regulations require employees to follow their Case: 16-11174 Document: 00513946985 Page: 2 Date Filed: 04/10/2017 No. 16-11174 employer’s “usual and customary” procedures for requesting FMLA leave absent “unusual circumstances,” 29 C.F.R. § 825.303(c). BACKGROUND Acker began working for GM in the fall of 2000 at its automobile plant in Kokomo, Indiana. In summer 2014, he voluntarily transferred to the GM assembly plant in Arlington, Texas. He is an electrician who typically works third shift. Acker suffers from acute iron-deficiency anemia that sometimes causes him to experience blackouts, grayouts, heart palpitations, and fatigue. As a consequence, Acker was certified for intermittent medical leave under the FMLA by his physician. GM has a detailed attendance policy. The product of collective bargaining between GM and the International Union, United Automobile, Aerospace and Agricultural Implement Workers of America, this attendance policy is codified in what is known as “Document No. 8—Memorandum of Understanding—Special Procedure for Attendance” (“Doc. 8”). As a current electrician covered by the collective bargaining agreement, Acker is subject to Doc. 8. For an unplanned absence, the collective bargaining agreement simply requires employees to notify GM at least thirty minutes before the shift starts. Failure to call by the deadline is considered an “instance” under Doc. 8, unless the employee can explain the untimeliness satisfactorily to management. When absences are unexcused, GM allocates up to eight hours per instance of that employee’s “Vacation Restricted” hours to each hour that the employee was absent. Under this arrangement, employees are permitted up to five “instances” of unexcused absence before they become subject to discipline under the policy. Acker testified that he understood this use of “Vacation Restricted” time as a “free pass.” After the “free” absences are used up, Doc. 8 imposes “Attendance Improvement Steps” for additional unexcused absences 2 Case: 16-11174 Document: 00513946985 Page: 3 Date Filed: 04/10/2017 No. 16-11174 through a six-step program that moves from two written warnings to unpaid disciplinary layoff to termination. GM also has a policy for requesting FMLA leave. Union benefit representatives at each GM facility assist employees with FMLA leave requests. Employees must make an initial request for FMLA leave with GM’s Benefits & Services center, administered by third-party vendor Sedgwick Claims Management Services, Inc. (“Sedgwick”). Once an employee has requested intermittent FMLA leave, Sedgwick sends the employee a letter reiterating GM’s policies for requesting and taking leave. This policy is described in an employee letter as follows: If you have requested intermittent leave, you are required to report any time taken under the Family and Medical Leave Act (FMLA), at least 30 minutes PRIOR to the start of your normal scheduled work shift, by calling the GM Absence Call In Line [redacted] and selecting the “FMLA” option when prompted (option #8). You are also required to call the GM Benefits & Services Center at [redacted] by the end of your normally scheduled work shift to report your FMLA absence. When calling, select the prompt for “FMLA”. Acker testified that he was familiar with this procedure and received a packet including this letter. By September 2014, Acker testified, he had used all of his “free pass” days. In mid-November 2014, Acker contacted Sedgwick to request FMLA leave. Acker received instruction from Sedgwick to obtain a medical certification by November 28, and he complied. On December 9, Sedgwick notified him that he was approved for intermittent FMLA leave from November 11, 2014 to May 11, 2015. Nevertheless, he began receiving discipline for several unapproved absences according to GM’s procedures. The record is undisputed concerning the disciplinary procedure GM followed and the facts underlying the discipline. Acker was absent from work on September 29 and received his first written disciplinary warning under Doc. 3 Case: 16-11174 Document: 00513946985 Page: 4 Date Filed: 04/10/2017 No. 16-11174 8 on October 7. Acker testified that he did not request FMLA leave for the September 29 absence. Acker was absent a month later, on October 30, and was disciplined with a second written warning a day later. Acker testified that he did not request FMLA leave for this absence, either. Acker was absent again November 12, 13, and 14, which were counted as two “instances” of unexcused absence under GM’s policy. Combined with the first two unexcused absences, Acker became subject to two weeks’ unpaid suspension as a disciplinary layoff. Acker contacted Sedgwick to request FMLA leave for the November 12 and 13 absences, and his request was approved by Sedgwick. When GM was made aware of this approval, GM rescinded its disciplinary action for November 12 and 13. However, Acker testified that, for the November 14 absence, he failed to call in 30 minutes before his shift began and missed the FMLA absence call-in time by over an hour. For this November 14 default, GM treated the first week of the earlier disciplinary layoff, which Acker had already undergone, as discipline pursuant to Doc. 8. Acker was also absent on November 22 and 23. Phone records produced by Acker confirm that none of his three calls to the GM shift absence line were timely. Acker was issued another disciplinary layoff with two weeks of unpaid suspension for these unexcused absences, in line with the Doc. 8 policy of progressive discipline. Acker was absent again on December 6, 7, and 8. His absence for December 7 was approved because Acker timely called both the GM absence line and the GM Benefits & Services line. While Acker did contact the GM absence line for December 6 and December 8, he failed to contact the Benefits & Services line in time on both occasions. Thus on January 14, 2015, Acker was denied FMLA coverage for both days and issued a disciplinary layoff under GM policy, this time a 30 day unpaid suspension. Although the Doc. 8 policy 4 Case: 16-11174 Document: 00513946985 Page: 5 Date Filed: 04/10/2017 No. 16-11174 required Acker’s termination for these additional unexcused absences, GM retained him with an opportunity to correct his attendance issues. The last disciplinary action GM had to take with respect to Acker’s attendance was on January 14. Since February 2015, Acker testified, he has taken more than 30 days of intermittent FMLA leave and managed to timely call the GM Absence and Benefits & Services lines according to the collective bargaining agreement. Nevertheless, Acker filed suit against GM in September 2015 for damages concerning the unpaid suspensions. After discovery, GM moved for and was granted summary judgment by the district court. Acker timely appealed. STANDARD OF REVIEW “Summary judgment is required ‘if the movant shows that there is no genuine dispute as to any material fact and the movant is entitled to judgment as a matter of law.’” Lawrence v. Fed. Home Loan Mortg. Corp., 808 F.3d 670, 673 (5th Cir. 2015) (quoting Fed. R. Civ. P. 56(a)). Summary judgment cannot be defeated through “[c]onclusional allegations and denials, speculation, improbable inferences, unsubstantiated assertions, and legalistic argumentation.” Oliver v. Scott, 276 F.3d 736, 744 (5th Cir. 2002). DISCUSSION Acker raises three issues on appeal. First, regarding his FMLA interference claim, he contends that his calls to GM and the Benefits & Services lines were sufficient to raise a genuine issue of material fact as to whether he provided reasonable notice of his need for unplanned FMLA leave. Second, he claims that the disciplinary layoffs were in retaliation for exercising his FMLA rights. Third, he argues that his request for FMLA leave was also a request for a reasonable accommodation for a disability under the ADA and TCHRA, and that the disciplinary layoffs thus also constituted disability discrimination. 5 Case: 16-11174 Document: 00513946985 Page: 6 Date Filed: 04/10/2017 No. 16-11174 A. FMLA Interference To prove an interference claim, a plaintiff “must at least show that [the defendant] interfered with, restrained, or denied [his] exercise or attempt to exercise FMLA rights, and that the violation prejudiced [him].” Bryant v. Tex. Dep’t of Aging & Disability Servs., 781 F.3d 764, 770 (5th Cir. 2015) (quoting Cuellar v. Keppel Amfels, L.L.C., 731 F.3d 342, 347 (5th Cir. 2013)). An “interference claim merely requires proof that the employer denied the employee his entitlements under the FMLA.” Stallings v. Hussmann Corp., 447 F.3d 1041, 1051 (8th Cir. 2006). While the employee has a right to take leave under the FMLA, the employee must give his employer notice of his intention to take leave in order to be entitled to it. See 29 U.S.C. § 2612(e)(1) (“Requirement of notice”); (2) (“Duties of employee”). See also 29 C.F.R. § 825.303. When the need for leave is foreseeable, the employee generally “must provide the employer at least 30 days advance notice before FMLA leave is to begin.” 29 C.F.R. § 825.302(a). If 30 days’ notice is not practicable, “notice must be given as soon as practicable.” Id. In all instances, “an employee must comply with the employer’s usual and customary notice and procedural requirements for requesting leave, absent unusual circumstances.” Id. § 825.302(d). “Where an employee does not comply with the employer’s usual notice and procedural requirements, and no unusual circumstances justify the failure to comply, FMLA–protected leave may be delayed or denied.” Id. This regulation “explicitly permits employers to condition FMLA-protected leave upon an employee’s compliance with the employer’s usual notice and procedural requirements, absent unusual circumstances.” Srouder v. Dana Light Axle Mfg., LLC, 725 F.3d 608, 614 (6th Cir. 2013). Even when an employee’s need for leave is unforeseeable, the regulations make clear the employee’s duty to comply with the employer’s policy. “When 6 Case: 16-11174 Document: 00513946985 Page: 7 Date Filed: 04/10/2017 No. 16-11174 the need for leave is not foreseeable, an employee must comply with the employer’s usual and customary notice and procedural requirements for requesting leave, absent unusual circumstances.” 29 C.F.R. § 825.303(c). “[A]n employer generally does not violate the FMLA if it terminates an employee for failing to comply with a policy requiring notice of absences, even if the absences that the employee failed to report were protected by the FMLA.” Twigg v. Hawker Beechcraft Corp., 659 F.3d 987, 1008–09 (10th Cir. 2011). See also Bacon v. Hennepin Cty. Med. Ctr., 550 F.3d 711, 715 (8th Cir. 2008) (“Employers who enforce [call-in] policies by firing employees on FMLA leave for noncompliance do not violate the FMLA.”). An employer may thus require that an employee hew to the employer’s usual and customary procedures for requesting FMLA leave. Discipline resulting from the employee’s failure to do so does not constitute interference with the exercise of FMLA rights unless the employee can show unusual circumstances. “Formal notice-of-absence policies serve an employer’s legitimate business interests in keeping apprised of the status of its employees and ensuring that it has an adequate workforce to carry out its normal operations.” Twigg, 659 F.3d at 1009; Goff v. Singing River Health Sys., 6 F. Supp. 3d 704, 711 (S.D. Miss. 2014) (summary judgment is appropriate in FMLA case without evidence of unusual circumstances excusing employee’s failure to call employer timely). It is undisputed that Acker’s phone records show he failed to call in timely under GM’s procedure on the dates for which he received disciplinary layoff: November 14, 22, 23, and December 6 and 8. Acker cannot rely on his deposition testimony, inconsistent with phone records that he described as the “universe” of his calls during the relevant period, to create a fact issue on timeliness. Vais Arms, Inc. v. Vais, 383 F.3d 287, 294 (5th Cir. 2004) (“vague, self-serving statements” are “not sufficient to raise a genuine issue of material 7 Case: 16-11174 Document: 00513946985 Page: 8 Date Filed: 04/10/2017 No. 16-11174 fact”); see also Jackson v. Cal-W. Packaging Corp., 602 F.3d 374, 379 (5th Cir. 2010). Thus, in order to establish FMLA interference, Acker has to show that for each of these non-FMLA-approved absences, unusual circumstances prevented him from following the union-negotiated procedures. This he has not done. Acker testified that his disability causes him to experience severe disorientation, blackouts, grayouts, heart palpitations, and extreme fatigue when in the acute phase, and that his disability can reach the acute phase suddenly and could constitute a sudden medical issue or emergency. He offered no factual support, however, that he reached the acute stage or experienced a medical emergency on the days in question. Indeed, he testified that he was too “dizzy” to follow GM’s call-in procedure only on November 14, but he was given FMLA leave and was not disciplined under Doc. 8 for that absence. He did not explain why “unusual circumstances” left him capable of calling one line, but not the other: on November 22, December 6, and December 8, Acker timely called the GM absence line, but failed to call the GM Benefits & Services line. There is no proof that unusual circumstances arising from his condition prevented him from complying with GM’s call-in policy with respect to one line but not the other. Relying on Saenz v. Harlingen Med. Ctr., L.P., 613 F.3d 576 (5th Cir. 2010) as well as Millea v. Metro-North R.R. Co., 658 F.3d 154 (2d Cir. 2011), Acker argues that failure to comply with an employer’s usual and customary procedures cannot be grounds for discipline when the employee provides “reasonable” notice of an unforeseen absence. He thus argues that there is a fact issue whether his (untimely) phone calls provided reasonable notice to GM irrespective of company policies. Acker’s reliance on these cases is misplaced. First, the holdings in each of those cases are predicated on outdated, materially different regulations. The 8 Case: 16-11174 Document: 00513946985 Page: 9 Date Filed: 04/10/2017 No. 16-11174 Sixth Circuit noted the material changes to the FMLA regulations that went into effect on January 16, 2009. See Srouder, 725 F.3d 608. Based on the previous regulations, the Sixth Circuit had held that the “FMLA does not permit an employer to limit his employee’s FMLA rights by denying them whenever an employee fails to comply with internal procedural requirements that are more strict than those contemplated by the FMLA.” Id. at 613–614 (citing Cavin v. Honda of Am. Mfg., Inc., 346 F.3d 713 (6th Cir. 2003). But the revised regulations explicitly allow employers to condition FMLA leave on following the employer’s policy. Srouder, 725 F.3d at 614. Indeed, this court in Saenz acknowledged that the post-2009 regulations, if applicable, could have required summary judgment for the employer: the 2009 revisions to the FMLA regulations governing notice should not apply to the instant case . . . the most salient regulatory change—the revisions to 29 C.F.R. § 825.303—arguably increases the duties imposed upon employees seeking FMLA leave. Were we to apply the new regulations, [the employer] might very well be entitled to summary judgment . . . we decline to retroactively apply the new regulations, and all citations to the governing FMLA regulations refer to the pre-2009 Code of Federal Regulations edition. Saenz, 613 F.3d at 582 n.9. The new regulations control the standard for this case, and Acker has not raised a fact issue for FMLA interference. 1 B. FMLA Retaliation To prove FMLA retaliation, the employee must demonstrate: “1) he was protected under the FMLA; 2) he suffered an adverse employment action; and 3) he was treated less favorably than an employee who had not requested leave under the FMLA or the adverse decision was made because he sought 1 Likewise Millea involved an incident in 2006, three years before the material change in the regulations. See 658 F.3d at 159–60 (describing the relevant incident in 2006). In addition, that case is factually distinct because unlike here, where Acker did not follow the timing requirements of his employer’s FMLA request policy, the employer in Millea “received timely, although indirect, notice of Millea’s use of FMLA leave.” Id. 9 Case: 16-11174 Document: 00513946985 Page: 10 Date Filed: 04/10/2017 No. 16-11174 protection under the FMLA.” Mauder v. Metro. Transit Auth. of Harris Cty., Tex., 446 F.3d 574, 583 (5th Cir. 2006). The third element requires the employee to show “there is a causal link” between the FMLA-protected activity and the adverse action. Richardson v. Monitronics Int’l, Inc., 434 F.3d 327, 332 (5th Cir. 2005). Acker cannot make a prima facie case. He has not shown how his disciplinary leave was caused by his attempts to seek protection under the FMLA instead of his failure to follow GM’s attendance and absence approval process. Acker is still employed by GM. He has taken more than 30 days of intermittent FMLA leave since his last disciplinary layoff by following GM’s call-in procedure. It is undisputed that GM’s policy should have resulted in Acker’s termination for his absence on December 6, but GM offered Acker the opportunity to correct his attendance problems. These undisputed facts belie any casual connection between his claimed adverse action and his attempt to seek FMLA leave. C. ADA/TCHRA Acker also argues that in disciplining him for violation of the Doc. 8 procedures, GM failed to accommodate his disability by means of FMLA leave. He contends that his requests for FMLA leave, although made outside of the process GM provided, were simultaneously requests for a reasonable accommodation under the ADA, and concomitantly, the TCHRA. 2 Acker argues that because a request for medical leave generally is a request for an accommodation in some instances, a request for FMLA leave is also a request 2 The Texas Supreme Court has held that the TCHRA can be interpreted in lockstep with the federal ADA. By adopting the TCHR, “the Legislature intended to correlate state law with federal law in employment discrimination cases . . . Therefore, we look to federal law to interpret the Act’s provisions.” AutoZone, Inc. v. Reyes, 272 S.W.3d 588, 592 (Tex. 2008) (quotations and citations omitted). 10 Case: 16-11174 Document: 00513946985 Page: 11 Date Filed: 04/10/2017 No. 16-11174 under the ADA. The district court disagreed and held that Acker did not make a request for a reasonable accommodation. Employees who require accommodation due to a disability are responsible for requesting a reasonable accommodation. See Griffin v. United Parcel Serv., Inc., 661 F.3d 216 (5th Cir. 2011) (quoting E.E.O.C. v. Chevron Phillips Chem. Co., L.P., 570 F.3d 606, 621 (5th Cir. 2009)). However, a request for FMLA leave is not a request for a reasonable accommodation under the ADA. “The ADA and the FMLA have divergent aims, operate in different ways, and offer disparate relief.” Navarro v. Pfizer Corp., 261 F.3d 90, 101 (1st Cir. 2001). “FMLA leave is not a reasonable accommodation under the ADA; rather it is a right enforceable under a separate statutory provision.” Harville v. Tex. A&M Univ., 833 F. Supp. 2d 645, 661 (S.D. Tex. 2011) (citing Trevino v. United Parcel Serv., No. 3:08–CV–889–B, 2009 WL 3423039, 12 (N.D.Tex. Oct. 23, 2009)). Textual comparison of the FMLA with the ADA demonstrates why requesting FMLA leave alone is not a request for an ADA reasonable accommodation. An employee who requests FMLA leave asserts he has a “serious health condition that makes the employee unable to perform the functions of the position of such employee.” 29 U.S.C. § 2612(a)(1)(D) (“Entitlement to leave”). A request for a reasonable accommodation under the ADA is a claim that the employee “with or without reasonable accommodation, can perform the essential functions of the employment position that such individual holds or desires.” 42 U.S.C. § 12111(8) (“Definitions: Qualified Individual”). See Capps v. Mondelēz Global LLC, 147 F. Supp. 3d 327, 340–41 (E.D. Penn. 2015) (“an employee who requests leave does not clearly communicate to her employer that she is disabled and desires an accommodation.”) (quoting Rutt v. City of Reading, Pa., No. CIV.A. 13–4559, 2014 WL 5390428, 4 (E.D. Pa. Oct. 22, 2014). Thus, an employee seeking 11 Case: 16-11174 Document: 00513946985 Page: 12 Date Filed: 04/10/2017 No. 16-11174 FMLA leave is by nature arguing that he cannot perform the functions of the job, while an employee requesting a reasonable accommodation communicates that he can perform the essential functions of the job. Acker has not demonstrated any dispute of material fact that his untimely phone calls could have sought a reasonable accommodation under the ADA. He failed to follow GM’s absence procedure, was disciplined, and has successfully followed GM’s absence procedure since. As a consequence, Acker has not proved how GM denied him any accommodation. CONCLUSION For the foregoing reasons, the judgment of the district court is AFFIRMED. 12	{ "pile_set_name": "FreeLaw" }
How Mixcloud serves 15 million users a month Mixcloud is an audio streaming platform for uploading and streaming radio shows, DJ mixes and podcasts. Since being founded in 2008 they’ve grown to host over 15 million shows by the likes of Wired, Harvard Business Review, TED Talks, Barack Obama, Carl Cox, Richie Hawtin, deadmau5, NTS Radio and Worldwide FM. In 2017 they signed a direct licencing agreement with Warner Music and then signed additional agreements with Universal Music Group, Sony and Merlin in 2018 while raising a further $11.5m to continue their expansion globally. Mixcloud currently handles approximately 350 million GraphQL queries a day. In a Behind the Screens interview, Mat Clayton (Co-founder at Mixcloud) gives insight into the tech that powers their platform, how it’s cheaper for them not to host with cloud providers, their love for GraphQL, why Relay is underrated and the media player libraries they use. Stack & Infrastructure Could you talk a bit about Mixcloud’s stack and infrastructure? We are a Django application. 99% of it is synchronous Python and Django with MariaDB, a fork of MySQL, on the backend. Then we run Memcached for caching, Elasticsearch for search and we use RabbitMQ for queue management and background tasks. We also use Redis for certain high-speed counters we can’t afford to lose in the long term. Back in the day, we were a Django app with MySQL. We fundamentally are the same now but we’ve just moved search into its own service and have supplemented things with caching using both Redis and Memcached for different types of caching. We obviously run a lot more copies of the web layer now than we did previously but it’s fundamentally the same code. We just have thousands of processes now instead of 10, it’s scaled up really nicely. Do you use any cloud services? There are always exceptions but no, the vast majority of the web app is run off co-located servers out of London. Two reasons for that: mainly cost, it's substantially cheaper but also performance is substantially better than the cloud. We host from London with points-of-presence (POPs) spread out across the globe, we fundamentally just outsource that to Cloudflare. So when a user connects to the service they do the SLL termination with a Cloudflare POP and then piggyback onto a backhaul into our data centre here in London. How do you achieve that cost optimisation because the common perception is that cloud services are more cost-effective? It is a common perception. Storage is now comparable to what you can do yourself, so in terms of storage costs, we pay about the same to store data on any of the cloud providers compared to what we can do ourselves. The main difference comes with bandwidth. As far as I can perceive, the bandwidth costs that cloud providers charge for egress (outgoing bandwidth) are substantially higher than what you could do yourself if you go and buy those peering arrangements. I think they’ve got a massive margin there, which once you hit a certain scale they’ll probably negotiate with you on. We just learned to survive without it. That’s my take, particularly from the perspective of our use case with audio streaming. It’s very similar to video. The bandwidth costs for video streaming are substantially higher per user than most services, so when there was a big margin to be taken by the cloud service providers it actually ends up becoming a substantial cost for a business like ours which would ultimately not make the business model work. So I think that’s where the difference is, not in the storage but in the bandwidth. Particularly the egress. Any unique challenges you face being a streaming service? Storage is always a pain point for us. Streaming essentially has two problems: storing data and streaming data. So that’s an area we’ve spent a lot of time on over the years. We’ve gone through multiple systems. That is also the area that I think is one of Mixcloud’s biggest assets, is that we know how to do that stuff cheaply and reliably at scale. Aside from keeping archives and backups for disaster recovery hosted in the cloud, we don’t stream from S3, Glacier or any of the cloud platforms for that matter because that would bankrupt us very quickly. We handle hundreds of gigabytes of bandwidth per second and have petabytes of storage, which is kind of like trying to build S3 yourself. We sort of went for it out of necessity because to survive we had no other option. We couldn’t afford to host with one of the main providers, it would have bankrupted us and I would say that now we have about a 10x difference in cost at current price points in terms of what it would cost us to host in the cloud. How have you handled performance bottlenecks during your growth? Database tuning is always a thing, that never goes away. There are always bad queries that you have to optimise as the scale of the database grows. You find that queries which worked before don’t work so well anymore because they scale exponentially rather than linearly. So there’s always work to be done there. There’s always new stuff that surprises us where we thought we had optimal setups. We could have one table that is a thousand rows, really small, and then we start pushing over some of the site traffic onto it and then we're like “ah crap, we’ve got 50 million rows there now” or “a billion rows” and we have to go through that journey again and again. So we take the same journey each time and keep applying it to new areas as we grow those product lines. For example, Select is one of the new ones we’ve been working on, and that is still in its infancy with thousands of users on it, not millions. But that will go through that growth curve of pain on the database. The nice thing though is the engineers now all know how to deal with it so they’re addressing those problems in advance. Not optimising prematurely, they just know how to design stuff that works at scale from day one rather than having to evolve it over time. Some of those design decisions from day one are great and you can kind of roll them out and there’s no real extra cost doing it the right way vs. the wrong way. It’s just that level of experience which guides you one way or the other. But some approaches can take ten times the engineering effort to build for scale and those are the ones where the team will opt for the simple approach first unless we know we’re going big very quickly in which case they will invest in scale. It doesn’t always work that way but generally, they’ve got a pretty good sense of it now. We also do a lot of work on profiling for measurement and optimisation. We open-sourced one of our projects, django-speedbar, which hooks into Django and gives you timing and profiling information for things like Memcached, Redis and MySQL when rendering pages or views. We have another version of that in-house because we’ve moved onto GraphQL and we’ve done some coupling there which probably wouldn’t make sense to open-source because it’s so closely tied into a lot of our other tech. But the open-source one is still pretty good. The version we use is like 95% the same, we just have a patch on top of the open-source one for our needs. GraphQL Could you talk about why you decided to move to GraphQL and how that’s gone? I think the world is slowly catching up with GraphQL. I think it took the world a little bit by surprise because you get people who are very dogmatic in terms of REST, and GraphQL went so against that, that it actually took people a long time to adapt. We’ve been using GraphQL in production for over 3 years now. 100% of desktop web, native mobile and our widget use it. The only platform we don’t have running on GraphQL now is mobile web and we will migrate that this year, almost certainly. As for what motivated the move, it’s really about two things. We use React on the frontend and Relay to connect the data layers between React and GraphQL. Relay is another open-source project from Facebook that very few people seem to talk about. Because we do this it allows us to break apart problems a bit better, so we can decouple from them. When you look at a web page, you see entities forming. You see things like user objects which have images, descriptions and biographies, it’s essentially a graph. Then users perform actions like, in our case, favourites and follows on other nouns. When you start breaking down your problem like that you find that actually REST is not a great way of representing it. Specifically, for us the use case that really falls down is mobile. If you think about the typical REST design you’d have user/1 , user/2 and then you’d have /notifications . So if you wanted to render a list of notifications, you’d get your /notifications , which is one REST endpoint, you’d look at that and then within that endpoint you’d be like okay, I need to fetch data for user 2, 4, and 7 and I need the data for show A, B and C. So I need to hit all of those endpoints now and get all that data back, then only have I got all the data that I need to render my final notifications list. So you’ve got this process where you end up doing lots of round-trips, if you’re being pure in terms of how you’d do REST, and that’s not performant. So what people end up doing is they end up batching that all together and having a consolidated notifications endpoint which gives you all the data you need for notifications in one go. Six weeks later you release a new version of mobile, and the nasty thing with mobile is that you’ve got lots of versions in production simultaneously. Whereas, with desktop when you do an upgrade, everyone who hits refresh gets the latest version. With mobile that’s just not the case because you ship through the App Store. So what you have to do is either add new fields to that /notifications endpoint, and over six months it slowly ends up with a lot of wasted computation generating fields which are no longer used and then you then have to come up with some deprecation plan. Or what tends to happen is that you have /notifications/v1/ , /notifications/v2/ and /notifications/v3/ , and then you end up in a support nightmare trying to figure out which one to use for current versions of the app and what your deprecation cycle is for later versions of the app to avoid over-fetching or under-fetching. Over-fetching is when you get too much data back from the server and you just don’t need it, so it’s wasted computation and wasted bandwidth. Under-fetching is more critical, you ask the server for data and it doesn’t know how to respond to it anymore. For example, this happens with older versions where we’ve turned off endpoints, that would be the typical case you’d really want to avoid. The nice thing with GraphQL is because the client declares what it needs we can have many different versions of the client in production and they’re all declaring their data requirements and the server satisfies those requirements on a per client basis, so we don’t end up with any over-fetching or under-fetching. We end up with this really streamlined query language backwards and forwards between the two. So for us, that was the killer use case, really. And then there are various other things like using it for typing. The server declares its API infrastructure, what it can provide, via a schema file. That schema file has got types in it and then from there, we can actually do full test coverage from the type system on the API all the way through the apps and all the way through the website as well. So there are a couple of key points, which are kind of hard to explain, but when you take a step back and look at what you want to achieve holistically. It’s almost an act of genius how they’ve pulled this together. Honestly, when we started using it, we were like “this kind of fits a couple of things we want” but then 3 years in we’re like the “there’s no way we’d ever go back to the old system, no way”. Every engineer that joins our team comes in and says “what the hell did you do here? Why aren’t you using REST?” I literally see it every single time. Give them a week and a half, maybe two weeks, and every single one says “I’m never using REST again” having used GraphQL at production scale. It’s phenomenal to watch given how dominant REST was. Relay Can you talk about your use of Relay? Yeah, so Relay is a JavaScript framework that we use to wrap around our React components. We then have a Relay component that takes a GraphQL string. So we are then able to say “this piece of data from our API is what is required by this component”. If we look at a React component, that’s rendering a display name with a city and a country for a user, we can bind those things together and say that this component now requires GraphQL to provide the display name, city and country from the user object. So if we do that across all of our components and then put a component around a group of them, it can automatically generate the GraphQL to execute from that. So it binds that API data layer to our visual UI. Then on top of that, we’ve now got all of this cached in JavaScript. So we now know all of our queries in-flight, all of the model types and all the connections between them. Where the real power comes in is that GraphQL has this idea of mutations, so we can now write classes which are mutating classes. A good example is the follow button, where you click it and that fires the mutation into the backend. Then there is this concept on top of a mutation called an optimistic response, which is where the UI components immediately update their state under the assumption that backend operation will complete successfully. So, for the follow button example, things like the follow state in the GraphQL model should change from unfollowing to following, the list of followers should have one more follower at the top and the following count should go up by one. So what it means is that when you click that follow button, the data model in memory suddenly changes and all states across the site automatically sync up to the expected result coming back from the server and when that result comes back from the server we synchronise the data store. So the real power of this is you click follow on any button on the site, and every follow count anybody’s ever used that is bound using this Relay component now automatically updates to the right data without us having to think about it. It’s kind of incredible once you see it working but it takes three or four steps to be able to visualise what it does. This is one of the other things we’ve seen with developers who’ve come in and used it, they swear never to go back to writing queries again. Our engineers never have to write API calls. We just say what data we need in our components and our data layers are responsible for making sure that it’s there, synched, lockstepped and handles offline situations, as is necessary with mobile. Relay is the library which provides all of that. The learning curve is really steep but once you get over that it’s incredibly efficient from a developer productivity point of view. However, expect to spend a week trying to boot the damn thing up. It’s one of these things where for a small hack project it might be overkill but I would definitely do it for a small hack project because we’ve now used it and understand it. It can be quite a learning curve to get it off the ground, but once you’ve got it going the benefits are substantial. The middle ground is a client called Apollo, which gets a lot of PR. I’d say technically, on our evaluations, Apollo doesn’t look as strong as Relay but it is much more user-friendly for developers. If you want to get going quicker, it’s probably an easier way of doing it, but that doesn’t necessarily mean you’re going to get something that is built to scale to thousands of developers and hundreds of millions of users, it’s taken some shortcuts along the way. But it will probably get you a lot more efficiency than doing it all yourself so it might be a good middle ground. When we got started Apollo wasn’t an option so we were kind of forced into Relay or nothing and so we got used to it pretty quickly. So at this point, it’s better the devil we know. Relay is definitely a solution built by a giant organisation like Facebook as opposed to a third party library where they’ve not really operated on the same scale. You can tell that the Relay team are in close proximity to the GraphQL and React teams working on integrating the two together. It’s the library which powers Facebook Marketplace for example so it’s used by fairly big teams but the open-source community seems to have not really taken to it. Media Players What about the challenges of building media players? We used to build our own players. We’ve got four or five platforms we need to support, the main ones being native iOS and Android, mobile web and desktop web. Mobile web and desktop web are very similar, right now we have two different players because we’re rebuilding mobile web so mobile web is very much on our old technology stack and desktop web is on our new technology stack. We wrote our own player for mobile web and desktop web originally but we’re going to switch to using a player called Shaka player, it’s an open-source project in JavaScript by Google, and it’s phenomenally good. So we’re just deprecating our technology and going with theirs. I believe it’s probably the player that’s powering YouTube, they’ve got a substantial team backing it. It’s primarily a video player but video and audio players are essentially the same thing. So we’ve bet quite heavily on that. For iOS, we take the built-in players from Apple and wrap them in an API which is to our liking. We don’t do much work on those, I kind of wish their player was more substantial, it’s got the fundamental building blocks but not much more beyond that. The final one is ExoPlayer, that powers Android. We used to use MediaPlayer which is the low-level media player library provided by Android. We now use ExoPlayer which again is an open-source project by Google and that one I’m 90% certain powers lots of industry services on Android at this point. I’m fairly certain YouTube is on there, I’ve seen BBC, Sky and I think I’ve even seen Spotify mention it at this point. It’s a phenomenal bit of software open-sourced by the Google team on Android for audio and video playback. Full support for pretty much everything. That along with Shaka player I’m almost certain are done by very similar teams sat in the same areas of Google. They’re very well done, incredible software, but don’t get much love in terms of the public eye is not really on them. They are open-source and are on Github and both of them are projects like React, where you go in there and have a look at them and you can tell that these are very well written, well-tested, established libraries, written by incredible teams. So we’re just moving onto them. They’ve done a better job than we could ever do. Testing Could you talk about your approach to testing and your thoughts on TDD? I don’t think that anyone who says they’re full-on TDD is actually full-on TDD. The reality is that often I find teams who claim to be are idealistic and probably not shipping the best quantities of software. We use Github for code hosting, we have CI toolchains backed on to that and we use CodeShip for desktop and CircleCI for mobile on different Mixcloud products. Just for legacy reasons because CodeShip came out before CircleCI, we haven’t moved. We have various different pipelines which we run in parallel. We do things like linting and static analysis, we’re pretty big on that. We run static analysis on JavaScript, CSS, Python, Objective-C, Java. Anything you can think of we run static analysis on because mostly with those they’re very cheap to set up, it’s a one-off cost, and they will keep telling you when you’ve done something dumb. Things like unused variables or divisible by zero errors, there are various things they’re capable of finding which unit tests might miss but you only have to set them up once in your pipeline and then for every commit your developers do from then on it will find those problems. They are ways of enforcing standards. So we’re really heavy on those. We then do unit testing across the board, so most areas of the code base have pretty strong unit test coverage, whether that be JavaScript or Python. We have tens of thousands of tests. Some people would say that’s hardly any, some people would say that’s a lot but for us, it’s a substantial amount. We don’t fixate on coverage but as part of the pull request review process, people will insist on having tests included. Then on top of that, we do full integration tests, so things like Selenium on desktop. We’re still building out our integration testing capabilities on mobile. We do have that capability as of this year, we invested heavily in January but I would say our number of tests there are still quite minimal. Whereas desktop is pretty extensively covered. Not just on deploy but on every single commit across the entire codebase. We believe very heavily in investing in that kind of toolchain because we think that it’s something which keeps on paying dividends so it takes a bit of investment to get it off the ground but then it just keeps on paying back. Snapshot testing is another area of testing we do a lot of. Because we use Relay and React we have these components which take properties, those properties define what the layout would be and what it should look like and do. We invest pretty heavily in testing the different constructs, like putting in different sets of properties and seeing what the expected outcome is. We do lots of those which essentially just takes snapshots or freezes of what the app output should be and then if somebody does make a change to the codebase we can see whether those changes are percolating through to the areas we would expect or whether they’ve had unexpected consequences somewhere else. It’s very good for checking that the UI doesn’t radically shift based on data changes. Team Lastly, could you talk a bit about the product engineering team at Mixcloud? So the product team is 24 people right now. 2 support people, 2 product managers, myself as director, 2 mobile engineers, one on data, one on infrastructure, one on record label reporting a manager across that team. We have a design team of three who work across all platforms. Then we have three Feature Lanes, which are pairs of people who work on features. They’re given a feature for a month at a time or two sprints, and they will focus on those exclusively. Those features go across all platforms simultaneously so they’d be working on iOS, Android and desktop at once. So they’re full-stack teams. Then we have another team called Fast Lane, which is a team of three people, that is dedicated to rapid changes to the product. Anything that needs to be turned around in 24 hours, bug fixes, random requests or very small feature fixes, stuff like that. What’s particularly unique about our team is the fact that people are full-stack. People usually do full-stack development on a small scale but I think we’ve demonstrated that you can run it at a scale bigger than most people are used to. We’re not a Google-sized team but 24 people is not a small team either. Mobile is about 95% React Native at this point, pretty much entirely written in JavaScript with core functionality like audio playback done by the team of two who are mobile specialists in Swift, Kotlin and Objective-C. We are looking for Python / Django engineers and React / React Native engineers for our London office. So if all of this sounds interesting we have a few opportunities for people to join our team. This post is part of a new series of Behind the Screens technical interviews with teams who build web products. You can subscribe to updates via RSS or join the Able developer community to receive updates in your email digest.	{ "pile_set_name": "OpenWebText2" }
When you hear the word camouflage, images of fake foliage, random brown blobs, or maybe even the US military's failed pixelated fatigues come to mind. But researchers at MIT have developed a new algorithm that generates camouflage patterns that let an object blend into any surroundings, not just a jungle or the desert. Designed to hide urban eyesores like electrical boxes in lush green parks, or an air conditioner sitting outside a historic building, the algorithm uses a series of images—taken at various angles around the object—to generate a camouflage pattern that can be turned into a covering. The goal is to make the object less noticeable at a glance, because unlike a soldier, an air conditioner can't adjust its position and hunker low to the ground, or slip behind a tree to help further disguise itself. In other words, it may not be a perfect invisibility cloak just yet, but as a way to improve aesthetics, there's a good chance Voldemort won't notice that hideous breaker box on the wall. [MIT News]	{ "pile_set_name": "OpenWebText2" }
Optimal patient care relies on a cohesive team of health care professionals who work synergistically, focusing on individual strengths to ensure the highest quality of patient care ([@CIT0001], [@CIT0002]). It has been shown that interprofessional collaboration enhances patient safety, decreases medical errors, and improves satisfaction among health professionals ([@CIT0002], [@CIT0003]). Skills necessary to function as part of an interprofessional team require cultivation and development during health professions training ([@CIT0004]). This has made training in interprofessional collaboration an increasingly appreciated component of medical education. Interprofessional education (IPE) occurs when two or more professions learn with, from, and about each other to improve collaboration and the quality of care ([@CIT0005]). The development and implementation of interprofessional education curriculum, however, can be a difficult task, requiring significant faculty involvement and curriculum development ([@CIT0006]). Student-led peer teaching conveys a number of benefits to the peer learner, the peer teacher, and the institution as a whole ([@CIT0007], [@CIT0008]). Peer teaching occurs when instructors and learners are at a similar stage in their education ([@CIT0009]). Students engaged in peer learning have been shown to be highly receptive to instruction from peer teachers due to the decreased power differential existing between peer teacher and peer learners ([@CIT0010]). In addition, student-led initiatives are cost-effective and can promote collegiality and socialization, leading to long-term sustainability of student-led programs ([@CIT0008]). Small-group problem-based learning (PBL) is a highly effective means of education ([@CIT0011]). During PBL sessions students are presented with a problem or clinical scenario and are then required to work together to come up with a solution with minimal input from the facilitator ([@CIT0012]). The problem-based model is designed around individual inquiry and is very effective in developing problem solving skills, independent learning, and teamwork ([@CIT0013]). This educational method presents a unique way of delivering IPE. We believe student-led small-group PBL seminars can be used to effectively deliver IPE and improve students' perceived need for interprofessional education. To measure the efficacy of IPE sessions, the Interprofessional Education Perception Scale (IEPS) tool was used ([@CIT0014]). The IEPS tool, originally developed by Leucht et al., is an 18-item questionnaire using a six-point Likert scale, designed to assess perceptions of interprofessional education. The questionnaire is then subdivided into four subscales of IPE: competence and autonomy (Subscale 1), perceived need for cooperation (Subscale 2), perception of actual cooperation (Subscale 3), and understanding of others values (Subscale 4). The IEPS was used to evaluate participants' opinions regarding IPE over 16 weeks ([Table 1](#T0001){ref-type="table"}). ###### IEPS subscale classifications ------------ --------------------------------------------- Subscale 1 Professional competence and autonomy Subscale 2 Perceived need for professional cooperation Subscale 3 Perception of interdependence Subscale 4 Willingness to share ideas ------------ --------------------------------------------- Methods {#S0002} ======= First- and second-year medical and pharmacy students at Creighton University were invited to participate in small-group PBL interprofessional seminars led by fellow second-year medical students who served as peer-teachers. The study was approved by the Institutional Review Board at Creighton University. Seminars were held weekly during the lunch hour for 16 weeks. Each seminar was led by one to two second-year medical students, serving as peer-teachers and consisted of 10--14 student learners, split evenly between medical and pharmacy students. The cases were adaptations of cases seen at the Creighton University Medical Center or cases published in peer-reviewed journals. At the beginning of each seminar the group was given a basic patient presentation. Student learners were then required to ask appropriate questions and find appropriate answers to create a differential diagnosis. Student learners were next asked to identify appropriate diagnostic testing to order. The designated test results and questions regarding history and physical were provided by the peer-teacher when appropriate. Through the course of the seminar the peer-teacher provided little to no guidance in keeping with the PBL design. During each seminar students were allowed to use any reference material they deemed necessary. Evaluation {#S0003} ========== A case--control study design was used to evaluate the efficacy of IPE seminars. Following 16 weeks of IPE seminars, student\'s attitudes toward IPE were assessed using the IEPS. Questionnaires were distributed to the entire first- and second-year medical and pharmacy student classes, including those who did not attend. Those students not attending the IPE seminars served as the control group for our study. All first- and second-year medical and pharmacy students were also given a questionnaire regarding barriers to IPE; this survey was designed by the authors of this study ([Table 2](#T0002){ref-type="table"}). ###### IEPS scaled results n Subscale 2 mean±SD Subscale 3 mean±SD ----------------------------------- ----- ---------------------------------------------- ---------------------------------------------- All medical students 62 94.76[a](#TF0001){ref-type="table-fn"}±6.44 75.91[b](#TF0002){ref-type="table-fn"}±10.32 All pharmacy students 35 90.24[a](#TF0001){ref-type="table-fn"}±10.00 84.29[b](#TF0002){ref-type="table-fn"}±10.05 Medical student participants 19 97.81[c](#TF0003){ref-type="table-fn"}±4.68 76.67±11.65 Medical student non-participants 43 93.45[c](#TF0003){ref-type="table-fn"}±7.02 74.76±10.04 Pharmacy student participants 10 95.37^d^±5.71 86.33±10.82 Pharmacy student non-participants 25 88.33[d](#TF0004){ref-type="table-fn"}±10.76 82.67±10.93 All medical students compared to all pharmacy students 'need for professional cooperation' p=0.02 all medical students compared to all pharmacy students 'perception of interdependence' p=0.002 medical student participants compared to medical student non-participants 'need for professional cooperation' p=0.006 pharmacy student participants compared to pharmacy student non-participants 'need for professional cooperation' p=0.02. Data from the IEPS were analyzed along four subscales as described previously ([@CIT0014]). The primary outcome was the difference in responses to the IEPS of those students who attended seminars versus those students who did not attend. The data were scaled to a score of 100 for easier interpretation. It is important to note that data can only be compared within each subscale and not between subscales. Statistical significance was determined using two-tailed t-test and a p value of 0.05. Student responses with regard to perceived barriers to interprofessional education were also recorded and served as secondary outcome data. Results {#S0004} ======= In total, 43 students (24 medical and 19 pharmacy) attended IPE seminars, of those 29 completed the IEPS (67.4% response rates). Sixty eight (43 medical and 29 pharmacy) out of 313 students who did not participate in IPE seminars completed the IEPS survey (21.7% response rate) ([Table 2](#T0002){ref-type="table"}). IEPS responses show that medical and pharmacy students who participated in seminars perceived a significantly higher need for cooperation when compared to those who did not participate (p=0.006 and p=0.02, respectively). Significance was not observed within subscale 1 or subscale 4 (data not shown). In addition, combined responses from participants and non-participants showed that pharmacy students perceived a significantly higher need for professional cooperation (p=0.02) and interdependence (p=0.002) when compared to medical students. In total, 109 (30.62%) out of 356 eligible students responded to the survey regarding current barriers to interprofessional education ([Table 3](#T0003){ref-type="table"}). The most common barrier to participation was 'I am not aware of interprofessional education programs' (61.5% of respondents). The second most common response was 'I do not have time' (52.3% of respondents). Zero respondents indicated, 'Interprofessional education is not an important part of my career'. ###### Student perceived barriers to IPE Student response \% n --------------------------------------------------------------------- ------ ----- I am interested in IPE but I do not have enough time to participate 52.3 57 I am not aware of currently available IPE activities 61.5 67 I have tried and all IPE sessions are full 5.5 6 I do not think IPE is important in my future 0.0 0 Discussion {#S0005} ========== The role that student leaders play in curricular development, especially pertaining to interprofessional education, can be of great value to educational institution as a whole. Current student-led initiatives in IPE have used designs such as social gatherings, conferences, lectures, and formal communications between health professions students ([@CIT0008]). Our data demonstrate that a student-led small-group PBL seminar can be used to effectively address certain IPE goals. In particular, students in our study who participated in IPE seminars demonstrated significantly greater perceived need for interprofessional cooperation when compared to those who did not attend. In addition, the most commonly cited barrier to involvement in IPE in our study was lack of awareness of IPE programs. In our case, the lack of awareness of IPE programs is due to the absence of IPE in the standard curriculum. IPE programs can be resource and time intensive because of the significant amount of coordination required to educate students in different health professions ([@CIT0015]). Peer-teachers are a significantly underutilized resource available to educators, and can be used to effectively achieve educational outcomes that may otherwise be difficult based on funds or faculty availability ([@CIT0016], [@CIT0017]). Seminars in our study were designed and led exclusively by medical students and were minimally resource intensive on faculty and school funding. Students also state that time is a major barrier to participation in interprofessional education. Minimal preseminar preparation and the relaxed nature of peer-led seminars significantly reduce the time constraint that students feel in more formal educational environments. These seminars fit nicely into a lunch hour, similar to noon-conference seminars used in many graduate medical education training programs. The use of small-group PBL sessions has been shown to be highly effective in developing problem solving skills and teamwork ([@CIT0013]). During our study it was evident that students frequently encountered problems they could not solve on their own and required the help of students from other health professions to solve such problems. This interprofessional reliance began to shape the attitudes and behaviors of students in our study and resulted in appreciation of the interprofessional collaboration required to optimally approach a patient or clinical problem. Other studies have observed similar findings using a broad range of IPE models ([@CIT0017]). There are certain limitations to this study; in particular our study was limited to pharmacy and medical students based on logistical constraints. It is yet to be proven whether these results are applicable to other health professions. Also, the voluntary nature of participation may select for those students who inherently desire growth in interprofessional collaboration, thus further studies are required to control for this variable and determine the generalizability to an entire student population. One of the most encouraging observations of this study was the vigor with which new students approached leadership roles within IPE seminars. Because of the progressive nature of medical education it is crucial that new leaders emerge who can effectively continue programs and improve upon previous iterations ([@CIT0008]). The minimal faculty involvement and complete student autonomy over IPE seminars seemed to inspire peer-learners to become peer-teachers. Conclusion {#S0006} ========== In conclusion, peer-teacher-led problem-based interprofessional seminars are effective in improving the perceptions of interprofessional collaboration among first- and second-year medical and pharmacy students. The peer-teaching model may be an effective adjunct to traditional curriculum in addressing IPE by overcoming major barriers to student involvement. Conflict of interest and funding {#S0007} ================================ The authors report no conflicts of interest.	{ "pile_set_name": "PubMed Central" }
Editor’s note: In November 2016, Consortiumnews.com was listed with about 200 other websites at the shadowy “PropOrNot” website, which was claiming to serve as a watchdog against undue “Russian influence” in the United States. The PropOrNot blacklist was elevated by the Washington Post as a credible source, despite the fact that the neo-McCarthyites who compiled the list hid behind a cloak of anonymity. As an article at Consortiumnews explained at the time, the Post granted PropOrNot anonymity “to smear journalists who don’t march in lockstep with official pronouncements from the State Department or some other impeccable fount of never-to-be-questioned truth.” The PropOrNot logo Now, George Eliason, an American journalist living in Ukraine, has published an article at Washington’s Blog – one of the other 200 blacklisted websites – examining the cast of characters who may be behind the PropOrNot endeavor. As explained in a disclaimer at the original article at Washington’s Blog: “A leading cybersecurity expert has publicly said that Mr. Eliason’s research as presented in this article does not violate the law. Washington’s Blog does not express an opinion about whether or not the claims set forth in this article are accurate or not. Make up your own mind.” By George Eliason A little over a year ago, the deep state graced the world with PropOrNot. Thanks to them, 2017 became the year of fake news. Every news website and opinion column now had the potential to be linked to the Steele dossier and Trump collusion with Russia. Every journalist was either “with us or against us.” Anyone who challenged the Russiagate narrative became Russia’s trolls. Fortunately for the free world, the anonymous group known as PropOrNot that tried to “out” every website as a potential Russian colluder, in the end only implicated themselves. Turnabout is fair play and that’s always the fun part, isn’t it? With that in mind, I know the dogs are going to howl this evening over this one. The damage PropOrNot did to scores of news and opinions websites in late 2016-2017 provides the basis of a massive civil suit. I mean huge, as in the potential is there for a tobacco company-sized class-action sized lawsuit. I can say that because I know a lot about a number of entities that are involved and the enormous amount of money behind them. How serious is this? In 2016, a $10,000 reward was put out for the identities of PropOrNot players. No one has claimed it yet, and now, I guess no one will. There are times in your life that taking a stand has a cost. To make sure the story gets out and is taken seriously, this is one of those times. In this article, you’ll meet some of the people staffing PropOrNot. You’ll meet the people and publications that provide their expenses and cover the logistics. You’ll meet a few of the deep state players. We’ll deal with them very soon. They need to see this as the warning shot over the bow and start playing nice with regular people. After that, you’ll meet the NGOs that are funding and orchestrating all of it. How am I doing so far?	{ "pile_set_name": "Pile-CC" }
The present invention relates to a portable nature stand, and more particularly to a stand of the type which can be transported into an area such as a forest having many trees and which can be easily mounted in operative position so as to provide a safe and comfortable vantage point from which to observe nature. Such stands are used by photographers or hunters and are often referred to as a deer stand or tree stand. Stands of this type can, of course, also be employed with upright wooden poles or the like, but the most common use is with trees having a diameter on the order of five inches or more. The stand should be of lightweight construction and be capable of being readily assembled and disassembled without the use of any tools. Nature stands are utilized with trees of many different sizes and configurations. Prior art stands have the disadvantage that they often are not suitable for use with trees having unusual shapes and trees that have many low branches or divided trunks. Furthermore, prior art stands make undesired noises or may have components thereof damaged upon movement of the associated tree caused by wind. It is therefore desirable to eliminate any undesired noises and possible damage to the stand irrespective of movement of the tree to which it is attached.	{ "pile_set_name": "USPTO Backgrounds" }
Monday, December 12, 2011Not playing on top line didn't help Smith By Jesse Rogers A preseason concussion was the beginning of a rough season for Ben Smith. CHICAGO -- So much for the return of one of last year's playoff heroes. Chicago Blackhawks forward Ben Smith was sent back to the minors after a quiet seven games with the Hawks. He scored a goal but it didn't ignite his play and he struggled at times. Still, Smith was only given a chance in a bottom-six role. Maybe that's not his game. Last year, he excelled playing with the Hawks' top players. Wouldn't he provide the grit needed to play on one of the top two lines? Joel Quenneville has tried just about every winger next to Jonathan Toews this season, but Smith never got his chance. In the last two games alone, Viktor Stalberg and Dan Carcillo alternated in that spot several different times. Why not Smith? Admittedly, it's a little bit of a Catch-22. Should Smith be given a chance on the top line if he hasn't earned it? But then again, can he excel without being given that chance? The bottom line with the Hawks, or any team, is you have to earn it in the role you're given. Stalberg did enough on the fourth line to move up and has had some good moments with Toews so Smith needed to do the same. It didn't help him that Dave Bolland struggled during his time as Smith's center but Smith stood out last postseason and he simply did not during his short stretch with the Hawks this year. Of course, his preseason concussion didn't help matters. You might wonder why Bryan Bickell wasn't sent down or any other player who's struggled this year. It's simple: Smith is on a two-way contract and doesn't have to clear waivers. Others do. More than likely he'll return to the Hawks at some point, but this opens the door for Bickell to play again after sitting out the past few games. With the top two lines producing Quenneville has the luxury of giving his third line another chance to find the spark they had last postseason. Bickell, Bolland and Michael Frolik need to find that chemistry again and start contributing. Until then, we're left to wonder why so many secondary players who were playoff stars a year ago are struggling. There's Smith and then Corey Crawford and the entire checking line. It's probably a coincidence, or maybe -- to get the most out of them -- they need to pretend the calendar says April instead of December.	{ "pile_set_name": "Pile-CC" }
Golaghat Rhino F.C. Golaghat Rhino Football Club is a professional football club based in Golaghat, Assam, that competes in the Assam State Premier League, the top flight of the state football. The club was founded in 2014 in its current stadium, GDSA Stadium at General Field, Golaghat. History In December 2013, the idea of raising a professionally managed football club was conceived by eight new young entrepreneurs of Golaghat. Sanjib Handique, Arun Goswami, Sanvit Sarma, Tapan Paul, Manoj Jain, Mrinal Saikia, Santanu Kalita and Paban Saikia, the founding members of the Golaghat Rhino F.C. with support from the Golaghat District Sports' Association (GDSA), envisioned to set up a club to promote football in the region and to provide the opportunity for young players to be part of a professional team. 2014–present Soon after a few months of its inception, the football club won the Assam Club Championship title held at Gossaigaon. The winning title positioned the team as one of the best football teams to exist in the state as part of newly formed club. In October 2014, Assam State Electricity Board SC (ASEB SC) defeated Rhino F.C. by 1–0 goals in the final match of the 13th Jwhwlao Swmbla Basumatary (JSB) Gold Cup Trophy defeating at the Bangaldoba ground in Chirang district.<ref>{{cite news \|title=ASEB lift JSB Gold Cup, Assam Times"\|url=https://www.assamtimes.org/node/12148\|work=Hantigiri Narzary\|date=19 October 2014\|accessdate=19 October 2014}}</ref> Golaghat Rhino F.C. played the first state football premier league in 2015. Consisting of 12 teams, the league was organised by the Assam Football Association, in association with the Celebrity Management Group. The club has also purchased a plot of land in its name to build infrastructure facilities, including a hostel for its players and aspiring footballers in the region. The Rhino F.C. has a total of 22 under–19 players from various districts of the state of Assam, including players from the Indian states of Odisha, Manipur, besides direct international hires from places like Nigeria. Crest and colours The club crest is derived from the Assam's state animal, the Indian rhinoceros\|one–horned rhinoceros: Rhinoceros unicornis'', native to the Kaziranga National Park in the Golaghat region. References Category:Organisations based in Golaghat Category:Golaghat district Category:Assam State Premier League Category:Football clubs in Assam Category:2014 establishments in India	{ "pile_set_name": "Wikipedia (en)" }
Taoiseach Enda Kenny has insisted he does not intend having to deal with any Independent TDs if forming the next government. Mr Kenny insisted he did not envisage Fine Gael and Labour needing additional support after the general election. It follows reports that Independent TD Michael Lowry and other Independents could be involved if Fine Gael needs support. Speaking on RTÉ's This Week he added: "There are no discussions, no connections, no contact with any Independent from the Fine Gael party. I don't envisage having to do any business with any Independent." When pressed whether he would rule out doing a deal with Independent TD Michael Lowry if he needed his support after the election, the Taoiseach said: " I have no intention of having to do business with any Independent I hope that is clear." Mr Lowry, who topped the poll in Tipperary North five years ago, previously agreed a deal with the Fianna Fáil/Green party coalition. Mr Kenny also defended Fine Gael's plan to abolish the Universal Social Charge - if re-elected. Speaking earlier on RTÉ's The Week in Politics, Mr Kenny said getting rid of the USC would put more money in people's pockets - and generate more revenue for public services. "If we abolish the Universal Social Charge, which was introduced by the Fianna Fáil government as a penal tax, we abolish that over the next five budgets it means that you reduce effectively the rate of personal income tax from 52% to 44%. "Abolishing USC over five years, it means that if you have a job you are going to have more pay; if you don't have a job you'll be able to get a job," Mr Kenny said. Meanwhile, Fianna Fáil leader Micheál Martin has again called on Mr Kenny to facilitate a head-to-head debate ahead of the general election. Mr Martin said: "Rather than engage on the issues and be honest in explaining their plans for the future of public services as they attempt to introduce 'US Style' taxes, Fine Gael instead seem to believe that just attacking Fianna Fáil is a credible alternative to having an actual vision for the country. "If Enda Kenny wants to dedicate his campaign to attacking Fianna Fáil that is his choice, but if there is any honesty in his position, he should at least agree to meet me directly in head-to-head debate so that voters can make a well informed decision about who is being honest about the future and who has a credible plan for a fairer recovery," he added.	{ "pile_set_name": "OpenWebText2" }
Members – show your valid Wests membership card when you buy $5 tickets and get $5 in tickets FREE SPEND $10 and receive a FREE ticket in the Monthly Draw to win a $500 Wests Gift Card Draw will take place at the end of the Sunday Raffle, on the last Sunday of the month. To enter place your FREE ticket in the barrel alongside the prize in the foyer of the Club. No exchange or refund on the prize. Promotion for a limited time. Hoi Cancelled until further notice. We apologise for any inconvenience. Exercise your brain in this terrific card based game of skill. Tuesday & Thursday – 11am to 1pm (boards on sale 10am) We Are Open \| June 1 We are pleased to confirm that from Monday 1 June we have reopened Wests New Lambton, Mayfield, Cardiff, City and Nelson Bay. Clubs have reopened in a modified format providing access for Wests members only from 10am daily (New Lambton from 9am Sat & Sun)	{ "pile_set_name": "Pile-CC" }
Lost or deleted WhatsApp chats on your iPhone/iPad/iPod Touch accidentally? No worry, iMyfone iPhone WhatsApp recovery tool will give you the chance to get back the lost WhatsApp messages no matter how you lost them.	{ "pile_set_name": "Pile-CC" }
{ "activePlaceCount": 0, "birth": { "place": { "name": "Chester, United Kingdom", "placeName": "Chester", "placeType": "inhabited_place" }, "time": { "startYear": 1911 } }, "birthYear": 1911, "date": "1911\u20131997", "death": { "time": { "startYear": 1997 } }, "fc": "Austin Wright", "gender": "Male", "id": 3095, "mda": "Wright, Austin", "movements": [], "startLetter": "W", "totalWorks": 1, "url": "http://www.tate.org.uk/art/artists/austin-wright-3095" }	{ "pile_set_name": "Github" }
By now we're sure you're well aware of the former Fulham and Tottenham star's penchant for spitting bars, but now some pesky Statesiders are trying to spark 'beef' between 'Deuce' and American rapper Lupe Fiasco. Well, sort of. Before the World Cup, Chicago-born star Fiasco – 'music director' of the USMNT for Brazil, which is apparently a thing – appeared on television promising Dempsey some lines on his new album Tetsuo & Youth. Yet when the album dropped last month, the Seattle Sounders man's dulcet tones were nowhere to be found (Ed Sheeran, though? Straight in). An outrage! Back in November 2014, FourFourTwo chatted to Deuce about his experiences in 'the game' (the rap one, of course)... "You know, when I was growing up the first car I had didn’t have a radio in it," he said. "So I would freestyle whenever I would drive, and my younger brother used to always tell me 'damn, shut up man!' But we didn’t have anything to listen to. "I grew up listening to Houston rap; my friends and I would freestyle over beats. When I went to college I was the new kid, and they rapped – that was part of your initiation. And when I went to MLS, and I was the new kid, they knew I rapped and so that’s what I did. "That actually allowed me to do one track with Big Hawk for Nike called Don’t Tread before the 2006 World Cup. About three or four months after we did that, he was killed (shot to death in 2006 by an unknown attacker). So that kind of put me off rap a little bit. "When I went to England, they were talking about it: 'Hey, you’re a part time rapper blah blah' and I was like, 'Nah, I play soccer, I only wanna focus on my soccer.' "When I came back to the States, the opportunity came up before the 2014 World Cup and I wasn’t sure. But then when I was hurt, in my down time, I just worked on it for fun and it actually became an album. "I wasn’t really thinking anything of it, it was just for fun, and the proceeds are going towards East Texas Food Banks. "For me it just to get away during that time when I was hurt in the off-season, just to put my mind on something else. I was frustrated with the fact that my body was breaking down and I was injured, so it was an outlet."	{ "pile_set_name": "Pile-CC" }
Home Daily News Dozens of 'well-connected' people granted… Judiciary Dozens of 'well-connected' people granted secret court cases in Chicago area, including 5 judges Image from Shutterstock. Five state and federal judges, as well as a number of lawyers, were among dozens of “well-off and well-connected” individuals who have had cases–often concerning domestic relations matters–either sealed by Chicago area judges or allowed to be filed using only the initials of the parties. Although the reasons routinely cited–financial privacy and safety–could fall within a 1987 Illinois state law that permits lawsuits to be filed under a pseudonym for “good cause,” some observers wonder why it is appropriate for lawyers, judges and other high-profile individuals to be granted special treatment, reported the Chicago Tribune (sub. req.) in a lengthy Sunday article. “If you avail yourself of the court system, you have to pay the price of it being public,” said attorney Nancy Chausow Shafer, the president of the American Academy of Matrimonial Lawyers chapter in Illinois. “If we start making exceptions for the rich and famous, it creates a dual court system, which goes against our populist belief of what a court should be, which is really justice for all without distinguishing between the rich and poor.”	{ "pile_set_name": "OpenWebText2" }
WASHINGTON (Reuters) - President Barack Obama consulted intelligence officials on Wednesday on ways to rein in U.S. surveillance practices as he nears the end of a review likely to lead to changes as to how bulk telephone data is handled as well as restrictions to spying on foreign leaders. U.S. President Barack Obama waves after he urges Congress to act and extend emergency unemployment insurance benefits while at an event in the East Room of the White House in Washington, January 7, 2014. REUTERS/Larry Downing Obama, who could announce his intelligence reforms in a speech as early as next week, is acting in an attempt to restore Americans’ confidence in U.S. intelligence services after damaging disclosures from former spy contractor Edward Snowden about the sweep of surveillance practices. Obama reviewed the progress of the administration’s review in a meeting with James Clapper, the director of U.S. intelligence, and Keith Alexander, the National Security Agency director, as well as Attorney General Eric Holder and Vice President Joe Biden. “This was an important chance for the president to hear directly from his team as he begins to make final decisions about how we move forward with key intelligence collection programs,” said Caitlin Hayden, spokeswoman for the White House National Security Council. Obama also met with members of the Privacy and Civil Liberties Oversight Board, a bipartisan independent panel that has been reviewing U.S. surveillance practices, including the collection of telephone data and the operations of the Foreign Intelligence Surveillance Court. The privacy oversight board said it would offer its findings to Obama in late January or early February, meaning its recommendations will not get to the president until after he has already announced his reform plans. Obama is due to meet several U.S. lawmakers on Thursday as he firms up his review. The reform plan is expected to include some restrictions on spying on foreign leaders, an issue that arose late last year when it was reported that the National Security Agency had monitored German Chancellor Angela Merkel’s cellphone. Obama spoke to Merkel by phone on Wednesday, but the White House said the conversation was for Obama to express condolences over her breaking her pelvis recently in a cross-country skiing accident. An outside group had recommended to Obama last month that before spying on foreign leaders, U.S. leaders should determine whether such surveillance is merited by significant threats to national security and whether the country involved is one “whose leaders we should accord a high degree of respect and deference.” Obama is also open to changes in taking the storage of bulk telephone data out of direct government control, administration officials say. One option would be to allow some bulk phone data collected by intelligence agencies to be kept by private companies instead of the U.S. government. Revelations about the government’s ability to monitor Americans’ phone and email traffic were among the most dramatic disclosures from Snowden, who is currently living in temporary asylum in Russia and sought by the United States to face espionage charges. Obama is also seeking to make sure that civil liberties concerns have greater prominence in the deliberations of the top-secret Foreign Intelligence Surveillance Court, which approves law enforcement requests to conduct surveillance of Americans or foreigners. One proposal he is considering is to put a public advocate on the court to ensure adversarial views are heard.	{ "pile_set_name": "OpenWebText2" }
A resident of a rooming house in New Westminster says he is lucky to be alive after fire ripped through a three-storey building early Friday. Troy Peters had just woken up to get ready for work, when he heard screaming coming from within the building, he told CBC News. He dressed quickly, grabbed his wallet and jacket, and ran out of his apartment. "I was surrounded by billowing smoke, I just ran to the fire exit," he said. "I'm lucky to be alive." Fire crews received a call about the fire at 1009 6th Avenue at 6.10 a.m. On arrival, they found heavy smoke and flames coming from the front of the building, Deputy Chief John Hatch said. A total of five occupants were rescued from the building by fire crews, Hatch said. There were no injuries sustained. He said they are trying to trace a further three people who have been known to occupy the rooming house. The cause of the fire is unknown.	{ "pile_set_name": "OpenWebText2" }
INTRODUCTION {#s1} ============ Cytomegalovirus (CMV) is a re-emerging human herpes virus, which causes substantial morbidity and occasional mortality in immunocompromised patients \[[@CIT0001]\]. Among these, solid organ transplant recipients who maintain an allograft by receiving immunosuppressive drugs are well-known to be at risk of infection. CMV infection after kidney transplantation (KT) reportedly ranges from asymptomatic infection to symptomatic CMV syndrome and tissue-invasive disease \[[@CIT0002]\]. Data from 2 retrospective studies in Thailand revealed the prevalence of CMV seropositivity in both donors and recipients was 99 percent. Despite preexisting immunity in most patientsindicated by CMV seropositivity, they remain at moderate risk of CMV infection. The prevalence of asymptomatic CMV infection and CMV disease in KT recipients were 5%--21% and 7%, respectively. Risk factors include advanced age of the recipient and use of antithymocyte globulin (ATG) for induction or steroid-resistant rejection therapy \[[@CIT0003], [@CIT0004]\]. Patients developing CMV diseases carry a greater risk of allograft failure and death compared with those free from CMV disease \[[@CIT0003]\]. Furthermore, KT recipients who developed drug-resistant CMV infection could suffer increased morbidity from prolonged CMV DNAemia and anti-CMV therapy \[[@CIT0005]\]. Prevention of this infection remains a suitable intervention to limit unfavorable consequences. Two international guidelines from the Transplantation Society and the American Society of Transplantation Infectious Disease Community of Practice encouraged implementation of prevention strategies for CMV infection among KT recipients \[[@CIT0006], [@CIT0007]\]. Although the guideline for prevention of CMV infection in Thai KT care was developed by the Thai Transplant Society, the strategies implemented among transplant centers in Thailand remained variable \[[@CIT0008]\]. Despite the fact that a preemptive approach is recommended in CMV-seropositive KT recipients by the aforementioned guideline, impracticability and financial restrictions could limit its utilization in real-world practice. Additionally, an optimal cut-off value of plasma CMV DNA load has not been standardized among physicians. Furthermore, an investigation of real-life strategies to prevent this specific infection has never been performed, especially in resource-limited settings. Therefore, we aimed to investigate CMV prevention strategies utilized among transplant centers in Thailand. We also investigated differing perspectives in terms of CMV prevention in KT recipients between infectious disease physicians (ID) and nephrologists (NP). METHODS {#s2} ======= Questionnaire {#s3} ------------- A survey was delivered to all 31 transplant centers in Thailand during October and November 2018. One ID and 1 NP, who were directly caring for KT recipients at each transplant center, were included. The names of the transplant centers and physicians were obtained from the Thai Transplant Society in October 2018. An email with a link to the electronic survey was sent to all physicians with a reminder email if a response was not received. The study protocol was approved by the Institutional Review Board of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. A questionnaire on CMV prevention strategies for KT recipients was developed using a web-based electronic survey website ([www.surveymonkey.com](http://www.surveymonkey.com)). The survey included the respondents' demographic data, such as sex, age, transplant center setting or years in KT practice, and CMV prevention strategies. CMV prevention strategies were defined according to the recently published guidelines \[[@CIT0006], [@CIT0007]\]. Prophylaxis was defined as administration of anti-CMV drugs, either intravenous (IV) ganciclovir or oral valganciclovir, for a defined period of time after KT. A preemptive approach was defined as surveillance of plasma CMV DNA load, quantified by real-time polymerase chain reaction (PCR) assay and initiation of anti-CMV drugs when the cut-off value was reached to prevent progression from asymptomatic CMV infection to disease. Plasma CMV DNA load was reported in both copies/mL and international units (IU)/mL, based on the use of a quantitative real-time PCR technique by COBAS AmpliPrep/COBAS TaqMan (TaqMan CMV Test, Roche Molecular Diagnostics, Branchburg, NJ). One copy/mL was calibrated to 0.91 IU/mL by the calibration of tests with the World Health Organization international standard \[[@CIT0009]\]. Targeted prophylaxis or preemptive approaches were defined as above, but they were focused on a defined high-risk group of patients rather than universal implementation. A hybrid approach was defined as surveillance by plasma CMV DNA quantification after cessation of a defined period of prophylaxis. A CMV-specific immunity-guided approach was defined as an intervention (prophylaxis, preemptive approach, or closed observation) guided by measurement of cell-mediated immunity, such as CMV-specific T-cell immunity assay. Statistical Analyses {#s4} -------------------- Demographic data of all physicians involved in the study were analyzed by descriptive analysis. Categorical data were described as frequencies and percentages and compared by Fisher exact test. A P value \< .05 was considered statistically significant. Statistical analyses were performed with the statistical software Stata version 15 (StataCorp, LLC, College Station, TX). RESULTS {#s5} ======= Demographic Data {#s6} ---------------- There were 43 respondents from 26 of the 31 (84%) transplant centers, including 26 (60%) IDs and 17 (40%) NPs. The demographic data of all physicians included in the survey are summarized in [Table 1](#T1){ref-type="table"}. Fifty-eight percent of respondents were aged 35--44 years and approximately half were males (49%). Two-thirds of the physicians had been working in a public hospital setting (63%) and encountering KT recipients for at least 2 years (74%). The demographic data between the ID and NP groups were comparable; however, there were slightly more male physicians among the IDs compared with the NP group (62% vs 29%; P = .06). There were also significantly more physicians from a public hospital setting in the ID group compared with the NP group (81% vs 36%; P \< .05). ###### Demographic Data of Infectious Disease Physicians and Nephrologists Who Participated in the Survey Characteristics Infectious Disease Physicians (n = 26) Nephrologists (n = 17) P value --------------------------------------------------- ---------------------------------------- ------------------------ ----------- Male, n (%) 16 (62) 5 (29) .06 Age, years, n (%) 25--34 5 (19) 9 (53) .04 35--44 18 (69) 7 (41) .11 45--54 3 (12) 1 (6) 1.00 Transplant center setting, n (%) Public general hospital 10 (39) 2 (12) .09 Public university hospital 11 (42) 4 (24) .33 Nonprofit hospital 1 (4) 8 (47) .001 Others 4 (15) 3 (17) 1.00 Years in kidney transplant recipients care, n (%) \<1 3 (12) 2 (12) 1.00 1--2 1 (4) 5 (29) .03 2--5 15 (57) 5 (29) .12 5--10 4 (15) 3 (18) 1.00 \>10 3 (12) 2 (12) 1.00 CMV Prevention Strategies {#s7} ------------------------- Overall responses in terms of CMV prevention strategies and the different perspectives between the ID and NP groups are shown in [Figure 1](#F1){ref-type="fig"}. Forty-one (95%) physicians agreed with a need for CMV prevention in KT recipients, although 33 physicians (77%) stated that they already utilized prevention strategies for their patients. Cytomegalovirus prevention strategies currently implemented include preemptive approaches (48%), universal prophylaxis (45%) (either by IV ganciclovir or oral valganciclovir), hybrid approaches; surveillance after prophylaxis (3%), and CMV-specific immunity-guided approach (3%). When specifically asked about the potential role of CMV prevention in Thai KT recipients, when the majority are CMV seropositive and likely to receive an allograft from a CMV seropositive donor, only 5% of physicians stated no need for prevention in this scenario. The remaining 95% reported that they preferred the preemptive approach (84%) over prophylaxis (12%). However, 81% of the former preferred targeted prophylaxis for those receiving ATG. ![Cytomegalovirus Prevention Strategies for Kidney Transplant Recipients in Thailand](ofz322f0001){#F1} Among physicians choosing to implement prophylaxis, the duration of prophylaxis ranged from less than 1 to more than 6 months, with half (51%) choosing to implement prophylaxis over a 3-month course. For the preemptive approach, 65% and 93% of all physicians initiated preemptive therapy when the plasma CMV DNA load reached 2000 and 3000 copies/mL (1820 and 2730 IU/mL) or 3.3 and 3.4 log10 copies/mL (3.2and 3.4 log10 IU/mL), respectively [Figure 2](#F2){ref-type="fig"}. At a plasma CMV DNA load cut-off value of 5000 copies/mL (4550 IU/mL), almost all physicians (98%), either ID or NP, had initiated preemptive therapy for their patients. There was no difference in CMV prevention strategies between the 2 groups of physicians. A significantly greater percentage of NPs initiated preemptive therapy at a plasma CMV load of 1820 IU/mL compared with IDs (88% vs 50%; P = .02). ![Cumulative Numbers of Physicians Initiating Preemptive Therapy in Kidney Transplant Recipients with Varying Plasma Cytomegalovirus DNA Cut-off Values](ofz322f0002){#F2} Barriers for CMV Prevention Strategies {#s8} -------------------------------------- The most common barrier to implementation of CMV prevention strategies was inaccessibility to care, including financial incompatibility resulting in restricted access to oral valganciclovir and quantitative CMV DNA testing in 67% and 12% of the physicians, respectively. Lack of logistic support for plasma CMV DNA load measurement due to impracticability in real-life practice was reported in 16% of respondents. Side effect intolerance of anti-CMV drug prophylaxis, especially bone marrow suppression from (val)ganciclovir, was reported in 5% of the physicians. Eighty-one percent felt that a guideline would enable physicians to more practically implement strategies for CMV prevention in their KT recipients. The remainder stated that greater self-education (14%) and transplant infectious disease consultation (5%) would be preferable. DISCUSSION {#s9} ========== A nationwide survey of CMV prevention practice in both IDs and NPs was conducted with a response rate of greater than 80%. We report here the first survey of CMV prevention strategies for KT recipients in a resource-limited setting. The majority of respondents agreed there was a need for CMV prevention in this immunocompromised population although the approach is currently variable among physicians. The preemptive approach is the most common strategy utilized; however, prophylaxis is more favorable in patients receiving intense immunosuppression, such as ATG. We also demonstrated common CMV DNA cut-off values for initiation of preemptive therapy for Thai KT recipients. Financial incompatibility is the main inhibitory factor in a successful intervention. However, most respondents believe that practical guideline would encourage physicians to implement CMV preventive strategies in Thai KT recipients. CMV has both direct and indirect effects in KT recipients. CMV disease, especially in those with allograft involvement, can cause significant morbidity. Allograft rejection, mortality, and opportunistic infection by infectious agents other than CMV are well-known consequences of CMV infection, which could be explained by the modulation of the immune system by CMV itself \[[@CIT0002]\]. In a resource-limited setting where the majority of adult KT recipients and donors are CMV seropositive, the risk of CMV infection after KT is considered to be moderate compared with western countries where CMV serostatus mismatches are common and pose a high risk. Data from previously cited studies in Thailand revealed prevention strategies are not universally utilized. A high rate of CMV disease in the period when quantitative CMV DNA testing is not practically available \[[@CIT0003]\]. A relatively lower rate of CMV disease and some with asymptomatic CMV DNAemia, which would likely discover more from accessibility to PCR assay in the later years. In Thailand, financial constraints remain an issue regarding access to oral valganciclovir in an outpatient setting. In our center, patients receiving ATG for induction therapy received IV ganciclovir early posttransplant while being admitted to hospital and then later switched to a preemptive approach, forming a so-called hybrid approach. We also attempted to use this strategy in patients with steroid-resistant rejection requiring ATG; however, the rate of compliance remains uncertain. In our study, we have revealed that CMV prevention strategies are generally accepted, although the real-life implementation is not fully practiced. In general, implementation of the preemptive approach and anti-CMV prophylaxis are comparable. However, upon further investigation, we also report a preference for the preemptive approach among physicians treating CMV-seropositive KT recipients. Of those treated preemptively, the optimal plasma CMV DNA cut-off value for initiation of therapy remains uncertain. Although the conversion of CMV DNA load from copies/mL to IU/mL was recommended for implementation across all transplant centers, the recent international guidelines remain vague regarding the preemptive threshold. They recommended standardizing the cut-off value based on center-specific rates of CMV infection and clinical practices. Our survey revealed the applied threshold could range from 2000 to 3000 copies/mL (1820 and 2730 IU/mL). At least 90% of physicians initiated therapy when the plasma CMV DNA load reached 3000 copies/mL (2730 IU/mL), with almost all physicians initiating therapy by 5000 copies/mL (4550 IU/mL). Martín-Gandul and colleagues conducted a retrospective study to determine a valid threshold in plasma for preemptive therapy of CMV infection in CMV-seropositive solid organ transplant, including KT recipients. They found 3983 IU/ml (2600 copies/ml) to be the optimal cut-off for initiating preemptive therapy, with a high negative predictive value of 99.6% that could almost exclude CMV disease without specific anti-CMV therapy, particularly in those with moderate risk similar to our patients. This optimal cut-off value also showed sensitivity and specificity of 89.9% and 88.9%, respectively \[[@CIT0010]\]. Our data reported a real-world plasma CMV DNA load threshold that encourages physicians to start preemptive therapy. We also found a trend of relatively early initiation of preemptive therapy in the NP group compared with the ID group. This could be explained by a greater percentage of patients being treated by NPs in a private setting where anti-CMV drug therapy is more available. However, dynamic monitoring of plasma CMV DNA load with the same clinical specimens and assays along with details of the clinical setting rather than single time-point interpretation is advised. The kinetics of CMV replication has been shown to be useful for the management of CMV infection in immunocompromised patients \[[@CIT0011], [@CIT0012]\]. Logistic support for measuring plasma CMV DNA load every week following transplantation is also not practical in our setting. A less frequent measurement, such as once every 2 weeks, in an outpatient clinic was commonly implemented in our practice. However, this strategy is not supported by Boillat Blanco et al, who revealed that less frequent monitoring may miss the opportunity to keep pace with the progression of the disease, especially in the postprophylaxis setting \[[@CIT0013]\]. Among centers utilizing prophylaxis, either IV ganciclovir or oral valganciclovir was commonly used. Duration of prophylaxis was variable with the majority of courses ranging from 1 to 6 months. Although the preemptive approach is recommended in the guidelines for CMV-seropositive KT recipients, anti-CMV prophylaxis is also acceptable, though 3 months is the recommended duration. Only in CMV serostatus mismatch settings was an extension to 6 months after transplant mentioned. When we specifically investigated the intervention for CMV-seropositive KT recipients, more physicians tended to report a preemptive approach for their patients and individually considered those with high risk for anti-CMV prophylaxis. Targeted prophylaxis has been stated in the guidelines in the setting of steroid-resistant cellular rejection that needs an additional immunosuppressant such as ATG. This practice is supported by the previously identified risk from receiving this lymphocyte-depleting agent in CMV-seropositive KT recipients \[[@CIT0003]\]. Reusing et al demonstrated some benefit of anti-CMV prophylaxis in CMV-seropositive KT recipients who received ATG in a retrospective study \[[@CIT0014]\]. More recently, Chiasakul and colleagues implemented targeted prophylaxis in those receiving a standard dose of ATG among high-risk patients such as those who underwent ABO incompatible KT with a favorable outcome \[[@CIT0004]\]. Chitasombat et al specifically conducted a cost-effectiveness analysis, revealing that few KT recipients who received ATG were prescribed oral valganciclovir as outpatients. Therefore, they developed CMV infection more frequently compared with those receiving oral valganciclovir, ultimately leading to a longer duration of hospitalization and direct and indirect costs of treatment for CMV infection compared with those without CMV reactivation \[[@CIT0015]\]. These data likely represent a burden of infectious complications among ATG-treated KT recipients, especially from CMV. More studies are required to better define the benefits of anti-CMV prophylaxis in these patient groups. In such individuals, anti-CMV prophylaxis is likely warranted, especially in those receiving immunosuppression augmented with ATG, and could be postulated for high-dose glucocorticoids. The practice setting in Thailand is likely to have an impact on decision-making in terms of prevention strategies. Although substantial portions of our respondents worked in a public hospital setting where patients rely on the national and social security budget, we found that only a small portion of physicians who reported using CMV-specific T-cell immunity to design an intervention for their patients. This intervention has been encouraged in a recent guideline, because each patient is considered to have a different state of immunity against CMV, depending on their level of risk and immunosuppression \[[@CIT0006], [@CIT0016]\]. Recent data supported measurement of patients' nonspecific and CMV-specific immunity to better stratify prevention strategies for each KT recipient \[[@CIT0017]\]. The most common barriers for establishing CMV prevention strategies in Thailand were lack of access to oral valganciclovir and quantitative CMV DNA testing due to high drug and laboratory assay costs, respectively. Based on the 2019 conversion rate of 32.5 THB to \$1 US, the cost of valganciclovir prophylaxis per 1 patient with normal glomerular filtration rate (900 mg/day) for 100 days was US \$7900, and the cost of weekly quantitative CMV DNA testing per 1 patient for 3 months was US \$936. Apart from the above mentioned, the impracticability of weekly measurement of plasma CMV DNA load was also an issue. Furthermore, a few participants reported an unacceptable side effect of bone marrow suppression from (val)ganciclovir. Our study has several limitations. First, we saw a relatively low response rate of respondents in the NP group. Second, only 1 ID and 1 NP were selected from each transplant center and these might not represent who the practice employed its entirety in that center. Lastly, other physicians who could be categorized outside of the ID and NP groups may be inadvertently excluded, even though they were potentially caring for KT recipients in some centers. Nonetheless, we have provided an overall picture of real-world CMV prevention awareness and practice in Thailand where resources are limited. This information will be helpful in highlighting the barriers faced, which must be addressed in a standardized guideline and direct efforts to implement a consistent practice for CMV prevention in Thai KT recipients. In summary, although most physicians agreed that CMV prevention was necessary for Thai KT recipients, a nationwide survey revealed a lack of uniformity in prevention strategies for CMV infection after KT. A preemptive approach is the most common intervention used, though prophylaxis is preferred in patients receiving intense immunosuppression. The financial implication of specific drugs and laboratory tests is the main barrier for CMV prevention in Thailand. A practical guideline for CMV prevention in KT recipients would be valuable in attempting to resolve these concerns. *Author contributions. J.B. conceptualized, performed data curation and formal analysis, and wrote, reviewed, and edited the manuscript. A.B. performed data curation and reviewed and edited the manuscript. Sa.K. performed formal analysis and reviewed and edited the manuscript. And Su.K. reviewed and edited the manuscript. Financial support. * None reported. *Potential conflicts of interest. * All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.	{ "pile_set_name": "PubMed Central" }
Association lashes out at the UberKittens promotion this week with its own donation to Wildlife Victoria The Victorian Taxi Association (VTA) has pounced on Uber’s ‘UberKittens’ promotion earlier this week with its own donation – this time, to Wildlife Victoria. The association announced it had made a contribution today to Wildlife Victoria in support of their efforts to rescue and assist injured, orphaned or distressed native animals. In its initial statement, the VTA said the donation was a direct response to the ‘UberKittens’ promotion, which it labelled the “latest in a string of glib marketing campaigns from a company more interested in finding ways to promote their own brand than providing a safe and legal transport service”. The group had initially said the donation was aimed at helping Wildlife Victoria control "feral" wildlife. This has since been amended and clarified as a donation to assisting Wildlife Victoria's emergency response services in helping injured, orphaned, sick and distressed native animals. The VTA criticised the timing of Uber’s feline stunt, pointing to hearings for 11 UberX drivers in the Melbourne Magistrate’s Court yesterday following prosecution by the Taxi Services Commission. The hearing has since been delayed. “Uber’s efforts should focus more on preventing alleged incidents like those that happened on New Year’s Day and complying with Victorian law,” the association stated. “Our contribution to Wildlife Victoria will support efforts to combat the impact of introduced species on the Australian landscape.” The VTA also pointed people to a petition on Change.org against Uber using rescue animals for a PR stunt: https://www.change.org/p/uber-please-end-using-rescue-animals-for-a-pr-stunt-cute-for-us-but-terrifying-for-these-babies. At time of press, more than 900 people had signed the petition online. For the Uber Kitten promotion yesterday, the shared car services company has partnered with animals shelters across six Australian cities to bring kittens to its customers while they’re in the office for a 15-minute cuddle. The initiative was aimed at encouraging Australians to put their disposable income into caring for neglected animals and asked consumers to donate $40 for the privilege. While it was successful when it first debuted in the US last year, the Australian promotion has provoked some concerns for the welfare of these furry friends. The rather controversial PR stunt also comes after Uber was forced to recognise a number of high-profile issues with its service, such as a surge in pricing during the Sydney Siege, and allegations of rape against one of its drivers in Sydney on New Year's Day. Director of CP communications and author of From Unknown to Expert, Catriona Pollard, said the one thing Uber’s kittens stunt did successfully was grab attention. “It used two things almost everyone loves - baby animals and cute cat photos - and combined them with the virility of social media. On the surface, the adorable factor was through the roof. It was also clever in highlighting Uber’s offering,” she commented. “But we stop there. With any public stunt of this nature, careful thought needs to be put into considering the potential negative fallout.” In this case, Uber and/or its agency partner didn’t cater for animal lover backlash or subsequent petition, Pollard said. The VTA’s response to the Uber stunt, meanwhile, is unnecessary, reactionary and also potentially risky, Pollard said. “There’s no authenticity there,” she claimed. “When a brand goes head-to-head with its competitors in a marketing sense, it’s very risky and very rarely results in a positive outcome. This is a perfect example of that. “VTA needs to stick to its own strategy, its own messages, rather than get lured into public mud-slinging matches with rivals. This is not the road to social media or business success.” Editor's note: This article has been amended following clarification from Wildlife Victoria that its efforts are around rescuing distressed native animals, not feral cats, as previously stated. Follow CMO on Twitter: @CMOAustralia, take part in the CMO Australia conversation on LinkedIn: CMO Australia, or join us on Facebook: https://www.facebook.com/CMOAustralia	{ "pile_set_name": "OpenWebText2" }
Have Unlimited I want to know how to get out of my contract? I was lied to, was sold an unlimited plan and told it would slow down during congested times, I was not told it would stop after 150g, which it does, can't do anything majority of the time	{ "pile_set_name": "Pile-CC" }
Impact of an assisted reassessment of antibiotic therapies on the quality of prescriptions in an intensive care unit. The study's objective was to assess the impact of a professional multifaceted intervention designed to improve the quality of inpatient empirical therapeutic antibiotic courses at the time of their reassessment, i.e. 24 to 96 hours after treatment initiation. We conducted a 5-month prospective pre- and post-intervention study in a medical Intensive Care Unit (ICU) in a teaching hospital, using time-series analysis. The intervention was a multifaceted professional intervention combining systematic 3-weekly visits of an infectious diseases specialist to discuss all antibiotic therapies, interactive teaching courses, and daily contact with a microbiologist. Eighty-one antibiotic prescriptions were assessed, 37 before and 44 after the intervention. The prevalence of adequate antibiotic prescriptions was high and not statistically different before and after the intervention (73% vs. 80%, P=0.31), both for sudden change (P=0.67) and linear trend (P=0.055), using interrupted time-series analysis. The intervention triggered a more frequent reassessment of the diagnosis between day 2 and day 4 (11% vs. 32%, P=0.02) and slightly improved the adaptation of antibiotic therapies to positive microbiology (25% before vs. 50% after, P=0.18). Our multifaceted intervention may have improved the quality of antibiotic therapies around day 3 of prescription, but the difference did not reach statistical significance, possibly because of a ceiling effect.	{ "pile_set_name": "PubMed Abstracts" }
Q: Downloadable font on firefox: bad URI or cross-site access not allowed I'm a webmaster at http://www.beperk.com (I'm giving you the URL so you are able to check the problem) and I'm having lots of problems using @font-face in CSS. I want to use the foundicons from zurb dot com so I hosted them at Amazon S3. I set up the bucket to allow crossdomain access as specified here: http://docs.aws.amazon.com/AmazonS3/latest/dev/cors.html#how-do-i-enable-cors And everything started to work seamless at webkit, trident and gecko... mostly: when browsing the web with firefox (version 17, 18 and 19 tested) all the icons fails randomly with this error: Timestamp: 22/02/13 13:18:01 Error: downloadable font: download failed (font-family: "GeneralFoundicons" style:normal weight:normal stretch:normal src index:1): bad URI or cross-site access not allowed And I say randomly since after a full reload of the page (with control/command + R) every single icon appears normally to fail again after some visits. Can anyone find the problem? A: On your server you will need to add: Access-Control-Allow-Origin To the header of the font files, so for example if you are using Apache you can add this to the .htaccess: <FilesMatch "\.(ttf\|otf\|eot\|woff\|woff2)$"> <IfModule mod_headers.c> Header set Access-Control-Allow-Origin "*" </IfModule> </FilesMatch> A: If anyone are using local resource and facing this problem in firefox. You can go to about:config and change the security.fileuri.strict_origin_policy preference to false. see : https://developer.mozilla.org/en-US/docs/Same-origin_policy_for_file:_URIs A: try to use implemented base64-encoded fonts like: @font-face { font-family:"font-name"; src:url(data:font/opentype;base64,[paste-64-code-here]); font-style:normal; font-weight:400; } see: http://sosweetcreative.com/2613/font-face-and-base64-data-uri it worked perfectly.	{ "pile_set_name": "StackExchange" }
Q: Use javascript/jquery to append URL? Is it possible to use javascript/jquery to append something on the end of a url when a link is clicked? For example, I have 5 tabs on a page (product.php), when I click a tab, then that tab opens. What I want to do is have the URL change to product.php#tab-3 (or whichever number tab is clicked) when you click on it. The reason I am doing this is so that users will be able to bookmark the page on a specific tab. Thanks A: No need to use JavaScript: <a href="#tab3">click</a> You can still use JavaScript if you need it though: location.hash = "tab3";	{ "pile_set_name": "StackExchange" }
var github = (function(){ function escapeHtml(str) { return $('<div/>').text(str).html(); } function render(target, repos){ var i = 0, fragment = '', t = $(target)[0]; fragment += '<ul class="list-group" id="github">'; for(i = 0; i < repos.length; i++) { fragment += '<li class="list-group-item"><a href="'+repos[i].html_url+'">'+repos[i].name+'</a><p><small>'+escapeHtml(repos[i].description\|\|'')+'</small></p></li>'; } fragment += '</ul>'; t.innerHTML = fragment; } return { showRepos: function(options){ $.ajax({ url: "https://api.github.com/users/"+options.user+"/repos?callback=?" , dataType: 'jsonp' , error: function (err) { $(options.target + ' li.loading').addClass('error').text("Error loading feed"); } , success: function(data) { var repos = []; if (!data \|\| !data.data) { return; } for (var i = 0; i < data.data.length; i++) { if (options.skip_forks && data.data[i].fork) { continue; } repos.push(data.data[i]); } repos.sort(function(a, b) { var aDate = new Date(a.pushed_at).valueOf(), bDate = new Date(b.pushed_at).valueOf(); if (aDate === bDate) { return 0; } return aDate > bDate ? -1 : 1; }); if (options.count) { repos.splice(options.count); } render(options.target, repos); } }); } }; })();	{ "pile_set_name": "Github" }
Thank you for your interest in Securing the Virtual Environment: How to Defend the Enterprise Against Attack (Valued at $50). We apologize that TradePub.com is no longer able to fulfill requests for this offer. Based on your selection, however, one or more of the following may be of interest to you:	{ "pile_set_name": "OpenWebText2" }
Get Spoon University delivered to you By adding your email you agree to get updates about Spoon University Healthier Where are you before the food is set out? Eating snacks and watching tvHaving a bit too much beerHelping the host cook and set-upChatting it up with everyone and playing with the kids There’s a pool. Do you go for a swim? No, I hate getting wet.Of course! And I’ll be sure to push someone else in tooI’d feel too guilty for not helping out If it’s nice out, why not? Where are you when it starts to rain? Breaking out the water guns. Everyone’s wet now anyway, what’s the harm?Sulking, upset that your food got soggyHelping put everything in the house. You won’t let some rain ruin the fun!Still laughing and having conversations with everyone. Rain doesn’t bother you! Ketchup or mustard on a hotdog? 100% ketchupNeither. Less messy that way!Mustard all the way. How dare someone ruin a classicBoth! Someone at the party falls. What do you do? Show your concern, but stay in the backgroundTell the person a story of when you fell to make them feel betterPoint and laughGet the first aid kit, and run over to help! The answer is: Photo by Kate Bentsen Hamburger You’re a traditional kind of person who knows exactly what you want. You come to the party right on time and hate when things don’t go as expected. You never try any new foods and get annoyed when people change classic recipes. The answer is: Photo by Kelly Logan Baked Beans People usually love baked beans or they don’t. Same goes for you. You’re the person that usually has a bit too much to drink at BBQs, and can get a little out of hand. You’re always telling jokes, and you love a good prank. The answer is: Photo by Tiare Brown Corn on the Cob Corn on the cob, while delicious, always gets stuck in your teeth. You’re the type of person that tries to please and help everyone, but ends up getting a bit too involved. You help so much that you don’t even get to enjoy yourself! The answer is: Photo by Rachel Piorka Cupcake Cupcakes are sweet, just like you! You’re the life of the party and everyone looks forward to seeing you. You’re fun, friendly and nothing ever seems to bring you down!	{ "pile_set_name": "Pile-CC" }
Cueva del Milodón Natural Monument Cueva del Milodón Natural Monument is a Natural Monument located in the Chilean Patagonia, northwest of Puerto Natales and north of Punta Arenas. The monument is situated along the flanks of Cerro Benitez. It comprises several caves and a rock formation called Silla del Diablo (Devil's Chair). The monument includes a cave which is notable for the discovery in 1895 of skin, bones and other parts of a giant ground sloth called Mylodon darwini. It is also part of the End of the World Route, a scenic touristic route. Milodón Cave The largest cave in the monument is the long Milodón Cave. It was discovered in 1895 by Hermann Eberhard, German explorer of Patagonia. He found a large, seemingly fresh piece of skin of an unidentified animal. In 1896 the cave was explored by Otto Nordenskjöld and later it was recognized that the skin belonged to Mylodon – an extinct animal which died 10,200–13,560 years ago. In the cave and other caves of the monument have been found remnants of other extinct animals and human remnants. At the entrance of the monument is a life size replica of the prehistoric Mylodon, which was a very large herbivore, somewhat resembling a large bear. It became extinct at the end of the Pleistocene Epoch. Mylodon remains Investigations determined the survival of the Milodon until about 5,000 years ago and confirmed the existence of other animals, such as the "Dwarf Horse" Hippidion, the saber-toothed cat Smilodon and the litoptern Macrauchenia Human remains Diverse elements of human habitation are found at Cueva del Milodón including fire-fractured rock, lithic tools and human remains. Human habitation at Cueva del Milodón is dated as early as 6000 BC. Panorama See also Cerro Toro Eberhard Fjord Martin Gusinde Anthropological Museum Hippidion saldiasi References Category:Protected areas of Magallanes Region Category:Archaeological sites in Chile Category:Natural monuments of Chile Category:Paleontology in Chile Category:Pleistocene paleontological sites of South America Category:1895 in paleontology	{ "pile_set_name": "Wikipedia (en)" }
Cross-country skiing at the 2018 Winter Paralympics – Women's 1.5 km sprint classical The women's 1.5 kilometre sprint classic competition of the 2018 Winter Paralympics was held at Alpensia Biathlon Centre in Pyeongchang. The competition took place on 14 March 2018. Medal table Visually impaired Qualification The qualification was held at 11:25. Semifinals Semifinal 1 Semifinal 2 Final The final was held at 14:16. Standing Qualification The qualification was held at 10:50. Semifinals Semifinal 1 Semifinal 2 Final The final was held at 13:48. Sitting Qualification The qualification was held at 10:17. Semifinals Semifinal 1 Semifinal 2 Final The final was held at 13:20. See also Cross-country skiing at the 2018 Winter Olympics References Women's 1.5 kilometre sprint classical Para	{ "pile_set_name": "Wikipedia (en)" }
Introduction {#s1} ============ Toxoplasma gondii is an obligate intracellular apicomplexan protozoan parasite that can infect all warm-blooded animals, mainly through oral and congenital infections (Tenter et al., [@B34]; Elmore et al., [@B11]; Zhou et al., [@B39]). This parasite has a significant medical and socioeconomic importance because it infects over two billion people worldwide. It is the causative agent of toxoplasmosis, an important zoonotic disease that can cause serious, even fatal health consequences in immunocompromised individuals, such as AIDS patients and organ transplant recipients (Liu et al., [@B22]; Xiao et al., [@B38]; Chemoh et al., [@B9]). Infection in immunocompetent individuals are generally asymptomatic, however the parasite persists as bradyzoites-containing cysts in brain and muscle tissues for many years. Primary infection in pregnant women can lead to fetus death, deformity, abortion, and long-term damage of the eye and central nervous system (Hill and Dubey, [@B19]). The remarkable ability of T. gondii to invade and colonize virtually all nucleated cells (Morisaki et al., [@B25]), and to adopt a successful intracellular lifestyle depends partly on the sequential secretion of effectors from the specialized secretory organelles micronemes, rhoptries and dense granules (Håkansson et al., [@B17]; Boothroyd and Dubremetz, [@B4]; Nadipuram et al., [@B26]). T. gondii tachyzoites enter the host cells through an active invasion mechanism and replicate within a membrane-bound parasitophorous vacuole (PV) inside the surrogate host cell cytoplasm (Coppens et al., [@B10]; Nam, [@B27]). After release from the host cell, newly formed parasites invade new mammalian host cells, and the replication cycle starts again. Most of the dense granule proteins (GRAs) are destined to the PV and parasitophorous vacuole membrane (PVM), and contribute to the biogenesis and maturation of the PV, and nutrient acquisition (Mercier and Cesbron-Delauw, [@B24]). Some GRA proteins have the ability to traffic to the host cytoplasm or nucleus and interfere with host cell signaling pathways. For example, GRA6 is a polymorphic dense granule protein and activates the host transcription nuclear factor of activated T cells 4 (NFAT4) in order to manipulate host immune responses to maximize the parasite virulence in a strain-specific manner (Ma et al., [@B23]). GRA15 is another strain-specific effector that activates NF-κB pathway and induces IL-12 secretion in type II, but not type I or III genotypes. GRA15-deficient type II strain cannot activate NF-κB pathway or induces IL-12 secretion, hence GRA15-deficient type II strains grow faster compared with wild-type strains (Rosowski et al., [@B29]). GRA16 and GRA24 also manipulate host gene expression and signaling pathways (Bougdour et al., [@B5]; Braun et al., [@B6]). GRA17 mediates the transfer of small molecules between the host cell and PV, and maintains the stability of the PV (Gold et al., [@B16]). GRA7, GRA25, and GRA39 are also virulence factor and can interfere with host cell signaling pathways (Alaganan et al., [@B1]; Shastri et al., [@B30]; Nadipuram et al., [@B26]). GRA22 and GRA41 are involved in the parasite egress (Okada et al., [@B28]; LaFavers et al., [@B21]). Despite the wealth of information regarding T. gondii\'s 40+ GRAs including sequence variation and expression of GRA coding genes, and their roles in the infection process, the contribution of many GRAs to the parasite growth and virulence are still unclear. The CRISPR-Cas9 system provides a novel and promising tool for editing T. gondii genes (Shen et al., [@B32]) and the genome (Sidik et al., [@B33]; Wang et al., [@B35]; Shen et al., [@B31]). Using CRISPR-Cas9 to target T. gondii\'s GRA genes may ultimately offer a new approach to achieving functional cure to toxoplasmosis. In this study, we used the CRISPR-Cas9 technique to edit 17 GRA genes, namely GRA11, GRA12 bis, GRA13, GRA14, GRA20, GRA21, GRA28-31, GRA33-38, and GRA40 in the virulent T. gondii RH strain and examined the effects of gene loss on the parasite\'s ability to grow and exit from host cells in vitro and to cause death in mice. Materials and methods {#s2} ===================== Parasite and cell cultures -------------------------- Tachyzoites of T. gondii RH strain (type I) were maintained in vitro by passages in human foreskin fibroblast (HFF, ATCC, Manassas, VA, USA). HFF cells were grown in 75-cm^2^ tissue culture flasks containing Dulbecco\'s Modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 10 μg/ml gentamycin, at 37°C under a 5% CO~2~ atmosphere. To purify tachyzoites, infected HFF cells were lysed through a 27-gauge needle and the tachyzoites were filtered using a 5 μm pore size Millipore filter. The number of purified parasites was counted using a hemocytometer under a phase-contrast microscopy. Construction of GRA knockout T. gondii strains using CRISPR-Cas9 ------------------------------------------------------------------ GRA knockout strains were constructed by using CRISPR-Cas9 as previously described (Wang et al., [@B36]). All plasmids, primers, and gRNAs used in this study are listed in Table [S1](#SM1){ref-type="supplementary-material"}. Briefly, sgRNA of each GRA was engineered into pSAG1::CAS9-U6::sgUPRT by PCR using the Q5 Mutagenesis Kit (NEB). Positive plasmid was extracted with Endo-Free Plasmid DNA Mini Kit Protocols (OMEGA). The resistance cassettes (DHFR^\^-Ts) were amplified from the plasmid pUPRT-DHFR-D and purified by agarose gel electrophoresis. About 40 μg positive plasmids and 15 μg purified DHFR^\^-Ts amplicons were co-transfected into freshly harvested T. gondii RH tachyzoites by electroporation. GRA-deficient tachyzoites were selected with pyrimethamine and examined by PCR analysis. Stable clones were confirmed by reverse transcription PCR (RT-PCR) by comparison to WT strains. Total RNA was extracted from tachyzoites of wild type (WT) or ΔGRA mutant T. gondii strains using TRIzol (Invitrogen). Reverse transcription was performed using a PrimeScriptTM 1st Strand cDNA Synthesis Kit (TaKaRa). The central region of each target gene cDNA was amplified by RT-PCR using specific primers (see Table [S1](#SM1){ref-type="supplementary-material"} in the Supplemental Material). Assessment of parasite growth using plaque assay ------------------------------------------------ The growth rates of individual GRA-deficient and WT RH strains were determined in HFF cells. Cells were grown to confluence overnight in 6-well cell culture plates. The cells were then infected with tachyzoites of ΔGRA mutant and WT RH strains (\~200 tachyzoites/well). Cells were incubated for 3 h to allow the parasites to enter the host cells and were then washed twice with sterile 1 × phosphate-buffered saline (PBS) to remove unbound parasites, and fresh medium was added. The plates were incubated for 7 days at 37°C in 5% CO~2~ environment. Then, the culture medium was removed and infected HFF cells were fixed with 4% paraformaldehyde in PBS (pH 7.4) for 15 min at ambient temperature. Then, fixed cells were incubated with crystal violet staining solution (2% \[wt/vol\] crystal violet, pH 7.4) for 10 min at ambient temperature. The size of plaques (i.e., areas in the cell culture devoid of cells caused by the proliferating parasites) was determined using inverted microscope as previously described (Wang et al., [@B37]). This experiment was performed in triplicate and the experiments were repeated three independent times. Egress assay ------------ Asexual reproduction of T. gondii culminates with the egress of the newly formed tachyzoites from the surrogate host cell and subsequent parasite invasion into new host cells. Therefore, parasite egress represents a very important event which is indispensable for the parasite dissemination in the host body. In order to determine the role of the GRAs in this important process, we examined the effect of ionophore A23187 modulating Ca2^+^ homeostasis on the egress of the parasite from the host cells. Briefly, HFF cells were incubated with 10^5^ freshly harvested T. gondii tachyzoites in 2 ml culture medium for 3 h, followed by washing twice with DMEM medium to remove the unbound parasites. After 30--36 h of incubation, the wells were washed twice with sterile PBS and 3 μM calcium ionophore A23187 (Sigma) diluted in DMSO were added to the HFF cells. Live cell microscopy was used to monitor the timing of parasite egress from HFF cells infected with the WT strain compared with HFF cells infected with the mutant strains after addition of 3 μM calcium ionophore A23187. Mouse infection with GRA-deficient strains -------------------------------------------- Specific-pathogen-free (SPF) inbred female BALB/c mice (8 weeks-old) were purchased from Center of Laboratory Animals, Lanzhou Veterinary Research Institute, Lanzhou, China. Mice (5 mice/cage) were housed in a SPF environment within the animal care facility during the experiment. Each mouse was injected intraperitoneally with 200 freshly harvested tachyzoites of GRA-deficient or WT RH strain (10 mice per strain). The negative control mice were injected with an equal amount PBS only. All mice were monitored daily for the signs of illness and time of death. Bioinformatics analysis of T. gondii dense granule proteins ------------------------------------------------------------- Information on the genomic features (signal peptide, the number of exons and transmembrane domains) and time-series expression data of the GRA genes by the parasite cell cycle phases, parasite life cycle stages (the oocyst, tachyzoite, and bradyzoites), and the parasite genotypes were downloaded from ToxoDB (<http://ToxoDB.org>; Gajria et al., [@B14]). GRA gene expression data were processed using Robust Multiarray Average (RMA) algorithm of the Partek Genomics Suite package (Partek, Inc, St Louis, MO, USA). Statistical analysis -------------------- Statistical analysis for the in vitro and in vivo experiments was carried out using Graphpad Software package (GraphPad Software, La Jolla, CA). All experiments in the present study were conducted with at least 3 replicate and data were shown as means ± standard deviations (SD). Significant differences between means were determined by Student\'s t-test. P-values below 0.05 were considered significant. Results and discussion {#s3} ====================== In this study, we assessed the impact of targeted disruption of the individual 17 GRA genes (GRA11, GRA12 bis, GRA13, GRA14, GRA20, GRA21, GRA28-31, GRA33-38, and GRA40) on the ability of the virulent T. gondii RH tachyzoites to grow and exit from the cultured HFF cells. We also examined the impact of the disruption of GRA genes on the virulence of T. gondii in BALB/c mice. Generation of single ΔGRA knockout RH strains ----------------------------------------------- CRISPR-Cas9 technique was used to disrupt the GRA genes in type I RH strain. We designed RNA-guided CRISPR-Cas9 targeting T. gondii 17 GRA genes individually. The larger pyrimethamine-resist fragment (DHFR^\^-Ts) was designed for inserting into the sgRNA-targeted coding region causing frameshift mutation for GRA proteins (Figure [1A](#F1){ref-type="fig"}). Then, single clones were identified by PCR, and small fragment (\~500 bp) was not amplified in GRA-deficient strains due to the insertion of the large DHFR^\^-Ts fragment with short extension time, however it was detected in the WT strain (Figures [1B,C](#F1){ref-type="fig"}). RT-PCR was used to amplify cDNA products, reverse transcribed from mRNA, of each GRA gene. Our result showed that CRISPR-Cas9 abolished the expression of GRA genes in the transfected strains compared with the WT strains (Figures [1D,E](#F1){ref-type="fig"}), indicating that the target GRA genes were mutated at the Cas9 cleavage sites and that 17 ΔGRA mutant strains were successfully generated. ![Overview of the CRISPR/Cas9 system and mutation analysis of Toxoplasma gondii dense granule proteins (GRA) genes. (A) Schematic representation of CRISPR-Cas9 system used for disrupting the 17 GRAs genes by insertion of DHFR^\^-Ts cassette. (B,C)* Diagnostic PCR shows GRA gene disruption in the mutants compared to the wild-type strain. The KO-forward and KO-reverse primers were used to amplify the small fragment with 30 s extension time. (D,E) RT-PCR of mRNA from parental RH (WT) and GRA-deficient strains, showing that the 17 GRA\'s coding sequences were successfully disrupted. Marker denotes the DNA ladder.](fcimb-08-00300-g0001){#F1} Deletion of GRA genes did not affect the parasite growth and egress --------------------------------------------------------------------- After confirming knockout by RT-PCR, we compared the plaque formation in HFF monolayers grown in 6-well culture plates 7 days after infection with 200 tachyzoites of wild-type and ΔGRA mutant strains by conventional crystal violet staining and microscopic examination. As shown in Figure [2A](#F2){ref-type="fig"}, no significant differences in the size of plaques were observed in cells infected with wild-type compared to cells infected with ΔGRA mutant strains (p = 0.1582). Next, we evaluated the role of GRAs in the parasite egress. The infected HFF cells were treated with 3 μM calcium ionophore A23187 and the timing of the parasite exit from the cells was monitored over 5 min (Figure [2B](#F2){ref-type="fig"}). No significant difference in the parasites egress was observed between ΔGRA mutants and WT strains. The 17 GRA KO strains and the WT strains remained within the PV after stimulation with DMSO. Calcium is a critical mediator of T. gondii invasion and egress processes. The calcium ionophore A23187 can stimulate the parasite to exit from the PV to the extracellular space (Arrizabalaga et al., [@B2]; Caldas et al., [@B8]). GRA41 can regulate the timing of egress and the sensitivity to calcium (LaFavers et al., [@B21]). However, none of the 17 GRA mutant strains tested in the present study seem to be responsive to the action of the A23187. In agreement with our results, a previous study has shown that deletion of 15 rhoptry organelle proteins ROPs (ROP10, ROP11, ROP15, ROP20, ROP23, ROP31, ROP32, ROP33, ROP34, ROP35, ROP36, ROP40, ROP41, ROP46, and ROP47) did not suppress the parasite\'s ability to grow in HFF cells or alter its pathogenicity for BALB/c mice (Wang et al., [@B37]). This lack of effect of GRA deletion on the phenotype of single parasite mutants argues for possible redundancy of function for GRAs. ![Phenotypic characterization of GRA Knockouts in vitro. (A) Two hundred freshly harvested T. gondii tachyzoites of WT RH strains and GRA-deficient RH strains per well were added to monolayers of HFF cells in 6-well culture plates. After 7 days, the number of plaques caused by the parasite\'s proliferation was counted using a microscope. No differences were detected in the number of plaques produced by wild-type (WT) RH strain vs. any of the GRA knockout strains. (B) Representative images show the parasite egress of the parental WT RH strain and one of the GRA mutant RH strains (Δgra11). Live cell imaging showed a similar egress pattern between WT and all mutant parasites after addition of 3 μM calcium ionophore A23187 at the indicated time points.](fcimb-08-00300-g0002){#F2} GRA deletion did not alter the parasite virulence in mice ----------------------------------------------------------- We tested whether deletion of GRA genes in T. gondii RH strains would cause any changes in the parasite virulence. We inoculated female BALB/c mice intraperitoneally with 200 T. gondii tachyzoites (wild-type or mutants) and monitored the mortality and signs of illness on a daily basis. All mice died within 7--9 days (Figure [3](#F3){ref-type="fig"}), suggesting that the 17 GRA genes tested in the present study might not contribute to the parasite virulence during infection. Previous studies have shown that some of dense granule proteins such as GRA25 may regulate the production of CCL2 and CCL1 in macrophages and thus affect virulence, which was different between Type II and Type III strains (Shastri et al., [@B30]). GRA39 is also an important virulence factor in Type II strains (Nadipuram et al., [@B26]). However, our results did not show any significant differences between WT and ΔGRA mutant strains. The fact that ΔGRA strains did not display any reduction or loss of pathogenicity in mice suggests that deletion of a single gene might not be enough to influence the highly virulent RH strain in which the knockout was performed. More research is required to elucidate the impact of individual or multiple GRA gene deletion on the phenotype and virulence of T. gondii strains. It is possible that these GRA genes have roles in the pathogenesis of T. gondii, but in T. gondii strains of other genotypes or in other hosts. Disruption of these GRAs in avirulent and more physiologically relevant cystogenic strains may allow the assessment of more subtle roles in the virulence, alteration in cyst formation or tissue tropism. ![Survival of BALB/c mice infected with Toxoplasma gondii wild-type or GRA-deficient RH strains. The mice were injected i.p., with 200 freshly harvested tachyzoites of the indicated strains. Ten mice were used per parasite strain. The survival time was recorded daily until all the mice have died within 7--9 days post challenge.](fcimb-08-00300-g0003){#F3} Sequence and expression analyses of GRAs in T. gondii --------------------------------------------------------- More than one-third of T. gondii mRNAs exhibit a tightly regulated expression pattern, probably driven by the diverse cell-cycle-dependent processes mediated by the parasite in the course of infection (Behnke et al., [@B3]). We mapped the transcriptomic data of the 17 GRAs available in ToxoDB and found that the expression profile of the majority of GRAs do not follow a particular cell cycle pattern, and that GRA11 and GRA12 bis expression level was low (Figure [4A](#F4){ref-type="fig"}). Bioinformatics features of GRAs, such as the number of exons, signal peptide and transmembrane domains are summarized in Table [1](#T1){ref-type="table"}. The majority of the known GRAs include a signal peptide at the N terminus and a single transmembrane domain in the C-terminal part of the protein. We found that some GRAs encode multi-exons (even eight) and a small amount of GRAs do not have a signal peptide or a transmembrane domain. The signal peptide plays an important role in protein targeting and protein translocation in and eukaryotic cells and is considered as a feature of the GRA proteins that enter the secretory pathway (Hakimi and Bougdour, [@B18]). Most of the previously identified GRA proteins have been predicted to contain classical or non-classical signal peptide, such as GRA1, GRA2, GRA6, GRA9, GRA16, and GRA21, whereas other GRAs (GRA10, GRA15, GRA20, and GRA22) did not (Mercier and Cesbron-Delauw, [@B24]). However, a few GRAs do not seem to depend on signal peptide to enter the secretory pathway, such as GRA5, which is secreted into the PV as a unique soluble protein and then binds to the PVM (Gendrin et al., [@B15]). Some GRA proteins lack the transmembrane domain, typically GRA19, GRA20, and GRA21, and may interact with the PVM through protein-protein interactions (Hsiao et al., [@B20]). Other GRAs (38, 39, and 40) lack the transmembrane domains or other identifiable sequences for membrane association, suggesting they are soluble protein of the PV (Nadipuram et al., [@B26]). It is possible that GRAs that lack signal peptide or transmembrane domain perform their roles by as yet unknown mechanisms. ![The trend charts of the distinct expression profiles of Toxoplasma gondii GRAs. (A) Time-series expression profile of 17 GRA genes of T. gondii RH strain by cell cycle phases of the parasite as described by Behnke et al. ([@B3]). (B) Transcriptomic expression profiles of 17 GRA genes in Type I (RH and GT1), Type II (Pru and ME49), and Type III (CTG and VEG) strains. (C) Transcriptomic profiles of 17 GRA genes related to the parasite life cycle stages (oocyst, tachyzoite and bradyzoite). Expression profile of 17 GRA genes of the oocysts recovered from cat feces, at 0 day (unsporulated), 4 days (4 day sporulated), and 10 days (10 day sporulated), tachyzoites grown for 2 days in HFF cells (2 day in vitro), bradyzoites grown in HFF cells for 4 days and 8 days (4 day in vitro and 8 day in vitro), and 21 days tissue cyst-containing bradyzoites harvested from infected mouse brains (21 day in vivo). Each line represents the expression value of the corresponding gene. The data were obtained from ToxoDB (36 release) and the graph was generated using GraphPad Prism version 5.0.](fcimb-08-00300-g0004){#F4} ###### Bioinformatics features of GRA proteins of Toxoplasma gondii. Name Gene ID Product description Exons Phenotype value TMHMM[^a^](#TN1){ref-type="table-fn"} Predicted signal peptide Acute infection [^b^](#TN2){ref-type="table-fn"} Chronic infection [^b^](#TN2){ref-type="table-fn"} ----------- ------------------------------ ----------------------------- ----------- --------------------- ------------------------------------------- ------------------------------ ------------------------------------------------------ -------------------------------------------------------- GRA11 [TGGT1_212410](TGGT1_212410) Dense granule protein GRA11 1 ND Yes Yes 5.97 5.21 GRA12 bis [TGGT1_275850](TGGT1_275850) Dense granule protein GRA12 3 1.31 No Yes 3.00 2.63 GRA13 [TGGT1_237880](TGGT1_237880) Hypothetical protein 1 0.76 Yes Yes 120.50 34.28 GRA14 [TGGT1_239740](TGGT1_239740) Dense granule protein GRA14 1 2.00 No Yes 116.36 53.11 GRA20 [TGGT1_200010](TGGT1_200010) Hypothetical protein 2 2.54 No No 37.97 30.74 GRA21 [TGGT1_241610](TGGT1_241610) Hypothetical protein 2 ND No Yes 18.40 13.56 GRA28 [TGGT1_231960](TGGT1_231960) Putative omega secalin 3 1.48 No Yes 33.28 3.58 GRA29 [TGGT1_269690](TGGT1_269690) Hypothetical protein 1 1.54 Yes Yes 47.08 77.60 GRA30 [TGGT1_232000](TGGT1_232000) Hypothetical protein 2 2.29 Yes Yes 33.46 44.61 GRA31 [TGGT1_220240](TGGT1_220240) Hypothetical protein 1 0.90 Yes Yes 33.92 22.57 GRA33 [TGGT1_247440](TGGT1_247440) Hypothetical protein 1 1.72 Yes Yes 48.06 45.42 GRA34 [TGGT1_203290](TGGT1_203290) Hypothetical protein 1 2.26 No Yes 64.29 248.97 GRA35 [TGGT1_226380](TGGT1_226380) Hypothetical protein 1 1.98 Yes Yes 48.74 32.29 GRA36 [TGGT1_213067](TGGT1_213067) Hypothetical protein 1 −0.21 Yes Yes 83.85 24.24 GRA37 [TGGT1_236890](TGGT1_236890) Hypothetical protein 2 2.10 Yes No 60.01 34.21 GRA38 [TGGT1_312420](TGGT1_312420) Hypothetical protein 4 −1.15 No Yes 27.17 17.82 GRA40 [TGGT1_219810](TGGT1_219810) Hypothetical protein 7 0.69 Yes No 114.88 97.16 ND, Not determined. Prediction of transmembrane helices was performed using the TMHMM program version 2.0. Gene expression levels of fragments per kilobase of exon model per million mapped reads (FPKM) at acute (10 days post infection) and chronic infection (28 days post infection). Source: <http://www.toxodb.org/toxo/> \[accessed 26 July 2018\]. We next analyzed the transcriptomic levels of 17 GRAs in different T. gondii genotypes (Type I, II, and III), and found that GRA20 and GRA34 were significantly different among the three genotypes (Figure [4B](#F4){ref-type="fig"}). This difference may be because these two GRAs play different roles in different strains. Levels of the transcriptomic expression of 17 GRA genes across T. gondii developmental stages are presented (Figure [4C](#F4){ref-type="fig"}). Our analysis showed that most GRAs are differentially expressed at different life cycle stages, but GRA11 and GRA21. The expression of some GRA genes can be specifically up- or down-regulated during parasite development (Fritz et al., [@B13]). For instance, the expression of GRA7 was significantly reduced in in vitro 4 day bradyzoites compared to that in the in vitro 2 day tachyzoites and then restored to near tachyzoite\'s levels in the in vitro 21 day bradyzoites (Buchholz et al., [@B7]). The expression of GRA4, GRA6, and GRA8 has been reported to be reduced or even non-detectable in the bradyzoites (Ferguson, [@B12]). The different expression levels of some GRAs in different life cycle stages indicate that the roles played by GRAs may play parasite stage-dependent. Conclusion {#s4} ========== GRAs play key roles in modulating host-parasite interactions, such as parasite vacuole remodeling, nutrient uptake and manipulation of host signaling pathways (Nadipuram et al., [@B26]). In this study, 17 ΔGRA mutant T. gondii strains were successfully generated using CRISPR-Cas9 technique. The role of these 17 GRA genes in the pathogenicity of T. gondii RH strain was investigated in vitro and in vivo. We report here that no significant difference was detected between ΔGRA knockouts and wild-type RH strains. These findings indicate that GRA genes examined in this study are not absolutely essential for T. gondii RH virulence, suggesting that other virulence factors may be involved in these processes or that virulence of T. gondii is the result of a multigene effect. We also investigated the patterns of gene expression and bioinformatics features of the 17 GRAs, by parasite cell cycle phases, life cycle stages and genotypes. Results indicated that the expression of GRAs can vary across life cycle stages or genotypes of T. gondii. Functional analysis of these GRAs in other parasite strains or life cycle forms is therefore of high importance and may further elucidate the pathogenic role of GRAs in T. gondii infection. Ethics statement {#s5} ================ The study was approved by the Animal Administration and Ethics Committee of Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science (Permit No. LVRIAEC-2017-006). All mice were handled humanely in strict accordance with the Guidelines and Animal Ethics Procedures of the People\'s Republic of China. Author contributions {#s6} ==================== X-QZ, J-LW, and HE designed the study and critically revised the manuscript. M-JB performed the experiments, analyzed data, and drafted the manuscript. Q-LL, KC, and L-BN participated in the implementation of the study. All the authors read and approved the final manuscript. Conflict of interest statement ------------------------------ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Professor Bang Shen (Huazhong Agricultural University) for providing the pSAG1::CAS9-U6::sgUPRT and pUPRT-DHFR-D vectors. Funding. Project financial support was kindly provided by the International Science and Technology Cooperation Project of Gansu Province (Grant No. 17JR7WA031), by the Elite Program of Chinese Academy of Agricultural Sciences, and by the Agricultural Science and Technology Innovation Program (ASTIP) (Grant No. CAAS-ASTIP-2016-LVRI-03). Supplementary material {#s7} ====================== The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fcimb.2018.00300/full#supplementary-material> ###### Click here for additional data file. [^1]: Edited by: Kenneth Pfarr, Universitätsklinikum Bonn, Germany [^2]: Reviewed by: Sabrina Absalon, Boston Children\'s Hospital and Harvard University, United States; Renato Augusto DaMatta, State University of Norte Fluminense, Brazil [^3]: This article was submitted to Parasite and Host, a section of the journal Frontiers in Cellular and Infection Microbiology	{ "pile_set_name": "PubMed Central" }
Introduction {#s1} ============ Sensory experience plays an essential role in establishing and refining neural organization during development. In fact, abnormal input or experiential modifications due to injury can produce severe changes in neuronal morphology including alterations in dendritic length, cell size, and can even influence the fate of a cell [@pone.0111243-LeviMontalcini1]--[@pone.0111243-Smith1]. Second-order auditory neurons in the chick brain stem have proven useful in investigating the importance of sensory experience during development [@pone.0111243-Rubel1]. Neurons in the cochlear nucleus, nucleus magnocellularis (NM) receive their sole excitatory input from the cochlea via the ipsilateral eighth nerve [@pone.0111243-Boord1], [@pone.0111243-Parks1]. Thus, unilateral cochlear ablation results in a complete loss of excitatory afferent input to the ipsilateral NM but leaves the contralateral side unaffected, allowing for within-subject comparisons of NM neurons on the intact versus the deafened side of the brain. Elimination of auditory nerve activity during a sensitive period of development leads to the death of approximately 20--30% of NM neurons on the deafened side of the brain [@pone.0111243-Born1]. The remaining neurons survive, albeit at a lower metabolic rate and with a reduction in soma size [@pone.0111243-Born1]--[@pone.0111243-Steward1]. The factors that determine which cells die and which cells survive still remain unclear; however, the chain of events that occur within NM as a consequence of deafening are well documented. Within 1 to 3 hrs following cochlear ablation, NM neurons show a threefold increase in intracellular calcium (\[Ca^2+^\]~i~) [@pone.0111243-Zirpel1], and a decrease in RNA and protein synthesis [@pone.0111243-Steward1], [@pone.0111243-Garden1], [@pone.0111243-Garden2]. At 6--12 hrs, deafened NM neurons appear to segregate into two populations: one population suffers a complete cessation of protein synthesis and eventually goes on to die, while the other population continues to synthesize proteins, albeit at a reduced level, and goes on to survive [@pone.0111243-Steward1]. The cessation of protein synthesis appears to be due to the dissociation of polyribosomes in NM neurons following cochlear ablation [@pone.0111243-Rubel2]. One way to visualize the rapid activity-dependent changes that occur in ribosomes following deafening is by using Y10B, a monoclonal antibody that recognizes a ribosomal epitope [@pone.0111243-Garden1], [@pone.0111243-Garden2], [@pone.0111243-Garden3], [@pone.0111243-Hyson1]. Changes in Y10B immunoreactivity match the changes observed in overall protein synthesis [@pone.0111243-Garden3], and these changes correspond with changes observed in ribosomes at the EM level [@pone.0111243-Garden2], [@pone.0111243-Rubel2]. Consequently, Y10B immunoreactivity provides an efficient and meaningful assay for examining changes in NM ribosomes, one of the earliest cellular changes to occur following deafferentation. Studies directed at identifying the trans-synaptic signals necessary for preventing the early changes that occur in NM neurons following cochlea removal have made use of an in vitro slice preparation of the chick auditory brain stem. In this condition, NM activity is eliminated bilaterally since both cochleae are destroyed. In order to mimic the case of unilateral deafening, auditory nerve fibers are electrically stimulated on one side of the slice while fibers on the opposite side of the same slice remain unstimulated. Within 1 hr, NM neurons on the stimulated side of the slice show greater protein synthesis [@pone.0111243-Hyson2] and Y10B labeling [@pone.0111243-Hyson1], [@pone.0111243-Hyson3], [@pone.0111243-Hyson4] than the neurons on the unstimulated side. Through the use of the in vitro slice preparation, it has been shown that glutamate\'s action on ionotropic glutamate receptors (iGluRs) is responsible for the electrical activity in postsynaptic NM neurons [@pone.0111243-Hyson3], [@pone.0111243-Nemeth1], and glutamate\'s action on metabotropic glutamate receptors (mGluRs) is responsible for providing trophic support to NM neurons [@pone.0111243-Hyson4], [@pone.0111243-Nicholas1], [@pone.0111243-Zirpel2]. Previous in vivo studies have also shown that mGluR activation is necessary for maintaining ribosomal antigenicity of Y10B and for the ultimate survival of NM neurons [@pone.0111243-Carzoli1]. For example, application of selective group I or group II mGluR antagonists results in NM neuronal cell death even with an intact cochlea. Although it is clear that mGluR activation is [necessary]{.ul} to preserve NM neurons in a healthy state, it is not known if mGluR activation is [sufficient]{.ul} to maintain these neurons or if other activity-dependent factors are also required. The present experiments evaluate whether or not activating mGluRs on deafferented NM neurons is sufficient for maintaining ribosomes in a healthy state during the period immediately following deafferentation. If adding mGluR activation to the deprived NM is sufficient to regulate NM neuronal ribosomes, then application of mGluR agonists should preserve ribosomal Y10B antigenicity, which is normally lost in the absence of auditory experience. Materials and Methods {#s2} ===================== Subjects {#s2a} -------- All subjects were 1 to 4 day old chicks of either sex, hatched from eggs obtained from a local supplier and reared at Florida State University. The procedures used in these experiments were approved by the Animal Care and Use Committee at Florida State University and conform to the guidelines set forth by the National Institutes of Health. All efforts were made to minimize the number of animals used and their suffering. Slice preparation {#s2b} ----------------- Subjects were anesthetized with isoflurane and decapitated. A 4 mm segment of the caudal skull containing the brain stem was removed with a razor blade, quickly submerged in room temperature artificial cerebral spinal fluid (ACSF), and was oxygenated using a 95% O~2~, and 5% CO~2~ gas mixture. ACSF consisted of (in mM) 130 NaCl, 3 KCl, 2 CaCl~2~, 2 MgCl~2~, 26 NaHCO~3~1.25 NaH~2~PO~4~ and 10 dextrose. The brain stem was rapidly dissected from the skull segment and mounted onto a custom-built stage for slicing using cyanoacrylate glue with additional support provided by a 30% gelatin compound. Using a vibrating blade microtome, a 300 µm, bilaterally symmetrical, coronal slice containing NM was obtained, transferred to a submersion-type recording chamber, and perfused (2--3 ml/min by gravity) with oxygenated ACSF. The slice was anchored in the recording chamber using nylon-strung metal "harp". Drug administration {#s2c} ------------------- Once the brain slice was placed in the chamber, a glass micropipette was lowered into the bath and positioned over the slice toward the lateral side of the IVth ventricle. Drugs were ejected onto one side of the brain slice using periodic pressure pulses (10 psi, 10--50 msec duration) through a picospritzer (General Valve Corporation, Fairfield, N.J.). The slice was oriented such that the laminar flow of ACSF through the chamber carried the drug only to NM on the outflow side of the chamber. Different groups of slices (n = 4 per group) were unilaterally treated with either vehicle, glutamate (1 mM), the general mGluR agonist, ± trans 1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) (400 µM), a selective group I mGluR agonist, 3,5-dihydroxyphenylglycine (DHPG) (200 µM), or a selective group II mGluR agonist, LY354740 (200 nM) for 1 hr. Drug concentrations in the pipette were selected based on their EC~50~ and predicting an approximately10-fold reduction in concentration by the time the drug flowed to NM. A dose-response curve for glutamate was constructed using concentrations of L-glutamic acid ranging from 0.01 to 10 mM in the ejection pipette (n = 3--4 slices per group). The vehicle was dextrose-free ACSF. Confirmation of unilateral drug application {#s2d} ------------------------------------------- Preliminary tests using fast green were performed to monitor the distribution of solution released by pressure application in order to ensure drug was being administered to only one side of the slice and that minimal backflow was affecting the opposite side of the same slice. Additional confirmation was obtained by ejecting a 1% solution of a fluorescent dextran, tetramethylrhodamine (fluoro-ruby) 10,000 MW (Invitrogen), from the micropipette. Distribution of dye clearly showed that ejected substances primarily, if not exclusively, reached only one NM (see [Figure 1](#pone-0111243-g001){ref-type="fig"}). Dye was used in slices to document the application procedure and was not included for drug-treated slices, so as not to interfere with immunoreactivity. ![Fluorescence image of a brain stem slice containing nucleus magnocellularis (NM) schematically showing the pipette placement at the lateral side of the IV^th^ ventricle and demonstrating the distribution and spread of focally administered drugs.\ Arrows indicate the direction of the laminar flow of fluid in the chamber. White outlines indicate location of NM. This image of Fluoro-Ruby application confirms that agents that are applied using this method will reach NM unilaterally with minimal back-flow affecting the opposite side of the same section.](pone.0111243.g001){#pone-0111243-g001} Tissue preparation {#s2e} ------------------ At the end of the 1-hr period of unilateral drug application, a notch was cut into the ventral portion of the side of the slice that received drug. The section was then post-fixed in 4% paraformaldehyde for 1 hr and cryoprotected in a 30% sucrose/phosphate-buffered saline (PBS) solution overnight. Since all comparisons were performed between opposite sides of the same tissue section, it was necessary to preserve symmetry between sides. This was accomplished by assuring that the slice was mounted flat for sectioning. A mound of tissue freezing medium was built up onto a cryostat chuck to approximately ½ inch in height. The chuck was then loaded into the cryostat and the top of the mound was sectioned off to obtain a flat surface. The 300 µm tissue slice was then placed onto a silanized microscope slide and excess fluid was removed with a kimwipe. The cryostat chuck was then placed on dry ice and a small amount of tissue freezing medium was deposited onto the flattened surface. The slide holding the brain slice was placed tissue-side-down into the fresh medium and a pellet of dry ice was placed on top of the slide to ensure rapid freezing. The microscope slide was then detached using a razor blade, leaving the brain slice embedded in the freezing medium. The mounted brain slice was allowed to equilibrate in the cryostat at −20°C for at least 30 min prior to sectioning. Using a Leica CM 1850 cryostat (Leica Microsystems Inc., Bannockburn, IL, USA), 20 µm sections were then collected from the mounted slice and were free-floated in a vial containing ice-cold PBS. Immunohistochemistry {#s2f} -------------------- Following sectioning, endogenous peroxidase activity was quenched by placing sections in 0.03% H~2~O~2~ in methanol for 20 min. After quenching, sections were rinsed 3×10 min in PBS, and were then preincubated in a 4% normal horse serum solution for 10 min. Sections were then incubated on a rotator overnight at room temperature in 1∶500 Y10B, a mouse monoclonal antibody that recognizes a ribosomal epitope. The Y10B antiserum was raised from a clone originally developed by J. Steitz and subsequently supplied to our laboratory by E. Rubel. This antibody is an established marker of changes in ribosomes [@pone.0111243-Lerner1], and has been used extensively as an indicator of the early changes resulting from deafferentation (e.g., [@pone.0111243-Garden2], [@pone.0111243-Garden3], [@pone.0111243-Hyson1], [@pone.0111243-Carzoli1], [@pone.0111243-McBride1]). Changes in antigenicity appear to match changes in overall protein synthesis and a deafferentation-induced reduction in Y10B labeling has been confirmed at the EM level [@pone.0111243-Garden2]. Control sections processed without primary antibody show no labeling. The following day, sections were washed 3×10 min in PBS then incubated for 1 hr in 1∶200 biotinylated horse anti-mouse secondary antibody. Sections were washed 3×10 min in PBS and then incubated in avidin-biotin-peroxidase complex (Vectastain ABC Kit, Vector Laboratories, Burlingame, CA, USA) for 1 hr. Following 2×10 min washes in PBS and a 10 min wash in 0.1 M phosphate buffer (PB), sections were reacted with diaminobenzidine tetrahydrochloride and 0.03% H~2~O~2~ for 15 min. Sections were mounted onto slides following 2 10-min washes in 0.1 M PB, and allowed to dry overnight. The next day, slides were cleared though graded ethanols and xylenes and then coverslipped using DPX mounting medium (Sigma-Aldrich, St. Louis, MO, USA). Densitometry {#s2g} ------------ To objectively analyze the level of immunolabeling, densitometric measurements of NM neurons were obtained using a digital image analysis program (NIH ImageJ). The staining densities of NM neurons on the drug-treated versus the untreated side of the same tissue section were compared. This within-subjects method improves statistical power. Although immunohistochemistry cannot provide quantitative differences in the amount of protein changed, it has crucial advantages over other methods (e.g., Western analysis) by selectively evaluating changes in neurons and examining if changes occur in all neurons or only a subpopulation of cells. All comparisons were between opposite sides of the same tissue section. This assures that variation in labeling intensity is attributable to the experimental treatment and not to variation in immunohistochemistry processing variables (e.g., incubation time in any of the reagents). For these analyses, the light levels and camera settings remained constant. Cells were visualized using a 40X objective and mean gray scale densities over approximately 40 NM neurons/side in a given tissue section were measured beginning with cells at the medial edge of NM and proceeding laterally. At least 3 sections from each subject were measured. The investigator analyzing the tissue remained blind to the identities of the drug-treated and the untreated sides of the section as well as to the drug group until after measurements were obtained. Differences in the density of labeling between sides of the slice that received ACSF or drug were compared using analysis of variance (ANOVA). Results {#s3} ======= Vehicle treatment to NM on one side of the slice for 1 hr had no apparent effect on Y10B immunoreactivity. Application of glutamate (1 mM) resulted in darker Y10B immunolabeling as did the general mGluR agonist, ACPD 400 µM. Relatively low concentrations of the group I mGluR agonist, DHPG (200 µM), and the potent group II mGluR agonist, LY354740 (200 nM), also resulted in darker Y10B labeling on the drug-treated side of the slice in comparison to the side of the slice that remained unexposed to drug. An example of this effect can be seen in [Figure 2A, B](#pone-0111243-g002){ref-type="fig"}. ![Photomicrograph comparing Y10B labeling between untreated (A) and mGluR agonist-treated (B) sides of the same brain slice.\ In this example, the group I selective mGluR agonist, DHPG, was applied to NM on one side of the slice for 1 hr. Tissue sections were immunolabeled with Y10B, a monoclonal antibody that recognizes a ribosomal epitope. There is darker Y10B immunolabeling of NM neurons on the drug-treated side of the brain section. (C) Percent differences in gray scale density for Y10B labeling between NM neurons on untreated versus drug-treated sides of the same brain slice ((mean treated density-mean untreated density)/mean treated density\100). Bars indicate standard error of the mean. Positive numbers indicate that the treated side had greater labeling for Y10B. Different groups of slices (n = 4 per group) received unilateral application of vehicle, L-glutamic acid, a general mGluR agonist, ACPD, an mGlu group I agonist, DHPG, or an mGlu-group II-selective agonist, LY354740. The vehicle-treated control slices showed no difference in Y10B labeling between sides while treatment with each agonist resulted in a darker Y10B labeling on the drug-treated side of the slice. (D) Dose-response curve plotting the mean percent difference in gray scale density for Y10B labeling following unilateral application of varying concentrations of L-glutamic acid. Positive numbers indicate that the treated side had darker Y10B immunolabeling. As concentration in the ejection pipette increased, the treated NM neurons first showed darker Y10B immunolabeling (at 1 mM) and then showed lighter immunolabeling (at 10 mM). The percent difference in labeling between opposite sides of the same slices was statistically lower at 10 mM than at any other concentration and the percent difference at 1 mM was statistically greater than at 0.01 mM but only marginally greater (p = 0.06) than the 0.1 mM group. These data suggest that the effect of glutamate transitions from neuroprotection at moderate concentrations, to neurotoxicity at high concentrations.](pone.0111243.g002){#pone-0111243-g002} Visual impressions were confirmed through objective analyses of labeling density. The labeling densities of individual NM neurons on the drug-treated versus the untreated side of the same tissue slice were compared. A two-way mixed ANOVA was performed on the gray scale measurements using side of the section as the within-subject variable and drug as the between-subjects variable. This analysis revealed no reliable effect of drug treatment (F (4, 15) \<1), an overall effect of side (F (1, 15) = 52.55, p\<0.001) and, importantly, a reliable drug treatment X side interaction (F (4, 15) = 5.16, p\<0.01). Post hoc (Newman-Keuls) pair-wise comparisons revealed that all agonist-treated groups showed a reliable difference between sides (p\<0.05) whereas control-treated slices demonstrated no reliable difference between sides (see [Figure 2C](#pone-0111243-g002){ref-type="fig"}). The protective effect of glutamate is somewhat surprising given its known excitotoxic effects in other systems (for review see [@pone.0111243-Choi1]). Consequently, a dose response curve was generated over a broad range of concentrations (0.01 to 10 mM) in the application pipette. A relatively low concentration of L-glutamic acid (0.01 mM) produced no difference in Y10B labeling between the glutamate-treated and untreated side of the same slice. Treatment with 0.1 mM glutamate showed only a hint of an effect, but treatment with 1 mM glutamate replicated the first experiment and clearly yielded darker ribosomal labeling in NM neurons on the treated side of the slice compared to neurons on to the untreated side of the same slice. While the percent difference between sides following 1 mM glutamate treatment was slightly lower that that obtained in the first experiment, this difference between experiments was not statistically significant (t-test, p = .22). A high concentration (10 mM) had the opposite effect, in that the glutamate had detrimental effects on Y10B labeling on the glutamate-treated side of the slice when compared to the untreated side of the same slice. Visual impressions were confirmed through objective analyses of staining density. The staining densities of individual NM neurons on the glutamate-treated versus the untreated side of the same tissue slice were compared. A two-way mixed ANOVA was performed on the gray scale density measurements using side of brain as the within-subjects variable and glutamate concentration as the between-subjects variable. Neither main effect of side (F (1,10) = 0.34, p\<1)) nor effect of concentration (F (3,10) = 3.34, p = 0.063)) was statistically significant. Importantly, there was a statistically significant Side X Concentration interaction (F (3,10) = 20.08, p\<0.0001). To further compare the effect of glutamate concentration between groups, density measurements were normalized across brains by transforming gray scale scores to percent difference ((treated-untreated)/treated \100). A one-way ANOVA on the percent difference scores revealed a reliable dose effect (F (3,13) = 13.3, p\<0.001). Post hoc (Newman-Keuls) pair-wise comparisons (p\<0.05) revealed that the percent difference in labeling for the 1 mM group was significantly higher than the 0.01 mM group but was only marginally different from the 0.1 mM group (p = 0.06). The 10 mM group showed a statistically reliable percent difference in labeling between sides, albeit in the opposite direction of all other groups (see [Figure 2D](#pone-0111243-g002){ref-type="fig"}). Discussion {#s4} ========== It is widely accepted that early experience is essential to normal brain development. Atypical sensory input during development can have dramatic and potentially damaging effects on the central nervous system that can persist into maturity. A number of classic experiments have demonstrated this by restricting the amount of experience an animal receives through a single sensory modality. Cell death is observed following sensory deprivation in the visual [@pone.0111243-Nucci1], somatosensory [@pone.0111243-Baldi1], olfactory [@pone.0111243-Brunjes1]--[@pone.0111243-Skeen1], vestibular [@pone.0111243-Peusner1], and auditory systems of both chicks and mammals [@pone.0111243-LeviMontalcini1], [@pone.0111243-Webster1], [@pone.0111243-Born1], [@pone.0111243-Hashisaki1], [@pone.0111243-Tierney1]. Despite this common finding across developing sensory systems, relatively little is known about the trophic mechanisms that govern such activity-dependent cell survival. The brain stem auditory system of the chick has proven to be a useful model system for examining the transneuronal signals necessary for activity-dependent cell survival. This is because deafening is relatively easy to produce in the chick. Moreover, the large cochlear nucleus cells form a relatively uniform population of neurons that undergo rapid and robust changes following deafferentation, leading to the ultimate death of a subpopulation of these cells. One early alteration that occurs following deafness in NM neurons is a change in ribosomal activity [@pone.0111243-Steward1]. This change in function corresponds with a reduction in antigenicity for Y10B, a monoclonal antibody that recognizes a ribosomal epitope [@pone.0111243-Garden1], [@pone.0111243-Garden2], [@pone.0111243-Garden3], [@pone.0111243-Hyson2], [@pone.0111243-Lerner1]. A number of studies have made use of the Y10B assay to examine the transneuronal signals necessary for the activity-dependent regulation of NM neurons. Earlier studies, have shown that electrical activity of the postsynaptic NM neuron is not sufficient to maintain NM neuronal ribosomes [@pone.0111243-Hyson1], [@pone.0111243-Hyson2], suggesting activity-dependent release of some important trophic factor from the active auditory nerve terminal. However, blockade of iGluR receptors, which are responsible for driving the electrical activity of NM neurons [@pone.0111243-Nemeth1], does not prevent the activity-dependent regulation of ribosomal antigenicity [@pone.0111243-Hyson3]. This implies that neither iGluR activation nor postsynaptic electrical activity is necessary to keep NM neurons in a healthy state. On the other hand, blockade of mGluRs does prevent this activity-dependent regulation [@pone.0111243-Hyson4], [@pone.0111243-Nicholas1]. The importance of mGluR activation has also been confirmed in vivo where it has been shown that blockade of mGluRs reduces ribosomal antigenicity and produces NM neuronal death even with an intact cochlea [@pone.0111243-Carzoli1]. The current set of experiments demonstrate that providing mGluR activation to NM neurons is sufficient, at least in the early stages that follow deafferentation, to maintain healthy ribosomes. Application of glutamate, a general mGluR agonist (ACPD), a selective group I mGluR agonist (DHPG), or a selective group II mGluR agonist (LY354740), effectively preserved ribosomal antigenicity in NM neurons on the treated side of the slice in comparison to those on the untreated side. Together with previous studies of this system, it appears that mGluR activation is both necessary and, in part, sufficient to provide trophic support to NM neurons, which undergo degenerative changes following the loss of afferent activation that results from deafness. One overall limitation of the studies discussed thus far is that an in vitro slice preparation isolates an individual brain slice from the rest of the body. This allows for the possibility that alternative sources of trophic support have also been eliminated in the slice preparation. Consequently, it is not known if mGluR activation is truly required for maintaining neuronal integrity in the intact system or if mGluR activation is only required when other forms of trophic support are no longer present. If such factors exist, however, they are released independent of auditory nerve activity, since there is no spontaneous activity in either the slice preparation or in vivo following cochlea ablation. Since the activity-dependent regulation of ribosomes is observed in vitro, any such co-factors are not circulating in the cerebrospinal fluid in vivo. The prospective co-factor is also unlikely to be glutamate acting at iGluRs since the present studies used selective agonists for mGluRs and previous studies have shown no effect of total iGluR blockade [@pone.0111243-Hyson3]. Consequently, if a co-factor is required, it is present in deafferented NM in vitro and could be any number of substances provided by glial cells or by synaptic release from neuron terminals that is independent of auditory nerve action potentials. MGluRs and neuroprotection {#s4a} -------------------------- There are various mechanisms by which the different mGluRs could provide for neuroprotection, and these mechanisms can be generally categorized as having either direct or indirect effects on the neuron. One of the direct effects by which mGluRs could be protecting NM neurons is through the control of Ca^2+^ homeostasis. Manipulations of auditory nerve input to NM neurons and in vitro pharmacological treatments produce changes in \[Ca^2+^\]~i~ that correlate with the Y10B assay used in the present set of experiments. For example, in the absence of activity there is a rapid rise in \[Ca^2+^\]~i~, which can be reversed by electrical stimulation of the auditory nerve or mGluR activation [@pone.0111243-Zirpel1], [@pone.0111243-Zirpel2]. Additionally, blockade of mGluRs results in a dramatic rise in \[Ca^2+^\]~i~, even if afferent activity is provided [@pone.0111243-Zirpel2]. It is possible that a change in Ca^2+^ homeostasis is a triggering event that results in the disruption of ribosomes observed in the present experiments. There are unusually high demands placed on chick cochlear nucleus neurons with respect to Ca^2+^ homeostasis. This is because NM neurons see some of the highest rates of activity in the CNS, even in the absence of acoustic stimuli [@pone.0111243-Warchol1]. This requires NM to be equipped with a variety of compensatory mechanisms to help maintain the fine balance of intracellular Ca^2+^ levels. One such mechanism could involve mGluR activation by glutamate overspill that occurs when the usual uptake systems become overwhelmed [@pone.0111243-Rubel3], [@pone.0111243-Rubel4]. In fact, this has been shown to be the case in several brain regions containing glutamatergic neurons that fire at high frequency [@pone.0111243-Gegelashvili1], [@pone.0111243-Min1]. Once activated, mGluRs are known to regulate Ca^2+^ through a number of signal transduction cascades. For example, mGluR activation of the adenylate cyclase cascade in NM can directly inhibit Ca^2+^ influx through voltage-operated calcium channels [@pone.0111243-Lachica1] via adenosine 3′,5′-cyclic monophosphate activation of protein kinase A, while activation of mGluRs that stimulate the phospholipase C cascade can indirectly regulate \[Ca^2+^\]~i~ through the generation of IP~3~ [@pone.0111243-Zirpel3], which subsequently liberates Ca^2+^ from internal stores [@pone.0111243-Zirpel4] and activates protein kinase C. In the present studies, selective agonists for group I and group II mGluRs were able to reduce the loss of antigenicity for Y10B on the side of the slice that was treated with agonist compared to the untreated side of the same slice. Additionally, the combined effect of activating both mGluR groups through use of the non-selective mGluR agonist, ACPD, appeared to be more beneficial than the activation of specific groups, suggesting that activation of both I and II subgroups of mGluRs are important for the regulation of NM ribosomes. There is a chance, however, that the differences in effect seen between drugs could simply be due to variations in the effective potency of the concentrations used and the possibility of synergistic effects was not directly evaluated. A possible indirect mechanism by which mGluR activation could lead to protection is by regulating inhibitory influences on NM neurons [@pone.0111243-Lu1]. Activation of mGluRs has been shown to suppress GABA release to NM neurons, while blockade of mGluRs reportedly increases GABA release [@pone.0111243-Lu2], [@pone.0111243-Lu3]. GABA-ergic transmission in neurons of the avian auditory brainstem is unusual in that it is depolarizing but inhibitory [@pone.0111243-Lu1], [@pone.0111243-Hyson5]. Membrane depolarizations activate voltage-gated Ca^2+^ channels and lead to Ca^2+^ influx, which could be detrimental to the cell. However, mGluR activity may effectively prevent GABA-evoked depolarizations, serving as yet another mechanism by which NM neurons buffer intracellular Ca^2+^. Finally, mGluR activation could also be exerting a neuroprotective effect by working at neighboring glial cells. Previous research in the chick auditory brainstem has demonstrated that there is rapid growth of astrocytic processes in NM following cochlea removal [@pone.0111243-Canady1]--[@pone.0111243-Rubel5]. The neuroprotective effect of mGluRs on glial cells has been documented in several systems. For example, stimulation of cortical glial cells via application of mGluR agonists has been shown to be highly neuroprotective in mixed cultures that have been exposed to toxic levels of NMDA [@pone.0111243-Bruno1]. It has also been suggested that substances released from glial cells in the hippocampus can influence local synapses [@pone.0111243-Liu1]. If this is the case in NM neurons, then it is possible that mGluR activation could promote the release of some trophic substance from astrocytes. Glutamate concentration dependence and technical considerations {#s4b} --------------------------------------------------------------- Although NM neurons are equipped with compensatory mechanisms that allow them to deal with higher levels of glutamate, the current experiments demonstrated that they are not immune to the toxic properties of glutamate. The ability of glutamate to regulate ribosomal antigenicity was contingent on concentration. Reliably darker labeling was observed when 1 mM glutamate was ejected into the media upstream of NM neurons, while a high concentration of glutamate (10 mM) had the opposite effect, yielding lighter labeling on the drug-treated side of the slice when compared to the control side of the same slice. These findings are not unexpected since it is well established that glutamate has neurotoxic properties when released in large amounts or when incompletely recycled (for review see [@pone.0111243-Choi1]). Studies looking at the role of glutamate transporters have shown that clearing glutamate from the synaptic cleft is an important regulatory control of synaptic strength and that this modulation could be traced to mGluRs located on glial cells [@pone.0111243-Turecek1]. It has also been shown that there is a proliferation of glial processes in NM following the cessation of auditory nerve activity [@pone.0111243-Canady1]. Perhaps the important aspect of mGluR activation is on glial cells, which then modulate the uptake of potentially toxic levels of glutamate. While the current experiment used a glutamate concentration of 1 mM in the ejection pipette, focal application through periodic pressure ejection allows for dilution of the drug. A disadvantage of this method of application is the uncertainty about the degree of drug dilution once expelled into the bath, which makes it impossible to know the precise drug concentration at the cell. Whole bath application would have allowed for more accurate dosimetry, but short pressure applications reduce receptor desensitization, and this method of agonist delivery more closely mimics the natural periodic activation by the endogenous transmitters. Similar to the present studies, bath superfusion of the mGluR agonist, ACPD has been shown to prevent the increase in \[Ca^2+^\]~i~ that occurs in the absence of auditory nerve stimulation, but unlike the present studies, bath superfusion of 1 mM glutamate has been shown to result in an increase in \[Ca^2+^\]~i~ [@pone.0111243-Zirpel2]. This apparent discrepancy could either be due to the additional dilution of drug in our application procedure, bringing the 1 mM pipette solution to sub-toxic levels, or it could be due to some receptor desensitization in the studies that applied drugs in the perfusate, thereby preventing the receptors from having a protective influence and disrupting Ca^2+^ homeostasis. Conclusions {#s5} =========== In summary, it is clear that activation of mGluRs protects NM neurons from early degenerative changes, both in the presence and absence of auditory nerve stimulation. Future research will have to determine the exact nature of this protective influence but there are likely multiple mediators. Activation of these receptors can modulate glutamate uptake at the auditory nerve-NM synapse, keeping glutamate at sub-toxic levels, or it could more directly protect the neuron by maintaining intracellular Ca^2+^ homeostasis, and perhaps act through a myriad of other modulatory functions that are regulated by 2nd messenger systems. [^1]: Competing Interests:The authors have declared that no competing interests exist. [^2]: Conceived and designed the experiments: KLC RLH. Performed the experiments: KLC. Analyzed the data: KLC RLH. Wrote the paper: KLC RLH. [^3]: Current address: Louisiana State University Health Sciences Center, Department of Cell Biology and Anatomy, New Orleans, LA, United States of America	{ "pile_set_name": "PubMed Central" }
By Timothy Heritage and Gabriela Baczynska MOSCOW (Reuters) - President Vladimir Putin greeted the new U.S. ambassador to Russia on Wednesday with a demand for Washington to treat Moscow as an equal partner and stay out of its internal affairs. The new envoy, John Tefft, said in a written statement after presenting his credentials that he wanted to strengthen "people-to-people" ties but there were serious differences over Ukraine. Their comments underlined the chasm between the former Cold War enemies as Tefft succeeds Michael McFaul, who was behind President Barack Obama's planned "reset" in relations with Russia and whose posting was marked by controversy and tension. Putin met Tefft with a slight smile and they then stood stiffly beside each other posing for photographers during a Kremlin ceremony for new ambassadors. "We are ready for practical cooperation with our American partners in different fields, based on the principles of respect for each others' interests, equal rights and non-interference in internal matters," Putin said in a short speech. His remarks were blunt though less fierce than some of his earlier criticism of Washington, which he has accused of trying to dominate world affairs and suppress Russia. The United States and the European Union have imposed sanctions on Moscow following its annexation of the Crimea peninsula from Ukraine and over its backing for separatists in the east opposed to Kiev's rule. In a statement issued after the ceremony, Tefft said he was committed to maintaining "open and frank lines of communication" with the Russian authorities. "We have serious differences over Russia’s policy in Ukraine. As President Obama said at the G20 summit in Brisbane, we hope Russia will choose 'a different path', to resolve the issue of Ukraine in a way that respects Ukraine’s sovereignty and is consistent with international law," he said. "We would prefer a Russia that is fully integrated with the global economy; that is thriving on behalf of its people; that can once again engage with us in cooperative efforts around global challenges.” Story continues Moscow approved the appointment of Tefft even though Russian officials said privately he was not entirely to their liking. Tefft was the United States' ambassador to Georgia during its short with Russia in 2008 and was the U.S. envoy to Ukraine for nearly four years until July last year. He was deputy chief of mission in Moscow in the second half of the 1990s. Other strains in ties are differences over regional conflicts such as the civil war in Syria, arms control and human rights issues, and Putin's treatment of opponents. (Reporting by Gabriela Baczynska, Editing by Timothy Heritage)	{ "pile_set_name": "OpenWebText2" }
Rand Paul for President — Because what the GOP needs is a humbling landslide defeat. — Republicans, let's get it over with. Fast forward to the finish line. Avoid the long and winding primary road. It can only weaken the nominee. And we know who he—yes, he—has to be. Why You Should Be Sympathetic Toward Cliven Bundy — On Saturday, I wrote about the standoff at Bundy Ranch. That post drew a remarkable amount of traffic, even though, as I wrote then, I had not quite decided what to make of the story. Since then, I have continued to study the facts and have drawn some conclusions. Census Survey Revisions Mask Health Law Effects — WASHINGTON — The Census Bureau, the authoritative source of health insurance data for more than three decades, is changing its annual survey so thoroughly that it will be difficult to measure the effects of President Obama's health care law … Read My Lips: More New Taxes! — A bigger April 15 bill would mean a better society — Happy Tax Day. Yes, I say that every year. Yes, I still mean it. Yes, I know that not many people feel the same way. — Nobody likes writing checks to the government. At best, it's something people tolerate. U.S. Deficit Cut by Almost One-Third to $492 Billion: CBO — The U.S. government's deficit will fall to $492 billion this year, according to the Congressional Budget Office, a steeper drop than originally predicted from $680 billion in fiscal year 2013. — The 2014 deficit will be 2.8 percent … Landrieu Reenacts Committee Hearing for Campaign Ad — Democratic senator Mary Landrieu of Louisiana is in a tough reelection battle because of her support for Obamacare. So its not surprising her latest TV ad focuses on the one high-profile fight she's had with the Obama administration, over oil and gas exploration. Bolton PACs Raise Big Money — John Bolton's political-action committees are pulling in big bucks. Together, the former United Nations ambassador's groups, a PAC and a super PAC that will back candidates who share Bolton's belief in a muscular foreign policy, raised nearly $2 million since their launch in November, sources say. I Was Racially Profiled in My Own Driveway — A retired Major League Baseball player explains how he's trying to turn an upsetting encounter with the police into an opportunity for dialogue. — It was an otherwise ordinary snow day in Hartford, Connecticut, and I was laughing as I headed outside to shovel my driveway. Can You Lie in Politics? Supreme Court Will Decide — The Supreme Court has made pretty clear that putting your money where your mouth is deserves broad protection as a form of free political speech. The justices are about to consider whether outright lying in a campaign deserves a similar First Amendment shield. The day's must-read political news and opinion pieces are scattered across hundreds of news outlets and blogs, too many for any one person to read. Fortunately, memeorandum arranges all of these links in a single, easy-to-scan page. It auto-generates a news summary every 5 minutes, drawing on experts and pundits, insiders and outsiders, media professionals and amateur bloggers.	{ "pile_set_name": "Pile-CC" }
An important class of problems amenable to machine learning is classification, that is, the unique assignment of input samples to a finite number of categories (or associated output labels) to which they belong. For example, in optical character recognition (OCR), input images assumed to represent characters, such as letters or numbers, receive distinct labels from a finite list of characters (e.g., alphanumeric characters). As another example, in speech recognition tasks, human voice recordings are transcribed into unambiguous text. These and other classification tasks can be automated using a suitable classifier model that either predicts unique output labels for the input samples directly, or specifies a probability distribution over all output labels for each input sample (allowing unique output labels to be determined, e.g., by selecting the label with the greatest probability). In machine learning, the model is initially provided in parametric form, and the parameters of the model are adjusted based on training data. Supervised machine learning utilizes labeled training data in which each of a set of training input samples is paired with a corresponding known output label. Providing a sufficiently large set of such pairs of input sample and output label often requires a significant manual labeling effort. Accordingly, there is a strong interest in unsupervised machine learning approaches that allow training classifiers without labeled training data.	{ "pile_set_name": "USPTO Backgrounds" }

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