Datasets:

finnstrom3693
/

pile-cp-free-100k-part-2

Dataset card Viewer Files Files and versions Community

Split (1)

train · 100k rows

text stringlengths 1 1.57M ⌀
Mike Weir 32 year old golfer Mike Weir is the most successful and the best known Canadian player currently active on the PGA tour. Weir is a native of Bright's Grove, Ontario, and has notched six career PGA victories since earning his tour card in 1998. Born Michael Richard Weir on May 12, 1970, the 5'9" and 155 pound Weir attended college at Brigham Young University, majoring in Recreational Management. Growing up in Bright's Grove, Weir, like many Canadians, was an avid hockey player. But by age 11, Weir discovered that his true love was golf, and he practiced just about every day under the tutelage of his father, Rich. At 13 years old, Weir wrote a letter to golf legend Jack Nicklaus, asking his advice on whether or not he should switch to playing right-handed. Nicklaus replied that Weir ought to stick to his natural swing-- advice which paid off later when Weir joined the CPGA following his graduation from BYU in 1992. In 1993, Weir won the CPGA's award for the best rookie. By the time he joined the PGA in 1998, he had proven himself to be Canada's top golfer. In 2000, Weir received the Lionel Conacher award, which is given to the best Canadian male athlete-- an award that hadn't been given to a golfer since 1932. But despite his obvious skill and athleticism, Weir's greatest assets are his patience and perseverance. After not recording a single tour victory in 2002 (his best finish was a tie for eleventh place), Weir has already won three events in 2003 (including the Bope Hope Classic in January, and the Nissan Open the following month). Weir currently resides in Draper, Utah, with his wife Bricia, and two young daughters, Elle and Lilli. His hobbies include hockey and fishing, and his caddy is Brennan Little of St. Thomas, Ontario. Oh, yeah, and he recently (April 13, 2003) became the first Canadian to ever win The Masters tournament, following his sudden-death playoff victory over Len Mattiace. Not too shabby for his first major victory.
Q: C# Winforms: programatically display Button's Hover State i am displaying a numeral keypad in on a winform to enter code. i am displaying nummpad with buttons... The users will be using only keyboards numpad to enter the code\\password\\? but off-course you can use mouse... If we use mouse to click button we get a blue-ish effect to display hover & down states.. i was thinking if i can somehow programatically display the down-state of a button according to he key that user pressed on the numpad... HOW TO A: It is not possible to simulate this behavior by using the default implementation of the button class. However, you can sub class the button to add this behavior: public class KeyboardButton : Button { public void SimulateButtonDown() { this.OnMouseDown(new MouseEventArgs(MouseButtons.Left, 0, 1, 1, 0)); } public void SimulateButtonUp() { this.OnMouseUp(new MouseEventArgs(MouseButtons.Left, 0, 1, 1, 0)); } } When you call SimulateButtonDown the button will go into a (visual) state imitating that mouse would have been clicked (and held) on the button. You can implement methods like these for hover events as well.
Q: Additional chat room owners? Since the moderators all have lives, we've been thinking about getting some additional eyes on chat in the form of room owners for The h Bar. In most chat rooms, ownership is meant to indicate who is "in charge" of a room and should be the point of contact for outsiders with questions about its culture. But since The h Bar is a primary site chat room, it's "owned" by the community, not by specific people. What we have in mind is probably more like a room maintainer than an owner. We think it'd be better if the chat community didn't always have to rely on the mods to keep the star wall clean, or to add feeds, or bring in new users who don't meet the rep requirement, schedule additional events, or kick-mute people if the conversation starts to get out of hand. (Kick-mute keeps a user from participating in that chat room for a short period of a few minutes.) Owners get a few privileges, beyond those available based on reputation, that would allow them to take care of these matters: room owner: edit the room name and description pin a message (a pin is a super-star) remove stars from messages grant explicit read or write access grant room ownership create and remove feeds move messages to a different room schedule events kick-mute users Of course, ideally using these powers would be rare, and most of the time room owners would just hang around chatting as usual. And if there are serious problems, they'd just ping a moderator anyway. Owners would be appointed by the moderators from trustworthy candidates who are willing to take on the role. It's not really worth going through a whole election process for what is ultimately a very small change in the status quo. Anyway, I'm making this post to focus on the general idea of having room owners, not as a forum to debate who it's going to be. Thoughts? Any objections we haven't thought of? In the spirit of "better safe than sorry", I figured I should probably put something on meta before we just go and make it happen - even though it's very possible there is not really anything to say about this. A: I say yes. And yes, I know my opinion doesn't carry a massive weight on this site itself, but since I'm around the chat a reasonable amount I thought I'd drop it in. Over the past few months there have been a number of flags from The h Bar. Only some of them have been valid, but each one has required a little moderator time to resolve (yes, I'm aware 10k users can see chat flags, but — forgive me — it's been a while since I saw a 10k'er resolve a situation). This reminds me of another chatroom I hang around. Or rather, of how that chatroom used to be — the attitudes in it are changed now, along with the flagging culture. I think that's in part down to the fact that the room got some room owners who could be around — not to impose, but to gently guide conversations away from topics that would trigger, and to help mediate in disputes. On the other hand, I don't see that much harm could come from this action (unless the power gets given to someone ill-qualified to wield it, but that can be dealt with easily enough). That leaves us with a win—no-change situation, where we never lose anything. It's worth giving a try, at least. A: Our first appointments as additional room owners are Chris White and John Rennie. Welcome to your new role! We'll continue to add additional room owners in the future as needed, and as qualified candidates become available.
End of the US Empire: Russian Warships Just Arrived in the Philippines Notable American foreign policy critic and linguist, Professor Noam Chomsky, has stated numerous times that the United States’ power has steadily been declining since the end of World War II. As Chomsky notes, in 1945, the United States had “literally half the world’s wealth, incredible security, controlled the entire Western Hemisphere, both oceans, [and[ the opposite sides of both oceans.” In that context – and in the context of the United States waging war in multiple countries across the globe with the most advanced military technology in the world – it is hard to understand how this has happened. But Chomsky is not wrong. Beginning with what was referred to as the “loss of China” in the 1940s, the United States slowly began to lose areas of Southeast Asia, which led America to brutally launch the Indochina wars. As Chomsky notes, by destroying South Vietnam in the heavily criticized Vietnam War — a move designed to prevent Vietnam from achieving independence and perhaps becoming a Communist state — the U.S. sent a message to the rest of Indochina that if a nation attempted to break free of U.S-European control, it would likely be bombed into oblivion. The strategy worked at the time; as Chomsky notes, by 1965, every country in the region had dictatorships that were prepared to rule in a way suitable to America’s foreign policy interests. As recent developments in the Asian region have shown, however, the success of this bully-style strategy has been short-lived indeed. Regardless, the United States has also lost South America. According to Chomsky, the “loss” of South America is easily observable: “One sign is that the United States has been driven out of every single military base in South America. We’re trying to restore a few, but right now there are none.” The Middle East was, therefore, ripe for the taking, and this continued to be the case up until the Syrian war. What people fail to understand, however, is that the United States is not bombing the Middle East into submission because of its immense power, but because it is losing its power, influence, and control throughout the region. As should be quite clear to anyone following the conflict, Russia has replaced the United States as judge, jury, and executioner (and supposed peace broker) in the five-year Syrian war, successfully retaking the major city of Aleppo from NATO-backed rebel groups. Russia’s advances in the Middle East have spilled over to the rest of the world. In October of last year, the U.S. officially “lost” its stranglehold over the Philippines. Though it was previously seen as an integral ally U.S. ally vital to countering China’s influence in the Asia-Pacific region, the Philippines openly and proudly boasted about their new ties with Russia and China. As it transpires, the Philippines has put its money where its mouth is. Russian warships arrived in Filipino territory this Tuesday. According to the Philippines’ Navy, the visit is merely a “goodwill visit,” but the future of joint exercises is to be discussed. A report from Russia’s state-run Sputnik News seemed to contradict this, stating the ships were there specifically to conduct joint exercises with Philippine forces for the purposes of fighting maritime piracy and terrorism. “You can choose to cooperate with United States of America or to cooperate with Russia,” Russian Rear Admiral Eduard Mikhailov said, speaking at the Manila Harbor.“But from our side we can help you in every way that you need. We are sure that in the future we’ll have exercises with you. Maybe just maneuvering or maybe use of combat systems and so on.” Mikhailov also seemed to indicate that other players in the region, such as China and Malaysia, would coordinate with the potential training exercises within the next few years. Russia has also offered the Philippines sophisticated weaponry, including aircraft and submarines. The United States has only one move left: surround Russia’s borders with NATO troops and missiles, which they are doing quite rapidly. Sooner or later, however, the United States will have to admit its very real decline in world standing and will have no choice but to learn to coordinate global affairs with the likes of Russia and China. About ew ew came of age during the winddown to the Vietnam War, and like many other Americans, as soon there wasn't an issue that didn't affect him personally, he became indifferent. This gradually changed during the Reagan and Bush I years, continued through the Clinton years and finally came to a head with the passage of the Patriot Act in 2001. He works as a freelance consultant/tester for various music hardware and software companies, and lives in Minnesota with his cat and other weird and wonderful noise machines.
Five Teams After Javier Pastore byDavidonJuly 5, 2011 Palermo President Maurizio Zamparini says Real Madrid, Malaga, Chelsea, Manchester United and Manchester City are all battling to sign Javier Pastore. Zamparini has previously said that Pastore, currently with Argentina competing in the Copa America, will not be allowed to leave for below £45 million. When asked where he thinks Pastore will end up Zamparini said: “He will go to England or Spain, but I’d exclude Barcelona because they already have Andres Iniesta and Xavi in that position. The favourites are Real Madrid and Malaga. Manchester City are also interested in him, as well as Manchester United and Chelsea. I’m sorry to let him go, because he is the only world-beater that I have had at the club as president.” But Zamparini warned interested parties they will have to act quickly to secure the services of Pastore. “We must solve it within 15 days, before the end of the Copa America, otherwise Pastore stays with us. However, there’s a 90 per cent chance that he’ll go away, because it is his desire. That is normal when you know that certain clubs want you.”
Let x = 0.101 - 0.13. Let f = w + x. Round f to 2 decimal places. -0.01 Let h(j) = 4169j3 + 42j*2 - 7j + 4. Let d be h(12). Round d to the nearest 1000000. 7000000 Let a be -1 + (-6 + 3 - -6). Let b(k) = 4k - 15001k3 + k2 - 4 + 6 - 3k. Let m be b(a). What is m rounded to the nearest 100000? -100000 Let j = -312 + 325.88. Let o = j - 14. Let y = 5.08 - o. Round y to the nearest integer. 5 Let o = 134.8 - 687.8. Let d = -544.06 - o. Let v = -1.04 + d. What is v rounded to zero decimal places? 8 Let v = 462.4 + -462.37197. What is v rounded to three decimal places? 0.028 Let g(v) be the third derivative of -23v6/24 - v5/6 + v*4/6 + 11v*3/6 - 17v*2. Let t be g(-9). Round t to the nearest 10000. 80000 Let y(w) = 121w*2 + 15w - 22. Suppose -2n + 35 - 1 = 0. Let i be y(n). Let h = i + -16202. Round h to the nearest 1000. 19000 Let x = -154.4 + 275.1. Let u = -116 + x. What is u rounded to the nearest integer? 5 Let a(z) = 2z + 26. Let l be a(-10). Let n(o) = -75o3 + 18o*2 + 8o + 4. Let s be n(l). Round s to the nearest 10000. -20000 Let s = -825997 - -1415997. Round s to the nearest 100000. 600000 Let q(n) = -1 + 18n - 7n + n*2 - 12n + 3. Let g be q(0). Let o be 8/(-2) - 20199992/g. What is o rounded to the nearest one million? -10000000 Let y = 0.74 - 0.47. Let f = 0.27000055 - y. Round f to seven decimal places. 0.0000006 Let r = 8645 + -8504.82. Let f = r + -139. Let c = 11.78 - f. Round c to the nearest integer. 11 Let p(q) = 6q3 - 3q*2 + 3q - 1. Let a be p(1). Suppose 2455 = -m - 10g + ag, 4g + 12296 = -5m. What is m rounded to the nearest 100? -2500 Let p = -267 + 269.5. Let c = -93.004065 - -95.504. Let f = c - p. Round f to five dps. -0.00007 Suppose -6v = -8v - 53422. Let o = v - -44311. What is o rounded to the nearest 1000? 18000 Let j = 104 - 92.3. Let f = -2.3 - j. Let x = -14.0000056 - f. Round x to six decimal places. -0.000006 Let f be (2/4)/(-7 + (-232)/(-32)). Suppose -4k - fv - 3v = 1742, 2k + 4v + 868 = 0. What is k rounded to the nearest 100? -400 Let l = -22 + 46. Let q = 17 - l. Let k = -6.99999899 - q. Round k to 7 decimal places. 0.000001 Let t = 64 - 64.14. Let j = -0.47 - t. Round j to 1 dp. -0.3 Let v = 8.7 + -8. Let d = 36.48322572 - 35.783226. Let z = d - v. What is z rounded to 7 dps? -0.0000003 Suppose 10c + 14417 = -19583. What is c rounded to the nearest one thousand? -3000 Let x = -3.7 + 3. Let i = 143124803.69999991 - 143124803. Let a = x + i. What is a rounded to 7 decimal places? -0.0000001 Let h = -3852726 - -3852774.00158. Let k = -48 + h. What is k rounded to four decimal places? 0.0016 Let p(u) = -2380066u - 1. Let n be p(5). Suppose -76w = -75w - 1200331. Let a = n + w. Round a to the nearest one million. -11000000 Let q = -454 + 446.29. Round q to one decimal place. -7.7 Let o = 0.03662 + 0.00356. Let w = -0.041 + o. Round w to four dps. -0.0008 Let j be 2400(15/(-6) - -3). Let u = j + -530. Suppose 4r = -2t + 2396, -2r = -2t - 534 - u. What is r rounded to the nearest 1000? 1000 Let o = 4.9 + -10.1. Let f = o - -1.5. What is f rounded to the nearest integer? -4 Let o = 377363.93 + -375657. Let y = o - 1715. What is y rounded to zero decimal places? -8 Let p(t) = 170152t3 - 8t*2 - 7t - 4. Suppose 3s - 2s = -6. Let x be p(s). Let r = x - -24153082. Round r to the nearest 1000000. -13000000 Let b be ((-6)/(-8) + (-36)/16)-22114. Let j = -46829 - b. What is j rounded to the nearest ten thousand? -80000 Suppose -2c + 158 = 4o, 247 = 5o - c + 46. Suppose 15s = 19s - o. Suppose -4d - 2 = s, 2k + d - 68799997 = 0. Round k to the nearest 1000000. 34000000 Let v = -2262590.999816 - -2262570. Let a = -21 - v. Round a to 5 decimal places. -0.00018 Let v = 10.4 + 90.6. Let a = v + -122.3. Let k = a + 28. Round k to the nearest integer. 7 Let d(a) = -10a3 - 3a*2 - 8a - 8. Let p be d(-10). Let f = -13727 + p. Let t = -7555 - f. Round t to the nearest 1000. -4000 Let a = -1153.146 + 1154. Round a to one decimal place. 0.9 Let t be 3/((-6)/8) + 8. Let f be (13 - 1)t/3. Suppose -4120000 = -12z + fz. What is z rounded to the nearest 100000? -1000000 Let i = 2.55 - 2.549812. Round i to 5 dps. 0.00019 Let v be ((-4)/(-6) - 2/(-6))/1. Let a be (-5200)/(45/150v/600). What is a rounded to the nearest 1000000? -10000000 Suppose 5q + b - 10995 = 0, -4b + 7b + 6615 = 3q. Round q to the nearest 100. 2200 Suppose 114491825 = -29c - 84245175. What is c rounded to the nearest 1000000? -7000000 Let k = 19.84 - 20. Let n = -2.11 - k. Let i = n - 6.35. Round i to the nearest integer. -8 Let r = -123 - -303. Let d = r - 179.99843. Round d to four decimal places. 0.0016 Let o = 1589825315.99915 + -1589793084. Let x = o + -32233. Let n = x - -1. Round n to 4 decimal places. -0.0009 Let y = -7353 - -10853. What is y rounded to the nearest 10000? 0 Let c = 7.07975102 - 156.07973682. Let w = 0.083 + -149.083. Let t = w - c. What is t rounded to six decimal places? -0.000014 Let f = 186.00000348 + -186. Round f to 7 dps. 0.0000035 Let w = 917115 - -243415. Let g = w - 20530. Round g to the nearest one hundred thousand. 1100000 Let u = -8694.69584722 + -3.18409778. Let w = u + 8698. Let m = w + -0.12. Round m to 5 decimal places. 0.00006 Let s be (-4)/(-6) - (-932310054)/(-81). Round s to the nearest 1000000. -12000000 Let m = -3.68 + 3.680331. What is m rounded to five decimal places? 0.00033 Let v = -334.6599866 + 634.65998517. Let z = 295.14 + 4.86. Let y = v - z. What is y rounded to seven dps? -0.0000014 Let g(v) = -40v + 70v - 39v - 2645 - 10055. Let o be g(0). Round o to the nearest one thousand. -13000 Let g = -2.9819 + 3.17. Let o = -0.18 + g. What is o rounded to three decimal places? 0.008 Suppose -44f + 42f = 2y - 21930, 4y + 21960 = 2f. What is f rounded to the nearest one thousand? 11000 Suppose -3118884 - 571151 = -5v. Suppose 5h + c + v = 69802, h = -3c - 133655. Let n = h + -386360. Round n to the nearest 100000. -500000 Let s = -6.76 + 7. Let p = 0.1 + s. Let n = p - 0.339. What is n rounded to 3 dps? 0.001 Let b = -21.4 + 21.402832. Round b to four decimal places. 0.0028 Let k = -45.895 + -0.105. Let t = k - -45.996. What is t rounded to two dps? 0 Let t = -23 - -147. Let u = t + 163. Let w = u - 287.0000233. Round w to 6 dps. -0.000023 Let z = 7 - 1.8. Let t = 19.504 + -24.81. Let n = z + t. Round n to two decimal places. -0.11 Let j = 395 + 674. Let f = j + -1064.71. Let g = -4.5 + f. What is g rounded to one dp? -0.2 Let q(w) = -6w2 + 9w - 183. Let x be q(15). What is x rounded to the nearest 10? -1400 Let r = 3.75 + -2.51. Round r to one dp. 1.2 Let i be (-40627999)/14 - 4/56. Round i to the nearest 100000. -2900000 Suppose 4s - 11251 = -o - 2o, -s = -3o + 11276. Round o to the nearest one hundred. 3800 Suppose -f + 3f + 8665 = 3i, 8640 = -2f - 2i. Let m = f + 2125. What is m rounded to the nearest one thousand? -2000 Let o(t) be the first derivative of 95t*2/2 - 5t + 5. Let k be o(-4). Let z be k/44(-800)/(-2). What is z rounded to the nearest one thousand? -4000 Let l be (17 - 17) + -1 + 39. Let m = l - 39. Round m to the nearest integer. -1 Let i be 64/10 + 4/(-10). Let f(j) = j2 - 31j + 24. Let v be f(30). Let p be 3178/i + v/(-18). What is p rounded to the nearest 100? 500 Let y(t) = -t*2 - 14t - 15. Let o be y(-9). Let d be 2(25/o)/(10/6). Round d to one decimal place. 1 Suppose -4a - s - 3 = 0, -2a + 2s + 1 = 5. Let c be a/2(8 - 6). Let f be 0 + -39999 + 1/c. What is f rounded to the nearest 100000? 0 Let w = -7.54118 + 7.416. Round w to two decimal places. -0.13 Suppose -c + 4h = -20, 5h = 5c - 0 - 25. Suppose c = -4x + 3588 + 8332. Round x to the nearest 100. 3000 Let m = -2411 + 2419.984. What is m rounded to the nearest integer? 9 Let b be 2/7 - (-72)/42. Let m(u) = 3u*b - 13 + 5u - 2u + 15 - 2u. Let c be m(-2). What is c rounded to zero decimal places? 12 Suppose -17a - 5968 = -25a. Let b = a - 189. What is b rounded to the nearest 10? 560 Let y(q) = -353q3 - 6q*2 - 6q - 5. Let r be y(-5). Suppose -2*u - r = -u. What is u rounded to the nearest ten thousand? -40000 Let t = -1.8 - -8.3. Let k = -6 + 2.9. Let c = k + t. What is c rounded to 0 dps? 3 Let c = -81.9
--- abstract: 'In a group, a generalized torsion element is a non-identity element whose some non-empty finite product of its conjugates yields the identity. Such an element is an obstruction for a group to be bi-orderable. We show that the Weeks manifold, the figure-eight sister manifold, and the complement of Whitehead sister link admit generalized torsion elements in their fundamental groups. In particular, the Whitehead sister link, which is the pretzel link of type $(-2,3,8)$, can be generalized to hyperbolic pretzel links of type $(-2,3,2n)\\ (n\\ge 4)$. These give the first examples of hyperbolic links whose link groups admit generalized torsion elements.' address: 'Department of Mathematic Education, Hiroshima University, 1-1-1 Kagamiyama, Higashi-hiroshima, 7398524, Japan' author: - Masakazu Teragaito title: Generalized torsion elements and hyperbolic links --- [^1] Introduction ============ In a group $G$, a non-trivial element $g$ is called a generalized torsion element if some non-empty finite product of its conjugates is equal to the identity. That is, $g^{a_1}g^{a_2}\\dots g^{a_k}=1$ for some $a_1,a_2,\\dots, a_k\\in G$. Here $g^a$ denotes a conjugate of $g$ by $a\\in G$. Every knot or link group is torsion free. However, it may contain a generalized torsion element. For example, all torus knot groups satisfy it. Naylor and Rolfsen [@NR] gave the first example of hyperbolic knot, which is the $(-2)$-twist knot, whose knot group contains a generalized torsion element. Then we showed that any negative twist knot enjoys the same property [@T]. The existence of generalized torsion element is an obstruction for a group $G$ to be bi-orderable. Recall that $G$ is said to be bi-orderable if it admits a strict total ordering which is invariant under multiplication from left and right sides; if $a<b$, then $gah<gbh$ for any $g$ and $h$ in $G$. If $G$ is bi-orderable, then any non-identity element $g$ is bigger or smaller than the identity. Let $g>1$. Since conjugation preserves the order, $g^a>1$ for any $a\\in G$. Then any product of such elements is still bigger than $1$. Similarly for the case $g<1$. Thus any bi-orderable group has no generalized torsion element. Conversely, even if $G$ has no generalized torsion element, we cannot claim that $G$ is bi-orderable [@B; @BL; @MR]. However, we expect that such phenomenon does not occur among $3$-manifold groups [@MT]. Many $3$-manifold groups are know to be not bi-orderable. For, any finitely generated bi-orderable group surjects on the infinite cyclic group (see [@CR]). In particular, if a $3$-manifold $M$ has finite first homology group, then $\\pi_1(M)$ is not bi-orderable. In [@MT], we propose a conjecture that if $\\pi_1(M)$ is not bi-orderable for a $3$-manifold $M$, then it contains a generalized torsion element. This is solved affirmatively for Seifert fibered manifolds, Solvable manifolds, and a few infinite families of hyperbolic manifolds. In this paper, we first examine small volume cusped hyperbolic $3$-manifolds. The Weeks manifold is the unique closed orientable hyperbolic $3$-manifold of smallest volume [@GMM]. By [@CM], the minimal volume orientable hyperbolic $3$-manifold with one cusp is homeomorphic to either the figure-eight knot complement or the figure-eight sister manifold, which is also called the sibling manifold. Furthermore, the minimal volume orientable hyperbolic $3$-manifold with two cusps is homeomorphic to either the Whitehead link complement or the Whitehead sister manifold, which is the $(-2,3,8)$-pretzel link complement. The figure-eight knot complement and the Whitehead link complement have bi-orderable fundamental groups [@PR; @KR], so they do not admit a generalized torsion element in their fundamental groups. Our first result claims that the others admit generalized torsion elements in the fundamental groups. \\[thm:main1\\] The Weeks manifold, the figure-eight sister manifold and the Whitehead sister manifold admit generalized torsion elements in their fundamental groups. As remarked above, the Whitehead sister manifold is the complement of the $(-2,3,8)$-pretzel link. Second, we generalize this to an infinite family of pretzel links. \\[thm:main2\\] Let $L$ be the two-component pretzel link $P(-2,3,2n)$. If $n\\ge 1$, then the link group $\\pi_1(S^3-L)$ contains a generalized torsion element. This theorem immediately gives the first examples of hyperbolic links whose link groups admit generalized torsion elements. There are infinitely many hyperbolic two-component links whose link groups admit generalized torsion elements. If $n\\ge 4$, then $P(-2,3,2n)$ is hyperbolic [@MP]. The conclusion immediately follows from Theorem \\[thm:main2\\]. Throughout the paper, we use the notation $\\bar{g}=g^{-1}$, $[g,h]=g^{-1}h^{-1}gh$ and $g^a=a^{-1}ga$ for the inverse, the commutator and the conjugate in a group. The Weeks manifold and the figure-eight sister manifold ======================================================= We start from the exterior $W$ of the Whitehead link. Then $\\pi_1(W)$ has the following Wirtinger presentation $$\\pi_1(W)=\\langle a, b \\mid aba\\bar{b}\\bar{a}bab=bab\\bar{a}\\bar{b}aba\\rangle,$$ where $a$ and $b$ are meridians of the components as shown in Fig. \\[fig:link\\]. ![The Whitehead link and the meridians $a$, $b$[]{data-label="fig:link"}](link.eps){width="4cm"} The figure-eight sister manifold is described as the resulting manifold by performing $5/1$-Dehn filling on one boundary component of $W$ (see [@G]). Two components of the Whitehead link are interchangeable by an isotopy, so there is no ambiguity for the choice of boundary component. \\[thm:w\\] For a slope $m/n\\ (n\\ge 1)$, let $W(m/n)$ be the resulting manifold by $m/n$-Dehn filling on one boundary component of the Whitehead link exterior $W$. If $m\\ge 2n$, then $\\pi_1(W(m/n))$ contains a generalized torsion element. In particular, the figure-eight sister manifold $W(5)$ satisfies this. Perform $m/n$-surgery along the component with meridian $a$. Then the surgery yields a relation $$(\\bar{b}^{ab\\bar{a}\\bar{b}}b)^n a^m=1,$$ because the longitude is $\\bar{b}^{ab\\bar{a}\\bar{b}}b$. This gives $$\\label{eq1} (ba\\bar{b}\\bar{a}\\bar{b}ab\\bar{a})^na^m=1.$$ Hence $$\\pi_1(W(m/n))=\\langle a,b \\mid aba\\bar{b}\\bar{a}bab=bab\\bar{a}\\bar{b}aba, (ba\\bar{b}\\bar{a}\\bar{b}ab\\bar{a})^na^m=1\\rangle.$$ The first relation gives $$\\label{eq2} ba\\bar{b}\\bar{a}\\bar{b}ab=a^{\\bar{b}\\bar{a}}a^b\\bar{a}.$$ Hence (\\[eq1\\]) and (\\[eq2\\]) yield $(a^{\\bar{b}\\bar{a}}a^b\\bar{a}^2)^na^m=1$, so we have $$\\label{eq3} UU^{a^2}U^{a^4}\\cdots U^{a^{2(n-1)}}a^{m-2n}=1,$$ where $U=a^{\\bar{b}\\bar{a}}a^b$. Thus if $m\\ge 2n$, then the left hand side of (\\[eq3\\]) is a product of conjugates of only $a$. Since $H_1(W(m/n))=\\mathbb{Z}\\oplus \\mathbb{Z}_{\|m\|}$ and the element $a$ goes to a generator of $\\mathbb{Z}_{\|m\|}$ summand, $a$ is non-trivial in $\\pi_1(W(m/n))$. Hence if $m\\ge 2n$, then (\\[eq3\\]) shows that the element $a$ is a generalized torsion element in $\\pi_1(W(m/n))$. 1. Since $W(1)$ is the exterior of the trefoil, $\\pi_1(W(1))$ contains a generalized torsion element (see [@NR]). 2. If $m=-1$, then $W(-1/n)$ gives the exterior of the $n$-twist knot. For example, $W(-1)$ is the figure-eight knot exterior. Since the knot group of any positive twist knot is known to be bi-orderable [@C], $\\pi_1(W(-1/n))$ does not contain a generalized torsion element for any $n\\ge 1$. On the other hand, if $m=1$, then $\\pi_1(W(1/n))$ contains a generalized torsion element, because the knot group of any negative twist knot admits a generalized torsion element [@T]. Let $M=W(m/n)$, and let $M(r)$ denote the $r$-Dehn filling on $M$. The Weeks manifold is $M(5/2)$ for $M=W(5)$ (see [@CD]). \\[cor:weeks\\] If $m\\ge 2n$. $\\pi_1(M(r))$ contains a generalized torsion element for any slope $r\\in \\mathbb{Q}\\cup \\{1/0\\}$. In particular, the Weeks manifold $M(5/2)$ satisfies this. Since $\\pi_1(M(r))$ is the quotient of $\\pi_1(W(m/n))$, the relation (\\[eq3\\]) still holds in $\\pi_1(M(r))$. Set $r=p/q$. The element $a$ projects to a generator of $\\mathbb{Z}_{\|m\|}$ summand of $H_1(M(r)))=\\mathbb{Z}_{\|p\|}\\oplus \\mathbb{Z}_{\|m\|}$, so it is nontrivial in $\\pi_1(M(r))$. Hence $a$ remains to be a generalized torsion element in $\\pi_1(M(r))$. The Whitehead sister link and pretzel links =========================================== Tunnel number one pretzel links ------------------------------- Let $L$ be the pretzel link $P(-2,3,2n)$ for $n\\ne 0$. In particular, $P(-2,3,8)$ is the Whitehead sister link. Let $G=\\pi_1(S^3-L)$ be the link group. The purpose of this subsection is to obtain a presentation of $G$ with two generators and a single relation based on the fact that $L$ has tunnel number one. Figure \\[fig:tunnel\\] shows the unknotting tunnel $\\gamma$ for $L$. This means that the exterior of the regular neighborhood $N$ of $L\\cup \\gamma$ is a genus two handlebody $H$. Hence the exterior of $L$ is obtained from $H$ by attaching a $2$-handle along the co-core $\\ell$ of the regular neighborhood of $\\gamma$, which is regarded as a $1$-handle attached on the regular neighborhood of $L$. This implies that the link group $G$ has two generators and a single relation which comes from the $2$-handle addition. ![The pretzel link $P(-2,3,2n)$, where $n=3$, and its unknotting tunnel $\\gamma$[]{data-label="fig:tunnel"}](pretzel.eps){width="10cm"} To get a rank two presentation of $G$, we will trace the co-core $\\ell$ on $\\partial N$ during the unknotting transformation of $N$. First, we replace the $2n$-twists on $L$ with $(-1/n)$-surgery on the additional unknotted circle as shown in Fig. \\[fig:tunnel\\]. Then Fig. \\[fig:start\\] shows $N$ and the co-core $\\ell$. ![The regular neightborhood $N$ of $L\\cup \\gamma$ and the co-core $\\ell$ on $\\partial N$[]{data-label="fig:start"}](handle0.eps){width="6cm"} As illustrated in Fig. \\[fig:h1\\], \\[fig:h2\\] and \\[fig:h3\\], we transform $N$. Here, the loop $\\ell$ in Fig. \\[fig:h2\\] and \\[fig:h3\\] is described as a band sum of two circles for simplicity. ![The first move of $N$[]{data-label="fig:h1"}](handle1.eps){width="7cm"} ![The second move of $N$. Here, the loop $\\ell$ is described as a band sum of two circles.[]{data-label="fig:h2"}](handle2.eps){width="10cm"} ![The third move of $N$[]{data-label="fig:h3"}](handle3.eps){width="8cm"} Figure \\[fig:h4\\] shows the final form of $N$ with $\\ell$ on $\\partial N$. It is easy to see that the outside of $N$ is also a genus two handlebody $H$. Here, the loops $\\alpha$ and $\\beta$ bound mutually disjoint non-separating meridian disks of $H$. Hence if we take the generators $a$ and $b$ of $\\pi_1(H)$ as the duals of $\\alpha$ and $\\beta$, then we can easily express $\\ell$ as a word of $a$ and $b$ in $\\pi_1(H)$ by following the intersection points between $\\ell$ and $\\alpha$ and $\\beta$. ![The outsider of $N$ is a genus two handlebody $H$. The loops $\\alpha$ and $\\beta$ bound disjoint meridian disks of $H$. Here, $n=3$.[]{data-label="fig:h4"}](handle4.eps){width="10cm"} \\[prop:p\\] The link group $G$ has the presentation $$\\label{eq:p} G=\\langle a, b \\mid a\\bar{b}^{n-1}a\\bar{b}ab=ba\\bar{b}a\\bar{b}^{n-1}a\\rangle.$$ The exterior of $L$ is obtained from the genus two handlebody $H$ by attaching a $2$-handle along the loop $\\ell$. Let $a$ and $b$ be the generators of $\\pi_1(H)$, which are duals of $\\alpha$ and $\\beta$ as shown in Fig. \\[fig:h4\\]. Hence the link group $G$ has a presentation with generators $a$ and $b$ and a single relation coming from $\\ell$. We orient $\\alpha$, $\\beta$ and $\\ell$ as in Fig. \\[fig:h4\\], and follow $\\ell$ from the dot. Then we get the relation as in the statement. Generalized torsion elements ---------------------------- \\[lem:rel\\] In $G$, $[a,b\\bar{a}b^{n-1}\\bar{a}b]=1$. The relation of (\\[eq:p\\]) gives $U a^b = a^{\\bar{b}} U$, where $U=a \\bar{b} ^{n-1} a$. Hence we have $U^b a^{b^2}=aU^b$, so $a=a^{b^2 \\bar{U}^b}$. This gives $[a,b^2\\bar{U}^b]=1$, which yields the conclusion. \\[lem:decomp\\] Let $w(\\bar{a},b)$ be a word containing only $\\bar{a}$ and $b$. Then the commutator $[a,w(\\bar{a},b)]$ can be expressed as a product of conjugates of the commutator $[a,b]$. In general, we have an equation $[a,uv]=[a,v][a,u]^v$. Since $[a,\\bar{a}]=1$, $[a,w(\\bar{a},b)]$ is decomposed into a product of conjugates of only $[a,b]$. \\[thm:pretzel\\] If $n\\ge 1$, then $G$ admits a generalized torsion element. By Lemma \\[lem:decomp\\], $[a,b\\bar{a}b^{n-1}\\bar{a}b]$ is expressed as a product of conjugates of $[a,b]$ if $n\\ge 1$. We know that $[a,b]\\ne 1$ in $G$, because $G$ is not abelian. (The only knots and links whose groups are abelian are the unknot and the Hopf link.) Then Lemma \\[lem:rel\\] implies that $[a,b]$ is a generalized torsion element in $G$. When $n=0$, then link $L$ is the connected sum of the trefoil and the Hopf link. Since the knot group of the trefoil contains a generalized torsion element, so does $G$. For $n<0$, our argument in the proof of Theorem \\[thm:pretzel\\] does not work. Proof of Theorem \\[thm:main1\\]. This follows from Theorems \\[thm:w\\] and \\[thm:pretzel\\] and Corollary \\[cor:weeks\\]. $\\Box$ Proof of Theorem \\[thm:main2\\]. This immediately follows from Theorem \\[thm:pretzel\\]. $\\Box$ Problems -------- Kin and Rolfsen [@KR] show that the pretzel links $P(-2,2k+1,2n)$ and $P(-2,-2k+1,2n)$ for $k\\ge 1$ and $n\\ge 2$ do not have bi-orderable link groups. Hence their link groups are expected to admit generalized torsion elements beyond our Theorem \\[thm:main2\\]. Fortunately, these pretzel links still have tunnel number one. Thus it is possible to apply our procedure to get a presentation of link group with two generators and a single relation. We tried this, but we could not find a generalized torsion element, because of the complicated relation. The exterior of pretzel links $P(-2,3,2n)$ is obtained from the magic manifold by suitable Dehn filling. If the magic manifold contains a generalized torsion element in its fundamental group, then there would be a chance for the element to give a generalized torsion element for $P(-2,3,2n)$ as in the proof of Corollary \\[cor:weeks\\]. However, the result of [@KR] seems to suggest that the magic manifold would have bi-orderable fundamental group, so there is no generalized torsion element. [16]{} I. Agol, [The minimal volume orientable hyperbolic $2$-cusped $3$-manifolds]{}, Proc. Amer. Math. Soc. [138]{} (2010), no. 10, 3723–3732. V. V. Bludov, [An example of an unordered group with strictly isolated identity element]{}, Algebra and Logic [11]{} (1972), 341–349. V. V. Bludov and E. S. Lapshina, [On ordering groups with a nilpotent commutant]{} (Russian), Sibirsk. Mat. Zh. [44]{} (2003), no. 3, 513–520; translation in Siberian Math. J. [44]{} (2003), no. 3, 405–410. D. Calegari and N. M. Dunfield, [Laminations and groups of homeomorphisms of the circle]{}, Invent. Math. [152]{} (2003), no. 1, 149–204. C. Cao and G. R. Meyerhoff, [The orientable cusped hyperbolic $3$-manifolds of minimum volume]{}, Invent. Math. [146]{} (2001), no. 3, 451–478. A. Clay, C. Desmarais and P. Naylor, [Testing bi-orderability of knot groups]{}, Canad. Math. Bull. [59]{} (2016), no. 3, 472–482. A. Clay and D. Rolfsen, [Ordered groups and topology]{}, Graduate Studies in Mathematics, 176. American Mathematical Society, Providence, RI, 2016. D. Gabai, R. Meyerhoff and P. Milley, [Minimum volume cusped hyperbolic threemanifolds]{}, J. Amer. Math. Soc. [22]{} (2009), no. 4, 1157–1215. C. McA. Gordon, [Dehn filling: a survey]{}, Knot theory (Warsaw, 1995), 129–144, Banach Center Publ., 42, Polish Acad. Sci. Inst. Math., Warsaw, 1998. E. Kin and D. Rolfsen, [Braids, orderings, and minimal volume cusped hyperbolic $3$-manifolds]{}, Groups Geom. Dyn. [12]{} (2018), no. 3, 961–1004. B. Martelli and C. Petronio, [Dehn filling of the “magic” $3$-manifold]{}, Comm. Anal. Geom. [14]{} (2006), no. 5, 969–1026. K. Motegi and M. Teragaito, [Generalized torsion elements and bi-orderability of $3$-manifold groups]{}, Canad. Math. Bull. [60]{} (2017), no. 4, 830–844. R. Mura and A. Rhemtulla, [Orderable groups]{}, Lecture Notes in Pure and Applied Mathematics, 27. Marcel Dekker, Inc., New York-Basel, 1977. G. Naylor and D. Rolfsen, [Generalized torsion in knot groups]{}, Canad. Math. Bull. [59]{} (2016), no. 1, 182–189. B. Perron and D. Rolfsen, [On orderability of fibred knot groups]{}, Math. Proc. Cambridge Philos. Soc. [135]{} (2003), no. 1, 147–153. M. Teragaito, [Generalized torsion elements in the knot groups of twist knots]{}, Proc. Amer. Math. Soc. [144]{} (2016), no. 6, 2677–2682. [^1]: This work was supported by JSPS KAKENHI Grant Number 20K03587.
[Cite as Easley v. Dept. of Rehab. & Corr., 2017-Ohio-2700.] DAVE EASLEY Case No. 2016-00530 Plaintiff Judge Patrick M. McGrath Magistrate Gary Peterson v. ENTRY GRANTING DEFENDANT’S DEPARTMENT OF REHABILITATION MOTION FOR SUMMARY JUDGMENT AND CORRECTION Defendant {¶1} On February 16, 2017, defendant filed a motion for summary judgment pursuant to Civ.R. 56(B). Plaintiff did not file a response. The motion is now before the court for a non-oral hearing pursuant to L.C.C.R. 4(D). {¶2} Civ.R. 56(C) states, in part, as follows: {¶3} “Summary judgment shall be rendered forthwith if the pleadings, depositions, answers to interrogatories, written admissions, affidavits, transcripts of evidence, and written stipulations of fact, if any, timely filed in the action, show that there is no genuine issue as to any material fact and that the moving party is entitled to judgment as a matter of law. No evidence or stipulation may be considered except as stated in this rule. A summary judgment shall not be rendered unless it appears from the evidence or stipulation, and only from the evidence or stipulation, that reasonable minds can come to but one conclusion and that conclusion is adverse to the party against whom the motion for summary judgment is made, that party being entitled to have the evidence or stipulation construed most strongly in the party’s favor.” See also Gilbert v. Summit Cty., 104 Ohio St.3d 660, 2004-Ohio-7108, citing Temple v. Wean United, Inc., 50 Ohio St.2d 317 (1977). {¶4} According to the complaint, plaintiff is an inmate in the custody and control of defendant. The complaint provides that plaintiff filed several lawsuits regarding his Case No. 2016-00530 -2- ENTRY interaction with defendant’s employees. Plaintiff states that on July 1, 2016, Captain Clark sent Corrections Officers (CO) Dotson and Dofflemyer 1 to search for a cellphone in his cell. Plaintiff appears to allege that the search occurred in retaliation for filing several lawsuits and that during the search of plaintiff’s person, CO Dotson grabbed his buttocks and inserted his finger into plaintiff’s rectum. Plaintiff states that a CO then slammed his head into the wall and then escorted him to an area out of view of a security camera where the COs continued to beat him. Plaintiff alleges that he was thereafter placed in solitary confinement where he requested a Prison Rape Elimination Act (PREA) investigation, but that such an investigation was not commenced. Plaintiff states that his action is for assault, battery, and negligence. {¶5} Defendant argues that plaintiff’s allegations are false. Defendant asserts that there was no assault, battery, or excessive use of force. In support of its motion, defendant submitted the affidavits of Mike Dotson, Darrold Clark, Robert Dofflemyer, and Melvin Smith. {¶6} CO Dotson avers in his affidavit that on July 1, 2016, he heard a sound like a cell phone ring coming from the middle of the range, an area that included plaintiff’s cell. After receiving permission to search the cells in that area, CO Dotson ordered the inmates out of their cells. Once out of his cell, CO Dotson performed a patdown of plaintiff prior to taking him to the shower to be strip searched. CO Dotson provides that “[a]t no time during my patdown of [plaintiff] did I put my finger in his rectum, put my hand in his butt crack, grab his buttocks, or otherwise touch him inappropriately. I also did not slam his head/face against the wall.” Affidavit at ¶ 9. CO Dotson adds that during the patdown, plaintiff attempted to spin away from the wall and that he put his hand on plaintiff’s back to force him back on the wall; plaintiff was subsequently placed in handcuffs. During the search of plaintiff’s cell, COs discovered white pills hidden in his mattress. As a result, plaintiff was ordered to go to the mini-infirmary for drug 1Plaintiff’s complaint lists Duffelmeyer rather than Dofflemyer. Case No. 2016-00530 -3- ENTRY testing; however, plaintiff refused direct orders to proceed to the mini-infirmary. CO Dotson provides that as a result plaintiff was escorted to J2 block for security control. CO Dotson avers that no one threatened to assault plaintiff nor did anyone assault plaintiff. {¶7} Captain Clark avers in his affidavit that on July 1, 2016, he authorized CO Dotson to perform a shakedown of cells, including plaintiff’s cell. Clark states that he was thereafter called to go to J2 due to allegations plaintiff made regarding PREA violations. Clark provides that he subsequently contacted the PREA victim support person and the PREA coordinator. Clark denies ordering any CO to search plaintiff’s cell in retaliation for lawsuits being filed. {¶8} CO Dofflemyer avers in his affidavit that on July 1, 2016, he assisted CO Dotson in searching inmates and their cells for contraband. CO Dofflemyer states that while escorting inmates to the showers for a strip search, he observed CO Dotson struggling with plaintiff. CO Dofflemyer proceeded to assist CO Dotson in placing handcuffs on plaintiff. CO Dofflemyer states that because they found unidentified pills in plaintiff’s mattress, plaintiff was ordered to proceed to the mini-infirmary to be drug tested; however, plaintiff refused orders to proceed directly to the mini-infirmary. CO Dofflemyer states that he then used an escort technique to return plaintiff to the mini-infirmary, but it was subsequently decided that plaintiff should proceed to J2 instead. CO Dofflemyer avers that at no time did anyone assault plaintiff, threaten to assault plaintiff, punch him in the face, or pull his pants down. {¶9} Lieutenant Smith avers in his affidavit that he was called to assist in shaking down cells in K8. Smith states that when he arrived, plaintiff was sitting at the table with his hands cuffed. Smith provides that after he was informed of the unidentified pills, he decided that plaintiff needed to be tested for drugs. Smith reports that plaintiff disobeyed orders to go to the mini-infirmary and instead proceeded to the K7 bullpen. Smith states that after plaintiff was escorted back to the mini-infirmary, he decided to Case No. 2016-00530 -4- ENTRY escort plaintiff to security control due to threating comments plaintiff made toward COs. Smith avers that no one punched plaintiff in the face, pulled his pants down, assaulted him, or threatened to assault him. {¶10} “To prove assault under Ohio law, plaintiff must show that the defendant willfully threatened or attempted to harm or touch the plaintiff offensively in a manner that reasonably placed the plaintiff in fear of the contact. To prove battery, the plaintiff must prove that the intentional contact by the defendant was harmful or offensive. Ohio courts have held that, in a civil action for assault and battery, the defendant has the burden of proving a defense of justification, such as the exercise of lawful authority.” (Citations omitted.) Miller v. Ohio Dept. of Rehab. & Corr., 10th Dist. Franklin No. 12AP-12, 2012-Ohio-3382, ¶ 11; see also Brown v. Dept. of Rehab. & Corr., 10th Dist. Franklin No. 13AP-804, 2014-Ohio-1810, ¶ 13 (“A defendant may defeat a battery claim by establishing a privilege or justification defense.”). {¶11} “To recover on a negligence claim, a plaintiff must prove by a preponderance of the evidence (1) that a defendant owed the plaintiff a duty, (2) that a defendant breached that duty, and (3) that the breach of the duty proximately caused a plaintiff’s injury.” Ford v. Ohio Dept. of Rehab. & Corr., 10th Dist. Franklin No. 05AP- 357, 2006-Ohio-2531, ¶ 10. “Ohio law imposes a duty of reasonable care upon the state to provide for its prisoners’ health, care, and well-being.” Ensman v. Ohio Dept. of Rehab. & Corr., 10th Dist. Franklin No. 06AP-592, 2006-Ohio-6788, ¶ 5. “The inmate also bears a responsibility ‘to use reasonable care to ensure his own safety.’” Gumins v. Ohio Dept. of Rehab. & Corr., 10th Dist. Franklin No. 10AP-941, 2011-Ohio-3314, ¶ 20, quoting Macklin v. Ohio Dept. of Rehab. & Corr., 10th Dist. Franklin No. 01AP-293, 2002-Ohio-5069, ¶ 21. {¶12} “The use of force is sometimes necessary to control inmates.” Jodrey v. Ohio Dept. of Rehab. & Corr., 10th Dist. Franklin No. 12AP-477, 2013-Ohio-289, ¶ 17. “Correctional officers considering the use of force must evaluate the need to use force Case No. 2016-00530 -5- ENTRY based on the circumstances as known and perceived at the time it is considered.” Brown at ¶ 15, citing Ohio Adm.Code 5120-9-01(C). “[T]he precise degree of force required to respond to a given situation requires an exercise of discretion by the corrections officer.” Ensman at ¶ 23. “In Ohio Adm.Code 5120-9-01, the Ohio Administrative Code sets forth the circumstances under which correctional officers are authorized to use force against an inmate.” Id. at ¶ 6. {¶13} Ohio Adm.Code 5120-9-01 provides, in pertinent part: {¶14} “(C) Guidelines regarding the use of force. * * * {¶15} “* * * {¶16} “(2) Less-than-deadly force. There are six general circumstances in which a staff member may use force against an inmate or third person. A staff member may use less-than-deadly force against an inmate in the following circumstances: {¶17} “(a) Self-defense from physical attack or threat of physical harm. {¶18} “(b) Defense of another from physical attack or threat of physical attack. {¶19} “(c) When necessary to control or subdue an inmate who refuses to obey prison rules, regulations or orders. {¶20} “(d) When necessary to stop an inmate from destroying property or engaging in a riot or other disturbance. {¶21} “(e) Prevention of an escape or apprehension of an escapee; or {¶22} “(f) Controlling or subduing an inmate in order to stop or prevent self- inflicted harm.” {¶23} “Pursuant to Ohio Adm.Code 5120-9-01(C)(1)(a), correctional officers ‘may use force only to the extent deemed necessary to control the situation.’ Additionally, correctional officers ‘should attempt to use only the amount of force reasonably necessary under the circumstances to control the situation and shall attempt to minimize physical injury.’ Ohio Adm.Code 5120-9-01(C)(1)(b).” Brown at ¶ 16. Also pertinent is Ohio Adm.Code 5120-9-01(B)(3), which defines “excessive force” as “an Case No. 2016-00530 -6- ENTRY application of force which, either by the type of force employed, or the extent to which such force is employed, exceeds that force which reasonably appears to be necessary under all the circumstances surrounding the incident.” {¶24} As stated previously, plaintiff failed to respond to defendant’s motion and failed to offer any evidence to contradict that put forth by defendant. Civ.R. 56(E) provides: “When a motion for summary judgment is made and supported as provided in this rule, an adverse party may not rest upon mere allegations or denials of the party’s pleadings, but the party’s response, by affidavit or as otherwise provided in this rule, must set forth specific facts showing that there is a genuine issue for trial. If the party does not so respond, summary judgment, if appropriate, shall be entered against the party.” {¶25} Upon review of the undisputed affidavit testimony put forth by defendant, the court can only conclude defendant’s employees used only the force necessary to control plaintiff. There is nothing to contradict the testimony put forth by defendant that plaintiff disobeyed direct orders and that no excessive force was used. Furthermore, there is no dispute that plaintiff was not otherwise inappropriately touched as alleged in the complaint. {¶26} Based upon the foregoing, the court concludes that there are no genuine issues of material fact and that defendant is entitled to judgment as a matter of law. As a result, defendant’s motion for summary judgment is GRANTED and judgment is hereby rendered in favor of defendant. All previously scheduled events are VACATED. Court costs are assessed against plaintiff. The clerk shall serve upon all parties notice of this judgment and its date of entry upon the journal. PATRICK M. MCGRATH Judge Case No. 2016-00530 -7- ENTRY cc: Dave Easley, #306-400 Jeanna V. Jacobus P.O. Box 45699 Assistant Attorney General Lucasville, Ohio 45699 150 East Gay Street, 18th Floor Columbus, Ohio 43215-3130 Filed April 13, 2017 Sent to S.C. Reporter 5/5/17
Jann Arden Jann Arden, (born Jann Arden Anne Richards; March 27, 1962) is a Canadian singer-songwriter and actress. She is famous for her signature ballads, "Could I Be Your Girl" and "Insensitive", which is her biggest hit to date. Early life and education Jann Arden was born in Calgary and moved as a child to Springbank, Alberta, where she attended Springbank Community High School. Career Arden was discovered in 1985 by Calgary manager Neil MacGonigill, who worked with her from 1985 to 1998, both managing her career and acting as executive producer of her earlier albums. The two subsequently became estranged. Arden released her critically acclaimed debut album, Time for Mercy in 1993, and followed with a single "I Would Die For You". Both were credited among the six Alberta Recording Industry Awards won by Arden in 1994. Arden's 1994 album Living Under June featured her biggest hit to date outside of Canada, "Insensitive", which was released as a single from the soundtrack to the Christian Slater film Bed of Roses (number 12 on the U.S. Billboard Hot 100). Another single from that same album, "Could I Be Your Girl", has also had significant, and consistent airplay on Canadian adult contemporary radio since its release, and featured a dance remix version which circulated on pop radio at the time. Subsequent albums include 1997's Happy?, 2000's Blood Red Cherry, and 2003's Love Is the Only Soldier. She also released a greatest hits album, Greatest Hurts, in 2001, and a live album, Jann Arden Live with the Vancouver Symphony Orchestra (2002). In 2005, she released her eighth album (her sixth album of new material); self-titled Jann Arden. In 1998, respondents to Chart magazine's year-end reader's poll named Arden the Canadian celebrity most deserving of her own talk show. Arden revealed that one of her brothers is serving a life sentence in prison, and that her song "Hangin' by a Thread" is dedicated to him. Arden released her ninth album, Uncover Me, on February 6, 2007. This album was her first comprising cover songs exclusively, except for one original piece, "Counterfeit Heart". This was followed by her Uncover Me Tour across Canada during the spring of 2007. On the weekend of March 24, 2007, Arden was admitted to intensive care for heart related concerns, diagnosed as Takotsubo cardiomyopathy, a condition commonly associated with acute stress and exhaustion. She had a 2007 USA summer tour with Michael Bublé. In 2010, they also carried the Olympic torch. She co-wrote his 2013 song "Close Your Eyes". In September 2009, Arden released her tenth album, Free, and its first single, "A Million Miles Away," in June. She then undertook a cross-country Canadian tour, which began in November 2009. She toured with proceeds going to the "Raise-a-Reader Concert Series". In November 2010, Arden released her first ever live CD and DVD set, entitled Spotlight. Her latest autobiography, Falling Backwards, was released on November 1, 2011, along with a second album of cover songs, Uncover Me 2. Arden's thirteenth album, Everything Almost, was released April 29, 2014, through Universal Music Canada. In October 2015, Arden released her fourteenth and first Christmas album, A Jann Arden Christmas. In addition to her music, she is also a writer of memoirs: If I Knew, Don't You Think I'd Tell You? (2002), I'll Tell You One Damn Thing, and That's All I Know! (2004), Falling Backwards (2011) and Feeding My Mother (2017). Published in 2017, Arden's book Feeding My Mother: Comfort and Laughter in the Kitchen as My Mom Lives with Memory Loss, relates her involvement with her mother while the latter was experiencing Alzheimer's. She discussed that era in the book: "I am a mother to my mother. It's a massive learning curve, not only because I didn't have children of my own, but because there isn't a handbook telling me what I should or shouldn't be doing. Alzheimer's is a different disease for every single person it inhabits. Everything is trial by fire." Released in 2018, her album These are the Days includes 11 songs about the most difficult time in her life. "My mom and dad both were diagnosed with basically dementia and Alzheimer’s and a litany of other things. My health wasn’t great. I was floundering," she recalled in a CBC interview. In 2018, she launched The Business of Life, a lifestyle podcast on topics such as entrepreneurship, motherhood, writing, relationships and navigating life challenges, which she cohosts with Arlene Dickinson. Acting Arden has also worked as an actress, with supporting or guest roles in the television series Robson Arms, Corner Gas, Hell on Wheels, The Detour, Workin' Moms and Wynonna Earp. She received a Canadian Screen Award nomination for Supporting Actress in a Comedy Series at the 7th Canadian Screen Awards in 2019, for her appearances as Jane Carlson in Workin' Moms. In June 2018, CTV announced that Arden would star in Jann, a comedy television series based on a "fictionalized version" of her own life. The series premiered on March 20, 2019. During the promotion of the series, in which the fictionalized version of Arden is depicted as having recently broken up with a long-term female partner, Arden spoke openly to the press for the first time about having been in relationships with both men and women throughout her life. , Jann is Canada's most popular comedy TV series, drawing more than one million viewers per episode. She has also performed on stage in productions of The Vagina Monologues. Accolades Arden has received a total of 19 Juno Award nominations to date. She has won eight of them, including solo artist of the year in 1994, Songwriter of the Year in 1995 and 2002, and Female Artist of the Year in 1995 and 2001. She has also won awards at the MuchMusic Video Awards, the Prairie Music Awards, the Western Canadian Music Awards and at the ARIA (Alberta Recording Industry Association) Awards. She has 17 top ten singles from eight albums. In March 2006, it was announced that she would receive a star on Canada's Walk of Fame. In November 2006, Arden received the National Achievement Award from the Society of Composers, Authors, and Music Publishers of Canada (SOCAN) for having six singles reach the 100,000 airplay mark on Canadian radio. She was awarded the prize at a gala in Toronto. In November 2007, Arden was inducted into the Canadian Association of Broadcasters Hall of Fame, and was the winner of the International Achievement Award at the 2007 Western Canadian Music Awards. In 2012, Arden was awarded the Queen's Diamond Jubilee Medal. On December 29, 2017, Arden was appointed as a Member of the Order of Canada for her 'achievements as a singer-songwriter and broadcaster, and for her extensive charitable work.' In 2020, Arden was named by the Canadian Academy of Recording Arts and Sciences as its 2020 inductee into the Canadian Music Hall of Fame. Notable appearances She has made a number of charity appearances, including appearances in Africa for World Vision, performing at Live 8 and the MAC Cosmetics Fashion Cares AIDS benefits. She also appeared in the opening segment of an episode from the sitcom Ellen starring Ellen DeGeneres, originally aired on January 8, 1997. She toured with Michael Bublé on the U.S. and European legs of his 2005 tour, and again toured with him on his 2007 U.S. tour. She sang "O Canada" at the 2006 NBA All-Star Game. She was a judge on season three of Top Chef Canada, episode 13 entitled "Wild Rose Finale", where she was the judge in the elimination portion of the episode. At the 2006 Juno Awards, to counter host Pamela Anderson's on-stage anti-seal hunting, Arden generated cheers and controversy when she joked that her bra was "made entirely of seal eyelids". "Run Like Mad" was originally recorded to be the international theme song for Dawson's Creek, however it was only used for the first season. The song was used again on the DVD sets from seasons 3-6 when Paula Cole's "I Don't Want to Wait" became too expensive to license. Other songs including "Good Mother" and "You Don't Know Me" were also featured on the series. Discography Time for Mercy (1993) Living Under June (1994) Happy? (1997) Blood Red Cherry (2000) Love Is the Only Soldier (2003) Jann Arden (2005) Uncover Me (2007) Free (2009) Uncover Me 2 (2011) Everything Almost (2014) A Jann Arden Christmas (2015) These Are the Days (2018) References External links Category:1962 births Category:Living people Category:People from Rocky View County Category:Canadian buskers Category:Canadian female guitarists Category:Canadian pop guitarists Category:Canadian female singer-songwriters Category:Actresses from Calgary Category:Musicians from Calgary Category:Juno Award for Single of the Year winners Category:A&M Records artists Category:Zoë Records artists Arden, Jann Category:Juno Award for Songwriter of the Year winners Category:Juno Award for Artist of the Year winners Category:Juno Award for Breakthrough Artist of the Year winners Category:Members of the Order of Canada Category:Canadian women podcasters Category:LGBT musicians from Canada Category:Canadian television actresses Category:20th-century Canadian singers Category:21st-century Canadian singers Category:21st-century Canadian actresses
Q: Why is a paraboloid hyperboloid shape preferred on some structures? Why is preferred on the construction of big stadium roofs and of cooling towers, per example? What is the advantage of this geometric figure that makes it more economical? A: Assuming that you mean a "Hyperbolic Paraboloid", the answer is that it's easy to make from common construction materials due to the fact that the surface can be made up of straight lines. There are other reasons to choose a shape like this over e.g. a flat or pitched roof (aesthetics, drainage, etc.), but I take your question to mean "why choose this specific mathematical shape, rather than something else similar (that apparently ticks all the same boxes)?"
--- abstract: 'We study the question of complete gauge independence of the fermion pole mass by choosing a general class of gauge fixing which interpolates between the covariant, the axial and the Coulomb gauges for different values of the gauge fixing parameters. We derive the Nielsen identity describing the gauge parameter variation of the fermion two point function in this general class of gauges. Furthermore, we relate the denominator of the fermion propagator to the two point function. This then allows us to study directly the gauge parameter dependence of the denominator of the propagator using the Nielsen identity for the two point function. This leads to a simple proof that, when infrared divergences and mass shell singularities are not present at the pole, the fermion pole mass is gauge independent, in the complete sense, to all orders in perturbation theory. Namely, the pole is not only independent of the gauge fixing parameters, but has also the same value in both covariant and non-covariant gauges.' author: - 'Ashok K. Das,$^{a,b}$ R. R. Francisco$^{c}$ and J. Frenkel$^{c}$ [^1]' title: On the gauge independence of the fermion pole mass --- Introduction ============ In a relativistic field theory the mass of a particle is given by the Casimir (operator) relation $$P_{\\mu}P^{\\mu} - M_{p}^{2} \\mathbbm{1} = 0,\\label{intro_1}$$ acting on the one particle state. In an interacting theory, this is computationally quite involved. Instead, therefore, one defines the physical mass of the particle to be given by the pole of its propagator. This follows because the dynamical equation for a relativistic field (free equation after taking quantum corrections into account) is expected to encode the Casimir relation in some form and, therefore, the zero of the two point function or the pole of the propagator defines the physical mass of the particle. This is computationally much simpler and the mass of a particle can be calculated in a straightforward manner order by order in perturbation theory. In a theory of fermions interacting with a gauge field, to do any calculaion in perturbation theory, one needs to choose a gauge. Normally one chooses a class of covariant gauge fixing by adding a term to the Lagrangian density of the form (say, in an Abelian theory) $${\\cal L}_{\\rm\\sc GF} = - \\frac{1}{2\\xi}\\, (\\partial\\cdot A)^{2},\\label{intro_2}$$ which maintains manifest covariance in the intermediate steps of any calculation. Here $\\xi$ denotes a gauge fixing parameter. For $\\xi=1$ the gauge is known as the Feynman gauge while, for $\\xi=0$, it is called the Landau gauge and so on. However, there are also other possible choices of gauge fixing, generically known as non-covariant gauges. Here the choice of gauge fixing depends on a direction conventionally denoted by $n^{\\mu}$ (we will discuss this in more detail in sections [2]{} and [3]{}). The class of generalized axial gauges and Coulomb gauges belong to this class and are also known as physical gauges. In these gauges (for example, in the axial gauges) properties such as asymptotic freedom (in a non-Abelian gauge theory) can be seen in a very simple manner since ghost particles decouple. As a result of gauge fixing in a gauge theory, the two point function and the propagator (which is a Green’s function) of a fermion interacting with a gauge field become gauge dependent. The gauge dependence has two distinct sources, namely, the propagator depends on the gauge fixing parameter (for example, $\\xi$ in covariant gauges) and second, its actual form depends on the class of gauge fixing chosen (for example, whether it is the class of covariant or axial or Coulomb gauges). Nevertheless, one expects that the pole of the propagator should be independent of gauge since it defines a physical quantity (mass). This gauge independence should be complete in the sense that the pole mass should not only be gauge parameter independent within a class of chosen gauges (say, in covariant gauges), but should also have the same value in different classes of gauges (covariant or non-covariant). It is indeed important to demonstrate that this expectation is true and this question has been studied within the class of covariant gauges from several points of view [@tarrach; @johnston; @reinders; @gray; @brown; @brecken; @kronfeld]. For example, in [@tarrach] it was shown in covariant gauges, both in QED and QCD, that the fermion mass is gauge parameter ($\\xi$) independent up to two loops in perturbation theory. In [@kronfeld] this argument was extended in covariant gauges to show that, in these theories, the fermion pole mass is infrared finite and gauge parameter independent to all orders in perturbation theory. The most direct way to study the gauge dependence of any Green’s function or amplitude is through the Nielsen identities [@nielsen; @das] which follow from the BRST invariance [@brst] of the theory. References [@johnston; @brecken], in particular, used this approach (again in covariant gauges) to address the question of the gauge parameter independence of the fermion pole mass to all orders in perturbation theory by studying the gauge parameter variation of the fermion two point function. These studies are all very important even though all of them are carried out within the given class of covariant gauges in . The gauge parameter independence shows, for example, that the fermion pole mass is the same in the Feynman gauge ($\\xi=1$) as in the Landau gauge ($\\xi=0$). However, these studies do not address the second source of gauge dependence, namely, one cannot conclude from these studies that the pole mass in the covariant gauges is the same as in non-covariant gauges like the axial gauges or the Coulomb gauges. This still remained to be demonstrated. On the other side, there was very little systematic study of the question of gauge independence of the fermion pole mass in non-covariant gauges [@kummer; @frenkel; @leibbrandt; @fradkin; @bernstein; @andrasi]. This is a consequence of the fact that when there is an additional structure ($n^{\\mu}$) present, the fermion two point function has a more complicated structure (than in covariant gauges) and extracting the mass from a study of the fermion two point function is nontrivial. In fact, since in this case amplitudes depend both on the momentum as well as the longitudinal component of the momentum (with respect to $n^{\\mu}$) of the particle independently, it was an open question as to whether a consistent mass can even be defined in such theories (we will discuss these issues in more detail in the next section). In a recent brief communication [@plb], using Nielsen identities we gave a simple proof of the complete gauge independence of the fermion pole mass in theories without any infrared divergence and mass shell singularities. This proof shows that the pole mass is gauge parameter independent in both covariant as well as non-covariant gauges and also shows that it is the same in different classes of gauges. This is achieved with three basic ingredients. First, we choose a general class of gauges which interpolate between the covariant and non-covariant gauges (axial and Coulomb) depending on the choice of the gauge fixing parameters [@taylor]. We derive the Nielsen identity for the gauge parameter variation of the fermion two point function in such a theory. Finally, since extracting the mass from the two point function is problematic in such a gauge, we study directly the gauge parameter variation of the denominator of the propagator by relating it to the fermion two point function (and using the Nielsen identity). In this long paper, we give details of our analysis and discuss various other aspects associated with this question. In section [2]{}, we describe the generalized axial gauge fixing (in QED) in detail as well as the structure of the fermion self-energy (in the presence of an additional direction $n^{\\mu}$) commonly assumed for such a theory. Using charge conjugation invariance in gauge theories, we show that this structure simplifies. The conventional definition of the fermion mass, in such theories, is taken directly from the properties of the fermion two point function in covariant gauges. We show that such a definition becomes gauge parameter dependent and does not coincide with the pole of the propagator starting at two loops. This is shown in two ways, first in a completely algebraic manner starting from the definition of the conventional mass taken for such theories and comparing it with the zero of the denominator of the propagator and second from an explicit two loop calculation. This makes clear that the standard definition of the mass taken from studies in covariant gauges does not work in non-covariant gauges and one should really look at the zero of the denominator (of the propagator) to determine the mass. In this section, we also relate the denominator of the fermion propagator to the two point function for later use in showing the gauge independence of the pole of the propagator. In section [3]{}, we discuss in detail the choice of an interpolating gauge (still in QED) and derive the Nielsen identity describing the gauge parameter variation of the fermion two point function. In section [4]{} we study directly the gauge parameter variation of the denominator of the propagator using the Nielsen identity for the fermion two point function as well as the relation between the denominator and the two point function. The proof of complete gauge independence then follows in a simple manner. In this section, we also show explicitly the gauge parameter independence of the zero of the denominator (pole of the propagator) up to two loops in the generalized axial gauges. The paper concludes with a short summary of our results and the derivation of the Nielsen identities in QCD in the interpolating gauge is described in the appendix. Axial gauges ============ As we have already mentioned, non-covariant gauges are gauges where the gauge fixing uses an additional direction, $n^{\\mu}$, to fix the gauge. (We recall that covariant gauges use only the covariant gradient vector to fix the gauge.) For example, one may fix the gauge using the longitudinal component of the gradient along the given direction. Such gauges are known as generalized axial gauges. One may alternatively use the transverse component of the gradient (to $n^{\\mu}$) to fix the gauge. In particular, if the direction $n^{\\mu}$ is timelike, then such gauges are known as generalized Coulomb gauges. Non-covariant gauges are also known as physical gauges. In generalized axial gauges, the gauge fixing Lagrangian density for QED is given by $${\\cal L}_{\\sc\\rm GF} = - \\frac{\\beta^{2}}{2} \\left(\\partial_{\\sc L}\\cdot A\\right)^{2},\\label{axial_0}$$ where $\\beta$ is the (constant) gauge fixing parameter and the longitudinal component of the gradient along $n^{\\mu}$ is given by $$\\partial^{\\mu}_{\\sc L} = \\frac{(n\\cdot \\partial) n^{\\mu}}{n^{2}}.\\label{axial_0a}$$ For simplicity of discussions we assume that $n^{2}\\neq 0$. With such a gauge fixing, the photon propagator has the form [@frenkel] $$D_{\\mu\\nu} (p) = - \\frac{1}{p^{2}}\\left[\\eta_{\\mu\\nu} - \\frac{n_{\\mu}p_{\\nu} + n_{\\nu}p_{\\mu}}{n\\cdot p} + \\frac{p_{\\mu}p_{\\nu}n^{2}}{(n\\cdot p)^{2}}\\left(1 + \\frac{n^{2} p^{2}}{\\beta^{2} (n\\cdot p)^{2}}\\right)\\right].\\label{axial_0b}$$ It is worth noting here that the terms inside the square brackets are dimensionless and of order zero in both $n$ and $p$. Furthermore, the propagator, in addition to being symmetric in $p^{\\mu}$, is also invariant under $n^{\\mu}\\leftrightarrow - n^{\\mu}$. This symmetry is quite important as we will see in a short while. (The homogeneous axial gauge is obtained in the limit $\\beta\\rightarrow \\infty$.) In axial gauges, the pole at $p^{2} = 0$ is treated, as usual, with the Feynman prescription while the poles at $n\\cdot p =0$ are handled with the principal value (PV) prescription. The other thing to emphasize is that the photon propagator has a part (the first term) that coincides with the propagator in the Feynman gauge and is independent of the gauge fixing parameters $\\beta, n^{\\mu}$ while the rest of the terms depend manifestly on these parameters. So, in calculations studying gauge independence, sometimes it is useful to write the photon propagator in the generalized axial gauge as $$D_{\\mu\\nu} = D_{\\mu\\nu}^{(Feynman)} + \\widetilde{D}_{\\mu\\nu} (n, \\beta).\\label{axial_0c}$$ In this section, we will start by recapitulating what is already known about the fermion mass in axial gauges. Let us recall that in covariant gauges the general structure of the fermion self-energy (in a massive theory) is simpler and has the form $$\\Sigma^{(c)} (p) = m A + B p\\sl,\\label{axial_1}$$ where the coefficients $A, B$ are dimensionless functions of the Lorentz invariants $(p^{2},m)$ (in addition to the gauge fixing parameter in a gauge theory). In non-covariant gauges, however, because of the presence of a nontrivial direction vector $n^{\\mu}$, the structure of the fermion self-energy becomes a bit more involved and is conventionally parameterized in the form [@pagels; @konetschny] $$\\Sigma^{\\rm (nc)} (p) = m A + B p\\sl + C p\\sl_{\\sc L} + \\frac{m D}{p^{2}_{\\sc L}}\\left(p\\sl_{\\sc L} p\\sl - p\\sl p\\sl_{\\sc L}\\right),\\label{axial_2}$$ where $p^{\\mu}_{\\sc L}$ denotes the component of the four momentum $p^{\\mu}$ along the given direction $n^{\\mu}$. We note here that given a direction vector $n^{\\mu}$, any other vector can be decomposed into components parallel and perpendicular to this vector. For example, the momentum vector of the fermion can now have components $$p^{\\mu}_{\\sc L} = \\frac{(n\\cdot p)}{n^{2}}\\,n^{\\mu},\\quad p^{\\mu}_{\\sc T} = p^{\\mu} - p^{\\mu}_{\\sc L}.\\label{axial_3}$$ Therefore, we can now construct three Lorentz invariants $p^{2}, p^{2}_{\\sc L}$ and $p^{2}_{\\sc T}$. However, not all three of these will be independent, rather they will be related as $p^{2} = p^{2}_{\\sc L} + p^{2}_{\\sc T}$. As a result, only two of them are independent and conventionally, one chooses $p^{\\mu}, p^{\\mu}_{\\sc L}$ as independent vectors which is reflected in . The coefficients $A, B, C$ and $D$ in are, in general, dimensionless functions of $(p^{2},p^{2}_{\\sc L}, n^{2}, m)$. One can understand the rationale behind the structures in and simply as follows. A complete basis for matrices in the Dirac space is given by the matrices (generators of the Clifford algebra) $\\mathbbm{1}, \\gamma^{\\mu}, \\gamma^{[\\mu}\\gamma^{\\nu]}, \\gamma^{[\\mu}\\gamma^{\\nu}\\gamma^{\\lambda]},\\cdots$. Here the square bracket implies anti-symmetrization in the indices. When there is only one independent vector $p^{\\mu}$ (as in covariant gauges), the most general structure for a Dirac matrix (without any Lorentz index), in a parity conserving theory, is given by . On the other hand, if there are two nontrivial independent vectors $p^{\\mu}, p^{\\mu}_{\\sc L}$, it allows for more terms in the expansion in the basis leading to (in a parity conserving theory). It is clear that not having an additional direction $n^{\\mu}$ (or $p^{\\mu}_{\\sc L}$) is equivalent to having the coefficients $C=D=0$ in and in this case, the structure reduces to . The general structure of the self-energy in follows only from the simple structures of the basis of the Clifford algebra and this form has been conventionally used in all earlier discussions. However, in a gauge theory like QED, there are other symmetries which may limit the number of terms in . One such symmetry is the discrete charge conjugation symmetry which requires that the fermion two point function satisfies $${\\cal C} \\left(S^{-1} (p)\\right)^{T} {\\cal C}^{-1} = S^{-1} (-p),\\label{axial_4}$$ where $T$ denotes the transpose of a matrix and ${\\cal C}$ denotes the charge conjugation matrix defined by (we distinguish this from the coefficient $C$ in with a curly letter) $${\\cal C}^{-1} \\gamma^{\\mu} {\\cal C} = - \\left(\\gamma^{\\mu}\\right)^{T},\\quad {\\cal C} \\left(\\gamma^{\\mu}\\right)^{T} {\\cal C}^{-1} = - \\gamma^{\\mu}.\\label{axial_5}$$ Requiring charge conjugation invariance, namely, for $$S^{-1}_{(nc)} (p) = p\\sl - m - \\Sigma^{(nc)} (p),\\label{axial_6}$$ leads to $$\\begin{aligned} A (-p) & = A(p),&\\quad &B (-p) = B (p),\\notag\\\\ C(-p) & = C(p),&\\quad &D(-p) = - D(p).\\label{axial_7}\\end{aligned}$$ The last condition on the coefficient $D$ can be satisfied only if it depends on $p^{\\mu}$ through an odd power of the Lorentz invariant $n\\cdot p$. However, this would violate the symmetry under $n^{\\mu}\\leftrightarrow -n^{\\mu}$ present in the photon propagator in (the $n^{\\mu}$ dependence in the self-energy arises through the photon propagator). Therefore, we see that charge conjugation invariance in gauge theories like QED requires that $$D = 0,\\label{axial_8}$$ We have verified explicitly that is true at one loop in $n$-dimensions. However, the charge conjugation symmetry restricts this coefficient to vanish identically to all orders. As a result, the general structure of the fermion self-energy is, in fact, simpler than conventionally assumed and has the form $$\\Sigma^{\\rm (nc)} (p) = m A + B p\\sl + C p\\sl_{\\sc L},\\label{axial_9}$$ with the coefficients $A, B, C$ depending only on $(p^{2}, p_{\\sc L}^{2}, m, n^{2})$ (as well as the gauge fixing parameter $\\beta$). The coefficients $A, B, C$ get contributions from loop diagrams at every order and represents the self-energy to all orders. Determining the mass -------------------- Let us recapitulate what is done in covariant gauges where things are simpler. The fermion two point function satisfies the equation $$\\begin{aligned} S^{-1}_{(c)}\\, u\\Big\|_{p^{2}=M_{(c)}^{2}} & = (p\\sl -m - \\Sigma^{(c)}) u\\Big\|_{p^{2}=M_{(c)}^{2}}\\notag\\\\ & = (p\\sl - M_{(c)}) u\\Big\|_{p^{2}=M_{(c)}^{2}} = 0,\\label{axial_10}\\end{aligned}$$ where $M_{(c)}$ corresponds to the pole of the propagator (or the vanishing of the determinant). It follows now that $$\\overline{u}\\, S^{-1}_{(c)}\\, u\\Big\|_{p^{2}=M_{(c)}^{2}} = \\overline{u}\\left(p\\sl -M_{(c)}\\right)u\\Big\|_{p^{2}= M_{(c)}^{2}} = 0,\\label{axial_11}$$ which allows us to identify $$M_{(c)} = m + \\overline{u}\\,\\Sigma^{(c)}\\, u\\Big\|_{p^{2} = M_{(c)}^{2}}.\\label{axial_12}$$ The dependence on an additional direction $n^{\\mu}$, on the other hand, makes the extraction of the physical mass more complicated. Conventionally, one assumes that the mass, $p^{2} = \\widetilde{M}^{2}$, can also be obtained, as in covariant gauges (see ), from the relation $$\\begin{aligned} \\overline{u} S^{-1}_{\\rm (nc)} (p) u\\Big\|_{p^{2}=\\widetilde{M}^{2}} & = \\overline{u}(p\\sl - m - \\Sigma^{(nc)}) u\\Big\|_{p^{2}=\\widetilde{M}^{2}}\\notag\\\\ & = \\overline{u} (p\\sl -\\widetilde{M})u\\Big\|_{p^{2}=\\widetilde{M}^{2}}= 0.\\label{axial_13}\\end{aligned}$$ This would then determine, as in , that the mass $\\widetilde{M}$ is given by $$\\widetilde{M} = m + \\overline{u}\\,\\Sigma^{\\rm (nc)}\\, u\\Big\|_{p^{2}=\\widetilde{M}^{2}}.\\label{axial_14}$$ In fact, this mass can be evaluated from the fermion self-energy order by order and at one loop it turns out [@konetschny] that $\\widetilde{M}$ is gauge parameter independent (independent of $\\beta, n^{\\mu}$). This one loop calculation has led to the expectation that the mass $\\widetilde{M}$ determined from is gauge parameter independent to all orders as in covariant gauges and should correspond to the pole of the propagator. However, this expectation fails beginning at two loops and we will show this, in the following, in two different ways. First, we will show algebraically that $\\widetilde{M}$ does not correspond to the pole of the fermion propagator and the difference between the two, starting at two loops, is manifestly gauge parameter dependent ($n^{\\mu}$ dependent). Second, we will demonstrate through an explicit calculation of the fermion self-energy at two loops that $\\overline{u}\\,\\Sigma^{\\rm (nc)}\\,u$ is manifestly gauge dependent at $p^{2} = \\widetilde{M}^{2}$ (consistent with the algebraic result) so that $\\widetilde{M} = \\widetilde{M} (n)$ if holds. (The explicit calculation shows that $\\widetilde{M}$ does not depend on the parameter $\\beta$ at two loops.) The reason for this unexpected behavior can be traced to the fact that in non-covariant gauges where there is an additional structure ($n^{\\mu}$) present, $\\overline{u}\\, S^{-1} (p)u\\big\|=0$ does not imply that $S^{-1} (p)u\\big\|=0$ where the restriction implies evaluating this at $p^{2}=\\widetilde{M}^{2}$ (of course, the converse is always true). As a result $\\widetilde{M}$ determined by relation does not represent the pole of the propagator beyond the one loop order. To demonstrate all this, we need the form of the fermion propagator which we derive in the next subsection. Fermion propagator ------------------ Let us recall from the form of the fermion self-energy in that in the (non-covariant) axial gauge the fermion two point function can be written as $$S^{-1}(p) = {\\cal A} - {\\cal B} \\mathbbm{1},\\label{axial_15}$$ where ${\\cal A}$ is a nontrivial matrix while ${\\cal B}$ is a scalar of the forms $${\\cal A} = (1-B) p\\sl - C p\\sl_{\\sc L},\\quad {\\cal B} = m (1+A).\\label{axial_16}$$ It is straightforward to check from (and the properties of the Dirac gamma matrices as well as the definition of the longitudinal momentum) that $${\\cal A}^{2} = \\left( (1-B)^{2} p^{2} + (C^{2} - 2C (1-B)) p_{\\sc L}^{2}\\right) \\mathbbm{1}.\\label{axial_17}$$ In such a case, the propagator (up to a factor $i$) can be obtained in a simple manner to have the form $$S (p) = \\frac{\\cal N}{\\cal D},\\label{axial_18}$$ where (the identity matrix in the denominator is not relevant and we have used ) $$\\begin{aligned} {\\cal N} & = {\\cal A} + {\\cal B} \\mathbbm{1} = - {\\cal C} (S^{-1} (p))^{T} {\\cal C}^{-1} = - S^{-1} (-p),\\label{axial_19}\\\\ {\\cal D} & = {\\cal A}^{2} - {\\cal B}^{2} = (1-B)^{2} p^{2} + (C^{2} - 2C (1-B))p_{\\sc L}^{2} - m^{2} (1+A)^{2}.\\label{axial_20}\\end{aligned}$$ The pole of the propagator is determined from the zero of the denominator ${\\cal D}$ and since the denominator depends on both $p^{2}$ and $p_{\\sc L}^{2}$, it is not clear [a priori]{} whether a mass can even be defined. (This is quite different from covariant gauges.) For example, suppose the zero of the denominator occurs at $p^{2} = M_{p}^{2}$, then from we obtain $$M_{p}^{2} = \\frac{[m^{2}(1+A)^{2} - (C^{2} - 2C(1-B))p_{\\sc L}^{2}]}{(1-B)^{2}}\\Big\|_{p^{2}=M_{p}^{2}},\\label{axial_21}$$ so that, in general, the location of the pole of the propagator seems to depend on the longitudinal momentum $p_{\\sc L}$ and, therefore, cannot define a mass (unless all the dependence on the longitudinal momentum $p_{\\sc L}$ cancels out). As we will show in section [4]{} using the Nielsen identity, this is indeed the case and $M_{p}$ is, in fact, independent of the gauge parameters $\\beta$ as well as $n^{\\mu}$. For later use, we note from - that we can write $$\\begin{aligned} {\\cal D} \\mathbbm{1} & = - S^{-1}(p) {\\cal C} (S^{-1}(p))^{T} {\\cal C}^{-1}\\notag\\\\ & = - S^{-1} (p) S^{-1} (-p).\\label{axial_22}\\end{aligned}$$ Alternatively, taking the matrix trace in we determine the scalar denominator of the propagator to be given by $$\\begin{aligned} {\\cal D} & = - \\frac{1}{2^{[n/2]}}\\, \\text{Tr} \\left(S^{-1}(p){\\cal C} (S^{-1} (p))^{T} {\\cal C}^{-1}\\right)\\notag\\\\ & = - \\frac{1}{2^{[n/2]}}\\,\\text{Tr}\\left(S^{-1}(p) S^{-1} (-p)\\right).\\label{axial_23}\\end{aligned}$$ Here $n$ denotes the dimensionality of space-time, $[n/2]$ represents the integer part of $n/2$ and we have used the fact that, in $n$-dimensions, the Dirac matrices are $2^{[n/2]}\\times 2^{[n/2]}$ matrices. (For completeness, note from and that $S^{-1} (p)$ and $S^{-1} (-p)$ commute.) We will show in section [4]{} that the pole of the propagator given in is gauge independent. For the moment, we only note that since $A,B,C$ receive contributions at various loops, the pole mass" $M_{p}$ can also be expanded in powers of loops as $$M_{p} = M_{p}^{(0)} + M_{p}^{(1)} + M_{p}^{(2)} + \\cdots,\\label{axial_24}$$ with the tree level mass identified with $M_{p}^{(0)} = m$ (namely, at tree level $A^{(0)}=B^{(0)}=C^{(0)}=0$). On the other hand, $\\widetilde{M}$ is defined in and to evaluate this we need an expression for $\\overline{u} \\gamma^{\\mu}u$. In covariant theories with momentum as the only available four vector, this is normally determined to be $\\overline{u} \\gamma^{\\mu} u\\big\|_{p^{2}=M^{2}} = \\frac{p^{\\mu}}{M}$ (so that we have $\\overline{u}\\,p\\sl\\, u\\big\|_{p^{2}=M^{2}} = M$). When there is an additional structure ($n^{\\mu}$ or $p_{\\sc L}^{\\mu}$) present, this generalizes to $$\\overline{u} \\gamma^{\\mu} u\\Big\|_{p^{2}=\\widetilde{M}^{2}} = (1-a)\\,\\frac{p^{\\mu}}{\\widetilde{M}} + a \\widetilde{M}\\,\\frac{p_{\\sc L}^{\\mu}}{p_{\\sc L}^{2}}.\\label{axial_25}$$ Here $a$ is a nontrivial parameter, in general, beginning at one loop and beyond since the additional structures arise in the self-energy only in that order. It follows from that (see also ) $$\\begin{aligned} & \\overline{u}\\, p\\sl\\, u\\Big\|_{p^{2}=\\widetilde{M}^{2}} = \\widetilde{M},\\notag\\\\ & \\overline{u}\\, p\\sl_{\\sc L}\\, u\\Big\|_{p^{2}=\\widetilde{M}^{2}} = \\frac{p_{\\sc L}^{2}}{\\widetilde{M}} - a \\widetilde{M}\\left(\\frac{p_{\\sc L}^{2}}{\\widetilde{M}^{2}} -1\\right).\\label{axial_26}\\end{aligned}$$ Using , we can now evaluate $\\widetilde{M}$ from the definition in leading to $$\\widetilde{M}^{2} = \\frac{1}{(1-B)^{2}}\\left[m^{2}(1+A)^{2} - C^{2} \\left(\\frac{p_{\\sc L}^{2}}{\\widetilde{M}} - a\\widetilde{M}\\left(\\frac{p_{\\sc L}^{2}}{\\widetilde{M}^{2}} -1\\right)\\right)^{2} + 2C(1-B) \\left(p_{\\sc L}^{2} - a \\widetilde{M}^{2} \\left(\\frac{p_{\\sc L}^{2}}{\\widetilde{M}^{2}} -1\\right)\\right)\\right]_{p^{2}=\\widetilde{M}^{2}}.\\label{axial_27}$$ Comparing and , it is clear that $M_{p}$ and $\\widetilde{M}$ are, in general, different, but it is not clear at what order the difference arises. To that end, we note that we can also expand $$\\widetilde{M} = \\widetilde{M}^{(0)} + \\widetilde{M}^{(1)} + \\widetilde{M}^{(2)} + \\cdots.\\label{axial_28}$$ From and we can now determine $$\\begin{aligned} \\widetilde{M}^{(0)} & = M_{p}^{(0)} = m,\\notag\\\\ \\widetilde{M}^{(1)} & = M_{p}^{(1)} = m (A^{(1)} + B^{(1)}) + C^{(1)}\\frac{p_{\\sc L}^{2}}{m}\\Big\|_{p^{2}=m^{2}},\\notag\\\\ \\widetilde{M}^{(2)} & = M_{p}^{(2)} - \\left(\\!(C^{(1)})^{2}\\frac{p_{\\sc L}^{2}}{2m} + ma^{(1)}C^{(1)}\\!\\right)\\!\\!\\left(\\frac{p_{\\sc L}^{2}}{m^{2}}-1\\right)_{p^{2}=m^{2}},\\label{axial_29}\\end{aligned}$$ and so on. Namely, $\\widetilde{M}$ defined by coincides with the pole of the propagator only up to one loop, but this equivalence fails beginning at two loops. If $M_{p}$ is gauge independent, as we will see in section [4]{}, then shows that $\\widetilde{M}$ becomes manifestly gauge dependent beginning at two loops. However, note from that in the special gauge $n^{\\mu}\\parallel p^{\\mu}$ or $p_{\\sc L}^{\\mu} = p^{\\mu}$, the difference vanishes. This is, in fact, not just an accident at two loops, rather it holds to all orders which can be seen as follows. In the gauge $p_{\\sc L}^{\\mu} = p_{\\mu}$, we note that and reduce to the same equation and, therefore, coincide to all orders. Another way of seeing this is to note that in the special gauge $p_{\\sc L}^{\\mu} = p^{\\mu}$, there is no additional structure and the fermion two point function has the same structure as in a covariant gauge for which the two equations and are equivalent. We can also explicitly evaluate the self-energy through Feynman diagrams and determine $\\widetilde{M}$ from there. It is already known from such a calculation that $\\widetilde{M}$ is gauge parameter independent (independent of $\\beta, n^{\\mu}$) at one loop. So, let us concentrate on the contributions at two loops. At this order the relevant Feynman diagrams are given by Fig. \\[fig1\\]. ![Feynman diagrams for the fermion self-energy in QED at two loops.[]{data-label="fig1"}](twoloop) Here the diagrams $(a), (b), (c)$ denote the standard two loop graphs while the diagram in $(d)$ represents the two loop contribution coming from the one loop mass correction. We note that since the photon self-energy in $(c)$ is transverse, the last term in the photon propagator in gives vanishing contribution so that this diagram is independent of $\\beta$. In fact, the $\\beta$ dependent terms in all the other diagrams identically vanish because of the PV prescription. There are several other cancellations in the $n^{\\mu}$ dependent terms involving diagrams $(a), (b), (c), (d)$ and the final result for $\\widetilde{M}$ from this explicit calculation takes the factorized form (in $n$-dimensions) $$\\widetilde{M} = M^{(Feynman)} + \\frac{e^{4}}{(2\\pi)^{2n}}\\,\\overline{u} (p) \\int \\frac{d^{n}q_{1}}{q_{1}^{2} (n\\cdot q_{1})}\\, n\\sl \\frac{1}{p\\sl + q\\sl_{1} - m}\\, (p\\sl - m) \\int \\frac{d^{n}q_{2}}{q_{2}^{2} (n\\cdot q_{2})}\\,\\frac{1}{p\\sl + q\\sl _{2} - m}\\, n\\sl\\, u (p)\\Big\|_{p^{2}=m^{2}},\\label{axial_30}$$ where $q_{1}, q_{2}$ denote the two internal loop momenta and $M^{(Feynman)}$ is the mass obtained from the first term ($\\beta, n^{\\mu}$ independent term) in the propagator in or . Since $M^{(Feynman)}$ is independent of the gauge parameters, it shows explicitly that $\\widetilde{M}$ is manifestly gauge dependent at two loops consistent with the algebraic result in . The reason for this gauge dependence is clear from the structure in , namely, that it is not the factor $(p\\sl - m)$, rather $n\\sl$ which occurs at the two ends. Since $p\\sl$ and $n\\sl$ do not commute, we cannot move $(p\\sl -m)$ move past $n\\sl$ to obtain a vanishing result for the second term. However, note that if $n^{\\mu}$ is parallel to $p^{\\mu}$, then each of the (factorized) integrals can be evaluated to have the form $(a p\\sl + b)$ which will commute with $(p\\sl -m)$ and, in this case, we can take the factor $(p\\sl - m)$ to one end to annihilate the spinor. So, only for this special gauge will $\\widetilde{M}$ coincide with $M^{(Feynman)}$ as we have also seen in the algebraic method. As we have tried to emphasize in this section, the conventionally accepted definition of mass of the fermion $\\widetilde{M}$ in non-covariant gauges, , does not coincide with the pole of the propagator $M_{p}$ beyond one loop and becomes manifestly gauge parameter dependent. However, we are yet to show that the actual pole defines a gauge independent mass. As we have already pointed out in , it is not clear that we can even define a meaningful mass in non-covariant gauges. In the next two sections, we will show through Nielsen identities that the pole $M_{p}$ indeed defines a mass and is gauge independent in the complete sense. Nielsen identity in an interpolating gauge ========================================== We know that the fermion self-energy and, therefore, the two point function become gauge dependent once a gauge fixing condition has been chosen and the gauge parameter variation of the fermion two point function is best studied through the Nielsen identities. However, we wish to study the question of gauge independence of the fermion pole mass completely in the sense that we wish to show that the pole mass is not only independent of the gauge fixing parameter within a given class of gauges such as covariant or Coulomb or axial gauges, but also has the same value in all of these gauges. We achieve this in three basic steps, (i) choose a gauge fixing which will interpolate between covariant, Coulomb and axial gauges for different values of the gauge fixing parameters, (ii) derive the Nielsen identity for the gauge parameter variation of the fermion two point function for such a gauge fixing and (iii) study the gauge parameter variation of the zero of the denominator (of the propagator) , using the Nielsen identity for the two point function as well as the relation between the denominator and the two point function already discussed in . In this section, we only take up the first two steps leaving the last to the next section. Choice of an interpolating gauge -------------------------------- Let us consider massive QED in $n$ space-time dimensions (the generalization to QCD is discussed in the appendix) described by the Lagrangian density $${\\cal L}_{\\rm inv} = - \\frac{1}{4}\\, F_{\\mu\\nu}F^{\\mu\\nu} + \\overline{\\psi} (i D\\!\\sl - m) \\psi.\\label{nielsen_1}$$ As the first step, our goal is to study this theory in a general class of gauges which can interpolate between the covariant, the Coulomb and the axial gauges. To that end, we choose a gauge fixing Lagrangian density of the form [@taylor] $${\\cal L}_{\\rm\\sc GF} = - \\frac{1}{2}\\left(\\Lambda^{\\mu} (\\partial) A_{\\mu}\\right)^{2},\\label{nielsen_2}$$ where $$\\Lambda^{\\mu} (\\partial) = \\alpha \\partial^{\\mu} + \\beta \\partial^{\\mu}_{\\sc L},\\quad \\partial^{\\mu}_{\\sc L} = \\frac{(n\\cdot \\partial)}{n^{2}}\\,n^{\\mu},\\label{nielsen_3}$$ and $\\alpha,\\beta$ are arbitrary constant parameters. Unlike usual gauge fixing Lagrangian densities which depend only on one gauge fixing parameter, here the dependence is on three independent parameters $\\alpha, \\beta$ and $n^{\\mu}$ which we denote collectively by $$\\phi_{(a)} = (\\alpha, \\beta, n^{\\mu}).\\label{nielsen_4}$$ The reason for this, as we have already emphasized earlier, is that this is an interpolating gauge between various classes of gauges in the sense that $$\\begin{aligned} \\beta & = 0,& & \\text{covariant gauges}\\ (\\text{with}\\ \\xi=\\alpha^{-2}),\\notag\\\\ \\alpha & = 0,& & \\text{generalized axial gauges},\\notag\\\\ \\beta & = -\\alpha, n^{2}>0,& & \\text{generalized Coulomb gauges}.\\label{nielsen_4a}\\end{aligned}$$ So, for different choices of the gauge fixing parameters one can easily go from covariant to axial to Coulomb gauges (which is our purpose in choosing such a gauge fixing term). Let us also note that, for the purposes of manifest BRST invariance (which is essential for deriving Ward identities and Nielsen identities), the gauge fixing Lagrangian density can also be written with an auxiliary (nondynamical) field $F$ as $${\\cal L}_{\\sc\\rm GF} = \\frac{1}{2}\\, F^{2} + \\left(\\Lambda^{\\mu} (\\partial) F\\right) A_{\\mu}.\\label{nielsen_5}$$ The ghost Lagrangian density corresponding to this general class of gauge choice, , is given by $${\\cal L}_{\\rm ghost} = \\left(\\Lambda^{\\mu} (\\partial) \\overline{c}\\right) \\partial_{\\mu}c,\\label{nielsen_6}$$ and the combined Lagrangian density $${\\cal L} = {\\cal L}_{\\rm inv} + {\\cal L}_{\\rm\\sc GF} + {\\cal L}_{\\rm ghost},\\label{nielsen_6a}$$ is manifestly invariant (with gauge fixing described by ) under the standard (nilpotent) BRST transformations of QED [@brst; @das], $$\\begin{aligned} & \\delta A_{\\mu} = \\omega \\partial_{\\mu}c, & & \\delta F = 0,\\notag\\\\ & \\delta \\psi = - ie\\omega c \\psi, & & \\delta \\overline{\\psi} = -ie\\omega \\overline{\\psi} c,\\notag\\\\ & \\delta c = 0, & & \\delta \\overline{c} = - \\omega F,\\label{nielsen_7}\\end{aligned}$$ where $\\omega$ represents an arbitrary constant Grassmann parameter. For completeness we note here that the photon propagator for this generalized gauge fixing can be easily obtained to have the form [@taylor] $$D_{\\mu\\nu} (p) = - \\frac{1}{p^{2}}\\left[\\eta_{\\mu\\nu} - \\frac{\\Lambda_{\\mu} (p) p_{\\nu} + \\Lambda_{\\nu}(p) p_{\\mu}}{\\Lambda(p)\\cdot p} + \\frac{p_{\\mu}p_{\\nu} (\\Lambda(p))^{2}}{(\\Lambda(p)\\cdot p)^{2}}\\left(1 + \\frac{p^{2}}{(\\Lambda(p))^{2}}\\right)\\right],\\label{nielsen_7a}$$ which can be compared with . Furthermore, it is straightforward to check that for different choices of the gauge fixing parameters, as in , this propagator reduces to the familiar propagators in the three different classes of gauges. Nielsen identities ------------------ To derive the Green’s functions of the theory we need to introduce sources for the fundamental fields and to determine the gauge parameter variations of the effective action and the Green’s functions (Nielsen identities), we also need to introduce some other sources and these are described by the Lagrangian density $$\\begin{aligned} {\\cal L}_{\\rm source} & = J^{\\mu}A_{\\mu} + JF + i\\left(\\overline{\\chi}\\psi - \\overline{\\psi}\\chi\\right) + i\\left(\\overline{\\eta} c - \\overline{c}\\eta\\right)\\notag\\\\ & + ie\\left(\\overline{M} c\\psi - \\overline{\\psi}c M\\right) + \\left(H_{(\\alpha)} (\\partial^{\\mu}\\overline{c}) + H_{(\\beta)} (\\partial^{\\mu}_{\\sc L}\\overline{c})\\right)A_{\\mu}\\notag\\\\ & + \\beta H_{(n)\\,\\mu} (N^{\\mu\\nu}\\overline{c})A_{\\nu}.\\label{nielsen_8}\\end{aligned}$$ Here we have identified $$N^{\\mu\\nu} = \\frac{\\partial \\partial^{\\nu}_{\\sc L}}{\\partial n_{\\mu}} = \\frac{(n\\cdot \\partial)}{n^{2}} \\left(\\eta^{\\mu\\nu} + \\frac{\\partial^{\\mu}n^{\\nu}}{n\\cdot\\partial} - \\frac{2n^{\\mu}n^{\\nu}}{n^{2}}\\right).\\label{nielsen_9}$$ Therefore, the total Lagrangian density for the gauge fixed theory (with sources) is given by $$\\begin{aligned} {\\cal L}_{\\rm\\sc TOT} & = {\\cal L}_{\\rm inv} + {\\cal L}_{\\rm\\sc GF} + {\\cal L}_{\\rm ghost} + {\\cal L}_{\\rm source},\\notag\\\\ S_{\\rm\\sc TOT} & = \\int d^{n}x\\, {\\cal L}_{\\rm\\sc TOT}.\\label{nielsen_10}\\end{aligned}$$ As mentioned above, we note from that $(J^{\\mu}, J, \\overline{\\chi}, \\chi, \\overline{\\eta}, \\eta)$ correspond respectively to the standard sources for the fields $(A_{\\mu}, F, \\psi, \\overline{\\psi}, c, \\overline{c})$; the sources $(\\overline{M}, M)$ generate respectively the composite BRST variations of $(\\psi, \\overline{\\psi})$ in . In addition, we have introduced three sources $$H_{(a)} = \\left(H_{(\\alpha)}, H_{(\\beta)}, H_{(n)}^{\\mu}\\right),\\label{nielsen_11}$$ such that the BRST variations of these three source terms lead to the gauge variations of ${\\cal L}_{\\rm inv} + {\\cal L}_{\\rm\\sc GF} + {\\cal L}_{\\rm ghost}$ with respect to the three parameters $\\phi_{(a)}$ defined in . Note here that the additional sources $(\\overline{M}, M)$ are commuting sources which carry spinor indices and ghost quantum numbers while the three sources $H_{(a)}$ defined in are anti-commuting and carry ghost quantum numbers (but have no spinor index). The generating functional for this gauge fixed theory is now given by $$Z [{\\cal J}] = e^{iW[{\\cal J}]} = N \\int {\\cal D}\\varphi\\, e^{iS_{\\rm\\sc TOT}},\\label{nielsen_12}$$ where we have denoted all the field variables and sources generically by $\\varphi$ and ${\\cal J}$ respectively and $N$ denotes the normalization constant for the path integral. If we make a field redefinition corresponding to the BRST transformations , namely, $$\\varphi \\rightarrow \\varphi + \\delta_{\\sc BRST}\\varphi,\\label{nielsen_13}$$ inside the path integral, the generating functional does not change since the path integral involves integration over all field configurations (alternatively, the generating functional depends only on the sources and not on the fields). As a result, we obtain $$\\delta Z [{\\cal J}] = 0 = iN\\int {\\cal D}\\varphi\\, (\\delta_{\\sc BRST} S_{\\rm\\sc TOT})\\, e^{iS_{\\rm\\sc TOT}}.\\label{nielsen_14}$$ Only the source terms in $S_{\\rm\\sc TOT}$ in are not BRST invariant and substituting the variations of these terms in leads to an identity involving the generating functional $W[{\\cal J}]$ of the form (we use the convention of left derivatives for anti-commuting variables) $$\\begin{aligned} & N e^{-iW}\\int {\\cal D}\\varphi \\int \\!\\!d^{n}x\\left(\\!H_{(a)}\\frac{\\partial {\\cal L}_{\\rm\\sc TOT}}{\\partial\\phi_{(a)}} + O ((H_{(a)})^{2})\\right) e^{iS_{\\rm\\sc TOT}}\\notag\\\\ & = i\\int d^{n}x\\left(J^{\\mu}\\partial_{\\mu} \\frac{\\delta W}{\\delta\\overline{\\eta}} - \\overline{\\chi} \\frac{\\delta W}{\\delta\\overline{M}} + \\frac{\\delta W}{\\delta M} \\chi - \\frac{\\delta W}{\\delta J} \\eta\\right).\\label{nielsen_15}\\end{aligned}$$ Furthermore, taking the functional derivative with respect to $H_{(a)}(x)$ and setting the sources $H_{(a)}=0$ and then integrating over $\\int d^{n}x$, we obtain the Master identity for the generating functional for connected Green’s functions $$\\frac{\\partial W}{\\partial \\phi_{(a)}} = i \\int d^{n}x\\,d^{n}y\\left(J^{\\mu}(y)\\partial^{(y)}_{\\mu} \\frac{\\delta^{2} W}{\\delta H_{(a)}(x)\\delta\\overline{\\eta}(y)} + \\overline{\\chi}(y) \\frac{\\delta^{2} W}{\\delta\\overline{M}(y) \\delta H_{(a)}(x)} + \\frac{\\delta^{2} W}{\\delta H_{(a)}(x) \\delta M(y)} \\chi (y) - \\frac{\\delta^{2} W}{\\delta H_{(a)}(x) \\delta J(y)} \\eta(y)\\right).\\label{nielsen_16}$$ Upon differentiation, this equation leads to the gauge parameter variation of the connected Green’s functions of the theory. We emphasize that all the sources $H_{(a)}$ have been set to zero in . To obtain the gauge parameter variation of the 1PI amplitudes of the theory, we make a Legendre transformation with respect to the standard sources for the dynamical fields of the theory, namely, (here the field variables correspond to the classical fields) $$\\Gamma = W - \\int d^{n}x \\left(J^{\\mu}A_{\\mu} + JF + i (\\overline{\\chi}\\psi - \\overline{\\psi} \\chi) + i (\\overline{\\eta}c - \\overline{c}\\eta)\\right).\\label{nielsen_17}$$ This leads (from ) to the Master identity for the gauge parameter variation of the effective action in the form $$\\begin{aligned} \\frac{\\partial \\Gamma}{\\partial\\phi_{(a)}} & = \\int d^{n}z d^{n}w\\left(\\frac{\\delta\\Gamma}{\\delta\\psi_{\\gamma}(w)} \\frac{\\delta^{2}\\Gamma}{\\delta \\overline{M}_{\\gamma} (w) \\delta H_{(a)}(z)}\\right.\\notag\\\\ &\\qquad\\left. + \\frac{\\delta^{2}\\Gamma}{\\delta H_{(a)}(z) \\delta M_{\\gamma}(w)} \\frac{\\delta\\Gamma}{\\delta \\overline{\\psi}_{\\gamma}(w)}\\right),\\label{nielsen_18}\\end{aligned}$$ where, again, the sources $H_{(a)}$ have been set to zero. By taking derivatives of this identity with respect to various fields and setting all the fields (including $M, \\overline{M}$) to zero, we can obtain the gauge parameter variation of any 1PI amplitude in the theory. For example, taking the functional derivative with respect to $\\frac{\\delta^{2}}{\\delta\\psi_{\\beta}(y)\\delta\\overline{\\psi}_{\\alpha}(x)}$ and setting all fields to zero, we obtain the gauge parameter variation of the fermion two point function $$\\begin{aligned} \\frac{\\partial S^{-1}_{\\alpha\\beta}(x-y)}{\\partial\\phi_{(a)}} & = \\int d^{n}z d^{n}w\\left({\\cal F}^{(a)}_{\\alpha\\gamma} (x,z,w) S^{-1}_{\\gamma\\beta} (w-y)\\right.\\notag\\\\ &\\quad \\left. + S^{-1}_{\\alpha\\gamma}(x-w) {\\cal G}^{(a)}_{\\gamma\\beta} (w,z,y)\\right).\\label{nielsen_19}\\end{aligned}$$ Here we have identified $$\\begin{aligned} S^{-1}_{\\alpha\\beta} (x-y) & = \\frac{\\delta^{2}\\Gamma}{\\delta\\psi_{\\beta} (y)\\delta\\overline{\\psi}_{\\alpha} (x)},\\notag\\\\ {\\cal F}^{(a)}_{\\alpha\\gamma}(x,z,w) & = \\frac{\\delta^{3}\\Gamma}{\\delta\\overline{\\psi}_{\\alpha}(x)\\delta H_{(a)}(z)\\delta M_{\\gamma}(w)},\\notag\\\\ {\\cal G}^{(a)}_{\\gamma\\beta} (w,z,y) & = \\frac{\\delta^{3}\\Gamma}{\\delta\\overline{M}_{\\gamma}(w)\\delta H_{(a)}(z)\\delta\\psi_{\\beta}(y)},\\label{nielsen_20}\\end{aligned}$$ with all field variables (including $M, \\overline{M}$) set to zero. In momentum space, the Nielsen identity takes the simple form $$\\frac{\\partial S^{-1}_{\\alpha\\beta} (p)}{\\partial \\phi_{(a)}} = {\\cal F}^{(a)}_{\\alpha\\gamma} (p) S^{-1}_{\\gamma\\beta} (p) + S^{-1}_{\\alpha\\gamma} (p) {\\cal G}^{(a)}_{\\gamma\\beta} (p),\\label{nielsen_21}$$ where we have identified the three point amplitudes $$\\begin{aligned} {\\cal F}^{(a)}_{\\alpha\\gamma} (p) & = {\\cal F}^{(a)}_{\\alpha\\gamma} (-p, 0,p),\\notag\\\\ {\\cal G}^{(a)}_{\\gamma\\beta} (p) & = {\\cal G}^{(a)}_{\\gamma\\beta} (-p.0.p).\\label{nielsen_22}\\end{aligned}$$ Equation shows how the fermion two point function changes with respect to the three independent parameters $(\\alpha,\\beta,n^{\\mu})$. We note here that since there are no vertices corresponding to ${\\cal F}^{(a)}_{\\alpha\\beta} (p), {\\cal G}^{(a)}_{\\alpha\\beta} (p)$ at the tree level Lagrangian density in , these amplitudes are nontrivial only at one loop and beyond. Therefore, the Nielsen identity implies that the dependence of the fermion two point function on the gauge fixing parameter arises only at one loop and beyond, as we expect. Gauge independence of the pole of the fermion propagator ======================================================== We are now ready to show the gauge independence of the pole of the fermion propagator. We note that studying the pole of the propagator is equivalent to studying the zero of the denominator ${\\cal D}$ of the propagator defined in and . Studying directly the gauge parameter independence of the zero of the denominator in the form (in a generalized interpolating gauge) is more involved than in the covariant gauge because of the presence of an additional structure. There is a much simpler way to do this which we discuss in the following. Let us recall from that the denominator of the fermion propagator can be related to the fermion two point function as $${\\cal D} = - \\frac{1}{2^{[n/2]}}\\, \\text{Tr} \\left( S^{-1} (p) {\\cal C} (S^{-1} (p))^{T} {\\cal C}^{-1}\\right).$$ Since the Nielsen identity describes how the fermion two point function changes with the change in any of the three gauge parameters, we can now use this to determine the gauge parameter variation of the denominator of the fermion propagator $$\\begin{aligned} & \\frac{\\partial {\\cal D}}{\\partial\\phi_{(a)}} = - \\frac{1}{2^{[n/2]}}\\,{\\rm Tr}\\left(\\frac{\\partial S^{-1} (p)}{\\partial\\phi_{(a)}} {\\cal C} (S^{-1}(p))^{T} {\\cal C}^{-1}\\right.\\notag\\\\ & \\qquad\\qquad\\qquad\\qquad\\left. + S^{-1}(p) {\\cal C} \\frac{\\partial (S^{-1}(p))^{T}}{\\partial\\phi_{(a)}} {\\cal C}^{-1}\\right)\\notag\\\\ & = {\\cal D}\\, {\\rm Tr}\\left(\\!{\\cal F}^{(a)}(p) + {\\cal G}^{(a)}(p) + {\\cal C} \\left({\\cal F}^{(a)}(p) + {\\cal G}^{(a)}(p)\\right)^{T}\\!{\\cal C}^{-1}\\!\\right)\\notag\\\\ & = 2 {\\cal D}\\, {\\rm Tr} ({\\cal F}^{(a)}(p) + {\\cal G}^{(a)}(p)).\\label{gaugeind_1}\\end{aligned}$$ Here we have used , cyclicity of trace as well as the fact that the trace of the transpose of a matrix coincides with that of the matrix itself. Equation shows explicitly that the denominator depends on the gauge parameters (is gauge dependent) and the gauge parameter variation of the denominator with respect to the three independent parameters is proportional to the denominator itself. As a result, it follows that, if the amplitudes $({\\cal F}^{(a)} (p), {\\cal G}^{(a)}(p))$ are well behaved, the zero of the denominator ${\\cal D}$ (which corresponds to the pole of the propagator) is, in fact, gauge parameter independent, namely, $$\\frac{\\partial {\\cal D}}{\\partial \\phi_{(a)}}\\Big\|_{{\\cal D}=0} = 0.\\label{gaugeind_2}$$ This would, in fact, be the case when the theory does not have any infrared divergences or mass shell singularities at the pole of the propagator. Actually, this turns out to be the case in perturbative QED (and in QCD) in $4$ space-time dimensions [@kronfeld]. On the other hand, in lower dimensions, $n < 4$, such singularities can be present in the amplitudes $({\\cal F}^{(a)} (p), {\\cal G}^{(a)} (p))$ so that the pole of the propagator may become gauge dependent. This has been explicitly studied in the massive Schwinger model (massive QED in $1+1$ dimensions) in [@schubert]. Noting that near the zero of ${\\cal D}$ (or the pole of the propagator), we can write $${\\cal D}\\xrightarrow{p^{2}\\rightarrow M^{2}_{p}} Z (p^{2} - M^{2}_{p}),\\label{gaugeind_3}$$ where the coefficient $Z$ is related to the wave function normalization $Z_{2}^{-1}$, equation leads to $$\\frac{\\partial M_{p}}{\\partial \\phi_{(a)}} = 0.\\label{gaugeind_4}$$ Namely, the pole of the propagator or the physical mass of the fermion is independent of the three gauge fixing parameters $(\\alpha, \\beta, n^{\\mu})$ in theories without infrared divergence and mass shell singularities at the pole. Furthermore, since the covariant, the axial and the Coulomb gauges correspond to specific values of these parameters which $M_{p}$ is independent of, the physical mass (or the location of the pole of the propagator) is the same in all three classes of gauges. This demonstrates the complete gauge independence of the fermion pole mass and it is worth emphasizing that this direct and simple demonstration of gauge invariance of the pole of the fermion propagator involves only three basic elements: choice of a general class of interpolating gauges, the Nielsen identity for the gauge variation of the fermion two point function for this gauge choice and the relation of the two point function to the denominator of the propagator. We have explicitly verified the gauge independence of the pole of the fermion propagator, up to two loops, in the generalized axial gauge as follows. It is already known that at one loop, the pole is gauge parameter independent (namely, $\\widetilde{M} = M_{p}$ is gauge parameter independent up to one loop). Therefore, we need to concentrate only on the contributions at two loops. At two loops, the contributions to the self-energy are given by the diagrams Fig. \\[fig1\\]. Using this in the expression for the denominator in the form, $${\\cal D} = - \\frac{1}{2^{[n/2]}}\\,{\\rm Tr} \\left(S^{-1}(p) S^{-1}(-p)\\right),$$ we can separate out the two loop contributions explicitly. Due to the transversality of the photon self-energy in diagram $(c)$ of Fig. \\[fig1\\], the gauge parameter ($(\\beta, n^{\\mu})$) dependent terms turn out to be proportional to $(p^{2}-m^{2})$ with a well behaved coefficient so that they vanish as $p^{2}\\rightarrow m^{2}$ (note that since the amplitude is already of order two loops, $M_{p}^{2}$ can be set equal to $m^{2}$ in this order). Similarly the $\\beta$ dependent terms in diagram $(d)$ as well as in the sum of the diagrams $(a)+(b)$ also have the same form with well behaved coefficients. Therefore, these also vanish at the pole and there is no $\\beta$ dependence at all in the amplitude. The remaining $n^{\\mu}$ dependent terms in the sum of the contributions from diagrams $(a)+(b)+(d)$ combine under the trace to be proportional to $(p^{2}-m^{2})$ (it is worth emphasizing that individual diagrams do not have this form). As a consequence, the complete two loop self-energy leads to $${\\cal D} = {\\cal D}^{(Feynman)} + Q(p,m,n) (p^{2}-m^{2}),\\label{gaugeind_5}$$ where ${\\cal D}^{(Feynman)}$ is manifestly gauge independent (calculated using $D_{\\mu\\nu}^{(Feynman)}$ in ) and $Q(p,m,n)$ is a complicated integral which is manifestly $n^{\\mu}$ dependent (but has no $\\beta$ dependence). It is clear from that if there are no mass shell singularities in $Q(p,m,n)$ at the pole, then the gauge dependent terms in vanish at the zero of the denominator, namely, as $p^{2}\\rightarrow m^{2}$ (to this order) completely consistent with the conclusion following from the Nielsen identity in . One can estimate the behavior of the coefficient function and near the mass shell it behaves like $Q(p,m,n) \\sim (p^{2}-m^{2})^{(n-4)/2}$ so that for $n\\geq 4$ it is well behaved. However, for $n\\leq 3$ mass shell singularities develop at the pole and one cannot conclude (as in ) that the pole of the propagator is gauge independent. We have seen this explicitly in an earlier study involving the massive Schwinger model [@schubert]. In fact, even in the Schwinger model (massless), where it is known that there is no infrared divergence, mass shell singularities do develop. For example, in the covariant gauge the fermion self-energy at one loop has the form (here we use the standard gauge fixing parameter $\\xi = \\alpha^{-2}$) $$\\Sigma^{(1)}_{(c)} (p) = \\frac{\\xi e^{2}}{2\\pi p^{2}}\\, p\\sl,\\label{gaugeind_6}$$ and the singularity as $p^{2}\\rightarrow 0$ is manifest in . In this case, the pole of the fermion propagator is easily determined to be $$M^{2}_{(c)} = \\frac{\\xi e^{2}}{2\\pi},\\label{gaugeind_7}$$ and is manifestly gauge parameter dependent. Furthermore, one can calculate the one loop fermion self-energy in the generalized axial gauge which has the form $$\\Sigma^{(1)}_{(axial)} (p) = - \\frac{e^{2}}{2\\pi p_{\\sc L}^{2}}\\,p\\sl_{\\sc L},\\label{gaugeind_8}$$ leading to a fermion pole mass (in the perturbative regime $e^{2}\\ll \|p_{\\sc L}^{2}\|$) $$M^{2}_{(axial)} = - \\frac{e^{2}}{\\pi}.\\label{gaugeind_9}$$ There are two things to note from and . First, the mass in the axial gauge is independent of the gauge fixing parameters $(\\beta, n^{\\mu})$ while that in the covariant gauge is manifestly gauge parameter dependent so that the two do not coincide in general. This is a simple example of how a gauge parameter independent pole within one class of gauges (in this case the axial gauge) does not automatically imply that it will be the same in all classes of gauges. Second, because the poles in the two gauges do not coincide, even if the pole in the axial gauge is gauge parameter independent, it will be incorrect to conclude that it represents a physical mass. In fact, we see from that this mass is purely imaginary and, therefore, completely unphysical. Conclusion ========== In this paper we have studied the question of complete gauge independence of the fermion pole mass. This involves showing the gauge parameter independence of the pole within a given class of gauges (such as covariant or axial or Coulomb) as well as showing that the pole has the same value in all of these three classes of gauges. The demonstration of complete gauge independence is achieved in a simple manner by using three basic ingredients. First, we choose a general class of gauges which interpolate between the covariant, the axial and the Coulomb gauges for different values of the gauge parameters. We derive the Nielsen identity describing the gauge parameter variation of the fermion two point function in this class of interpolating gauges. And we relate the denominator of the fermion propagator to the two point function so that the gauge parameter variation of the denominator (or the pole of the propagator) can be studied directly using the Nielsen identity for the fermion two point function. With these three basic ingredients we are able to show in a simple manner that, when there are no infrared divergences and mass shell singularities at the pole, the pole of the fermion propagator is gauge independent in the complete sense. The presence of mass shell singularities can invalidate such a proof and this is pointed out with a simple example of the Schwinger model where the pole mass is manifestly gauge parameter dependent in the covariant gauge while it is independent of gauge parameters in the generalized axial gauges. The pole masses in different classes of gauges do not coincide in this case and, therefore, it would be wrong to conclude from a study of the pole in the axial gauge (where it is gauge parameter independent) that the pole represents a physical mass. In fact, the pole mass in this case (in the axial gauge) turns out to be purely imaginary and, therefore, unphysical. Physically, of course, this can be understood from the fact that in $1+1$ dimensions, the Coulomb potential increases linearly with distance leading to confinement and preventing any physical fermions in the asymptotic states. [Acknowledgments]{} A. D. would like to thank the Departamento de Física Matematica for hospitality where this work was done. This work was supported in part by USP, by CNPq and by FAPESP. Quantum Chromodynamics ====================== In this appendix, we will briefly indicate how the derivation of the Nielsen identity generalizes to Quantum Chromodynamics in a straightforward manner. For a non-Abelian theory based on the gauge group $SU(N)$ the invariant Lagrangian density is given by $${\\cal L}_{\\rm inv} = - \\frac{1}{4}\\, F_{\\mu\\nu}^{a} F^{\\mu\\nu, a} + \\overline{\\psi}_{i} (i D\\!\\sl -m)\\psi_{i},\\label{app_1}$$ where $a=1,2,\\cdots , N^{2}-1$ and $i=1,2,\\cdots , N$ denote the color indices. The covariant derivative for the fermion is defined to be $$D_{\\mu}\\psi_{i} = \\partial_{\\mu}\\psi_{i} + i gA_{\\mu}^{a} (T^{a})_{ij} \\psi_{j},\\label{app_2}$$ where $T^{a}$ denotes the (Hermitian) generators of the group in the fundamental representation and $g$ denotes the coupling constant. One can generalize the interpolating gauge fixing in this case to be given by $${\\cal L}_{\\rm\\sc GF} = -\\frac{1}{2} \\left(\\Lambda\\cdot A^{a}\\right)^{2} = \\frac{1}{2}\\,F^{a}F^{a} + (\\Lambda^{\\mu}F^{a}) A_{\\mu}^{a}.\\label{app_3}$$ where $\\Lambda^{\\mu} = \\Lambda^{\\mu}(\\partial)$ is given in . The ghost Lagrangian density similarly generalizes to $${\\cal L}_{\\rm ghost} = (\\Lambda^{\\mu}\\overline{c}^{a}) D_{\\mu}c^{a},\\label{app_4}$$ where the covariant derivative in the adjoint representation is defined as $$D_{\\mu}c^{a} = \\partial_{\\mu}c^{a} - g f^{abc} A_{\\mu}^{b} c^{c},\\label{app_5}$$ with $f^{abc}$ representing the structure constants of the group. The Lagrangian density ${\\cal L}_{\\rm inv} + {\\cal L}_{\\rm\\sc GF} + {\\cal L}_{\\rm ghost}$ is manifestly invariant under the standard (nilpotent) BRST transformations (see also ) $$\\begin{aligned} \\delta A_{\\mu}^{a} & = \\omega (D_{\\mu}c)^{a},\\notag\\\\ \\delta \\psi_{i} & = -ig\\omega c^{a} (T^{a})_{ij}\\psi_{j},\\notag\\\\ \\delta \\overline{\\psi}_{i} & = - ig\\omega \\overline{\\psi}_{j} (T^{a})_{ji} c^{a},\\notag\\\\ \\delta c^{a} & = \\frac{g\\omega}{2}\\, f^{abc} c^{b}c^{c},\\notag\\\\ \\delta\\overline{c}^{a} & = -\\omega F^{a},\\notag\\\\ \\delta F^{a} & = 0,\\label{app_6}\\end{aligned}$$ where $\\omega$ denotes a constant Grassmann parameter. The important thing to note here is that in the non-Abelian theory, the quadratic part of the Lagrangian density is diagonal in the color space so that the two point functions have the same structure as in the Abelian theory except for diagonal color factors such as $\\delta^{ab}$ or $\\delta_{ij}$. Therefore, much of our discussion goes through with minimal change in this case. For example, the denominator for the fermion propagator can now be related to the fermion two point function as in with the Tr" representing a trace over the spinor as well as the color indices and the normalization factor will be correspondingly different. (These are minor generalizations which have no effect on the final result.) Since the BRST transformations are somewhat different (there are more composite variations), so are the source terms necessary to derive the Nielsen identity. In this case, the source Lagrangian density is given by $$\\begin{aligned} {\\cal L}_{\\rm source} & = J^{\\mu, a}A_{\\mu}^{a} + J^{a} F^{a} + i (\\overline{\\chi}_{i}\\psi_{i} - \\overline{\\psi}_{i}\\chi_{i} )+ i(\\overline{\\eta}^{a} c^{a} - \\overline{c}^{a}\\eta^{a}) + K^{\\mu a} D_{\\mu}c^{a} + ig (\\overline{M}_{i} c^{a}(T^{a})_{ij}\\psi_{j} - \\overline{\\psi}_{i}(T^{a})_{ij}c^{a}M_{j})\\notag\\\\ & \\ \\ + K^{a} \\left(\\frac{g}{2} f^{abc} c^{b}c^{c}\\right) + H_{(\\alpha)} (\\partial^{\\mu}\\overline{c}^{a}) A_{\\mu}^{a} + H_{(\\beta)} (\\partial_{\\sc L}^{\\mu}\\overline{c}^{a}) A_{\\mu}^{a} + \\beta H_{(n) \\mu} (N^{\\mu\\nu}\\overline{c}^{a}) A_{\\nu}^{a},\\label{app_7}\\end{aligned}$$ where $N^{\\mu\\nu}$ is defined in . With this we can define the total Lagrangian density for the theory to be $${\\cal L}_{\\rm\\sc TOT} = {\\cal L}_{\\rm inv} + {\\cal L}_{\\rm\\sc GF} + {\\cal L}_{\\rm ghost} + {\\cal L}_{\\rm source}.\\label{app_8}$$ One can now follow through the steps in - to obtain the Master identity for the gauge parameter variation of the generating functional for the connected Green’s functions (the Dirac spinor indices have been suppressed on the right hand side for simplicity) $$\\begin{aligned} \\frac{\\partial W}{\\partial\\phi_{(a)}} & = i\\int d^{n}x d^{n}y \\left(i J^{\\mu a} (y) \\frac{\\delta^{2}W}{\\delta H_{(a)} (x)\\delta K^{\\mu a} (y)} + \\overline{\\chi}_{i}(y) \\frac{\\delta^{2}W}{\\delta\\overline{M}_{i}(y) \\delta H_{(a)}(x)} + \\frac{\\delta^{2}W}{\\delta H_{(a)}(x)\\delta M_{i}(y)} \\chi_{i}(y)\\right.\\notag\\\\ & \\qquad\\qquad\\qquad \\left. - \\frac{\\delta^{2}W}{\\delta H_{(a)}(x)\\delta J^{a}(y)} \\eta^{a}(y) - \\overline{\\eta}^{a}(y) \\frac{\\delta^{2}W}{\\delta H_{(a)}(x)\\delta K^{a}(y)}\\right).\\label{app_9}\\end{aligned}$$ This can be compared with the identity for the Abelian case in . The Legendre transformation with respect to the standard sources for the field variables (see ) takes us to the Master identity for the gauge parameter variation of the effective action which has the form (we are suppressing the Dirac spinor indices on the right hand side for simplicity) $$\\begin{aligned} \\frac{\\partial\\Gamma}{\\partial\\phi_{(a)}} & = \\int d^{n}x d^{n} y\\left[\\frac{\\delta\\Gamma}{\\delta A_{\\mu}^{a} (y)} \\frac{\\delta^{2}\\Gamma}{\\delta H_{(a)}(x) \\delta K^{\\mu a} (y)} + \\frac{\\delta\\Gamma}{\\delta \\psi_{i}(y)}\\frac{\\delta^{2}\\Gamma}{\\delta \\overline{M}_{i} (y) \\delta H_{(a)} (x)} + \\frac{\\delta^{2}\\Gamma}{\\delta H_{(a)}(x) \\delta M_{i}(y)} \\frac{\\delta\\Gamma}{\\delta \\overline{\\psi}_{i}(y)}\\right.\\notag\\\\ &\\qquad\\qquad\\qquad \\left. - \\frac{\\delta\\Gamma}{\\delta c^{a} (y)} \\frac{\\delta^{2}\\Gamma}{\\delta H_{(a)} (x) \\delta K^{a}(y)}\\right],\\label{app_10}\\end{aligned}$$ where all the fields (and the sources $M_{i}, \\overline{M}_{i}$) have been set to zero. (This can be compared with for the Abelian theory.) Taking the functional derivative with respect $\\frac{\\delta^{2}}{\\delta\\psi_{j,\\beta} (y) \\delta\\overline{\\psi}_{i,\\alpha} (x)}$, we can now obtain the gauge parameter variation of the fermion two point function which, in the matrix form (for simplicity), is given by $$\\begin{aligned} \\frac{\\partial S^{-1} (x-y)}{\\partial\\phi_{(a)}} & = \\int d^{n}z d^{n} w\\left({\\cal F}^{(a)} (x,z,w) S^{-1} (w-y)\\right.\\notag\\\\ &\\qquad\\quad \\left. + S^{-1}(x-w) {\\cal G}^{(a)} (w,z,y)\\right),\\label{app_11}\\end{aligned}$$ where we have identified (here we put back all the indices) $$\\begin{aligned} & S^{-1}_{ij,\\alpha\\beta} (x-y) = \\frac{\\delta^{2}\\Gamma}{\\delta\\psi_{j,\\beta}(y) \\delta\\overline{\\psi}_{i,\\alpha}(x)},\\notag\\\\ & {\\cal F}^{(a)}_{ik,\\alpha\\gamma}(x,z,w) = \\frac{\\delta^{3}\\Gamma}{\\delta\\overline{\\psi}_{i,\\alpha}(x)\\delta H_{(a)}(z)\\delta M_{k,\\gamma}(w)},\\notag\\\\ & {\\cal G}^{(a)}_{kj,\\gamma\\beta} (w,z,y) = \\frac{\\delta^{3}\\Gamma}{\\delta\\overline{M}_{k,\\gamma}(w) \\delta H_{(a)}(z)\\delta \\psi_{j,\\beta}(y)}.\\label{app_12}\\end{aligned}$$ In momentum space this relation takes the simple (matrix) form $$\\frac{\\partial S^{-1} (p)}{\\partial\\phi_{(a)}} = {\\cal F}^{(a)} (p) S^{-1}(p) + S^{-1} (p) {\\cal G}^{(a)}(p),\\label{app_13}$$ where, as in , we have identified the matrices $$\\begin{aligned} {\\cal F}^{(a)} (p) & = {\\cal F}^{(a)} (-p,0,p),\\notag\\\\ {\\cal G}^{(a)} (p) & = {\\cal G}^{(a)} (-p,0,p).\\label{app_14}\\end{aligned}$$ We note that in the matrix form the gauge parameter variation of the fermion two point function has the same form as in , the difference being that in the non-Abelian case, the matrices are matrices in the color as well as spinor space. As we have mentioned earlier, the fermion two point function as well as the propagator are diagonal in the color space. So, still holds with the understanding that the identity matrix is a matrix in the color as well as the spinor space. This determines (see ) the denominator of the propagator to be given by $$\\begin{aligned} {\\cal D} & = - \\frac{1}{2^{[n/2]} N}\\,{\\rm Tr} \\left(S^{-1}(p) ({\\cal C} (S^{-1}(p))^{T} {\\cal C}^{-1})\\right)\\notag\\\\ & = - \\frac{1}{2^{[n/2]} N}\\, {\\rm Tr} \\left(S^{-1}(p) S^{-1}(-p)\\right),\\label{app_15}\\end{aligned}$$ where the trace is over color as well as spinor indices. We can now determine the variation of the denominator with respect to the gauge parameters using (exactly as was done in ) to be given by $$\\frac{\\partial{\\cal D}}{\\partial\\phi_{(a)}} = 2 {\\cal D}\\,{\\rm Tr} \\left({\\cal F}^{(a)} (p) + {\\cal G}^{(a)} (p)\\right),\\label{app_16}$$ and the gauge independence of the pole of the propagator follows exactly as discussed in section [4]{}. [10]{} R. Tarrach, Nucl. Phys. [B183]{}, 384 (1981). D. Johnston, preprint LPTHE Orsay 86/49 (unpublished). L. J. Reinders and K. Stam, Phys. Lett. [B195]{}, 465 (1987). N. Gray, D. J. Broadhurst, W. Grafe and K. Schilcher, Z. Phys. [C48]{}, 673 (1990). L. S. Brown, [Quantum Field Theory]{}, Cambridge University Press, Cambridge (1992). J. C. Breckenridge, M. J. Lavelle and T. G. Steele, Z. Phys. [C65]{}, 155 (1995). A. S. Kronfeld, Phys. Rev. [D58]{}, 051501 (1999). N. K. Nielsen, Nucl. Phys. [101]{}, 173 (1975). A. Das, [Finite Temperature Field Theory]{}, World Scientific, Singapore (1997). C. A. Becchi, A. Rouet and R. Stora, Comm. Math. Phys. [42]{}, 127 (1975); Ann. Phys. (N.Y.) [98]{}, 287 (1976). W. Kummer, Acta Physica Austriaca [41]{}, 316 (1975). J. Frenkel, Phys. Rev. [D13]{}, 2325 (1976). G. Leibbrandt, Rev. Mod. Phys. [59]{}, 1067 (1987). E. S. Fradkin and I. V. Tyutin, Phys. Rev. [D2]{}, 2841 (1970). J. Bernstein, Nucl. Phys. [B99]{}, 541 (1975). A. Andrasi and J. C. Taylor, Ann. Phys. [326]{}, 1053 (2011). A. Das and J. Frenkel, arXiv:1306.6307. J. Frenkel and J. C. Taylor, Nucl. Phys. [B109]{}, 439 (1976). H. Pagels, Phys. Rev. [D15]{}, 2091 (1977). W. Konetschny, Nuovo Cim. [44A]{}, 465 (1978). A. Das, J. Frenkel and C. Schubert, Phys. Lett. [B720]{}, 414 (2013). [^1]: $\\ $ e-mail: das@pas.rochester.edu, jfrenkel@fma.if.usp.br
import React from 'react' import styled from 'styled-components' import Page from 'comps/Page/Page' import readme from 'ui-src/components/EthIdenticon/README.md' import { EthIdenticon } from '@aragon/ui' import Container from '../components/Page/DemoContainer' const ADDRESS = '0xcafE1A77e83698c83CA8931F54A755176eF75f2d' const PageBadgeNumber = ({ title }) => ( <Page title={title} readme={readme}> <Page.Demo opaque height={200}> <Container centered css="height: 100vh"> <EthIdenticonRow> <div> <EthIdenticon address={ADDRESS} /> </div> <div> <EthIdenticon address={ADDRESS} scale={2} radius={25} /> </div> <div> <EthIdenticon address={ADDRESS} radius={8} scale={3} soften={0.7} /> </div> </EthIdenticonRow> </Container> </Page.Demo> </Page> ) const EthIdenticonRow = styled.div` display: flex; align-items: center; & > div { display: flex; align-items: center; margin-right: 20px; } ` export default PageBadgeNumber
Litchfield County Jail The 1812 Litchfield County Jail is a former correctional facility in Litchfield, Connecticut. It is the town's oldest public building and a former jail. History The facility, controlled by the Connecticut state government, historically held inmates convicted of minor offenses, and it had a capacity of 120 prisoners. Bill Ryan of The New York Times wrote that Litchfield Jail "is part of the lore of Litchfield" and that "For generations, the reputation of the jail was that of a country club of penal institutions where the living was positively easy." The first portion of the building was constructed in 1812 with subsequent additions in 1846 and 1890. The jail was originally operated by Litchfield County when Litchfield was the county seat of government. After 1960, when Connecticut dissolved county governance, the jail property was absorbed and operated by the State of Connecticut. The prison held British people during the War of 1812. In the early 20th century an addition was built joining Litchfield Jail to the First National Bank of Litchfield, an 1816 structure. In a period before the 1990's the state began allowing many prisoners into the facility, and it reached capacity. A prisoner escaped the prison, stabbed a guard, and held a man from the State of New York as a hostage, so the state government removed the violent prisoners and made it a drug treatment center for male inmates in 1992. The prisoner capacity was reduced to 30. Governor of Connecticut Lowell P. Weicker Jr. ordered the facility closed for financial reasons in 1993. It was converted into the McAuliffe Manor, a substance abuse treatment center for women operated by Naugatuck Valley HELP Inc., holding women who were convicted of drug-related crimes who would have otherwise been sent to Connecticut state prisons. In 2009 the contract between Naugatuck Valley HELP Inc. and the state expired, leading to the closure of McAuliffe Manor. In 2010 the state government made the jail property available for purchase. The Town of Litchfield refused multiple offers to take the former jail for free on the grounds of the costs and potential risks of owning the facility. In 2013 the state government sold the facility for $130,000 to Russell Barton, a businessperson and real estate investor from the area. Russell Barton commissioned architect Milton Gregory Grew, AIA of Woodbury, CT to design the rehabilitation and adaptive reuse of the building. While there was much discussion among town residents as to what would be the most appropriate reuse of the building, Barton and Grew determined that a mix of residential and business uses would be most appropriate, allowing new residents to live in the center of town and enhance the variety of businesses around the Litchfield Green. The exterior design was to be a controversial matter because a jail is not built to attract visitors. Barton, his partners, and architect Milton Gregory Grew, AIA attended many meetings with the Borough of Litchfield Historic District Commission reviewing design proposals. The Historic District Commission eventually approved Grew's design for an elevated walkway and ground level terrace to allow pedestrian access to the building on the side facing the Green. In addition, Grew added exterior stairs and walkway and a detached elevator to the rear courtyard to provide greater access to all portions of the building, including accessibility for the disabled. Barton, Grew and the development team also made presentations and received approvals from the Litchfield Zoning Board of Appeals and Planning and Zoning Commission for the proposed uses, site development and building modifications. As construction came to a close in late 2018, the building had been converted to four luxury residential apartments, two financial advisory firms, a bakery, several boutiques, and a popular restaurant. References Note Content originally posted in Litchfield, Connecticut External links Register Citizen newspaper, 2018-11-26, "Renovated Litchfield jail welcomes enthusiastic tenants" Category:Litchfield, Connecticut Category:1812 establishments in Connecticut Category:Defunct prisons in Connecticut
You are here Justice News Former Charleston-based Chase Bank Executive Sentenced To 3 Years In Prison For Embezzlement Scheme McCoy stole more than $500,000 from Chase; created unauthorized cashier’s checks to purchase a Cadillac SUV and a ’68 Chevy Camaro CHARLESTON, W.Va. –A former Charleston-based J.P. Morgan Chase Bank (“Chase Bank”) executive was sentenced today to three years in federal prison for embezzlement, announced United States Attorney Booth Goodwin. Mark Alan McCoy, 46, of Charleston, previously pleaded guilty in March to embezzlement by a bank officer. McCoy, who was employed as the Charleston branch vice president of private client banking services from September 2008 until June 2012, embezzled more than $500,000 from the bank. “Bankers are given a special position of trust,” said U.S. Attorney Booth Goodwin. “To abuse that trust is unconscionable.” Goodwin continued, “It’s a crime not only against the bank, but against the customers who counted on this defendant to keep their money safe and sound. The sentencing of Mr. McCoy shows that bank embezzlement has real consequences.” From November 30, 2009, and continuing until April 19, 2012, McCoy stole monies belonging to Chase Bank from approximately nine separate personal and corporate bank clients’ accounts. During the scheme, McCoy created cashier’s checks for himself or would use the proceeds from the original cashier’s checks to create additional unauthorized checks. On January 19, 2011, McCoy created an unauthorized cashier’s check from a client’s corporate bank account for $59,000, and made the check payable to Moses automotive dealership. McCoy used the fraudulent cashier’s check to purchase a Cadillac Escalade. Similarly, on October 19, 2011, McCoy created an unauthorized cashier’s check from a client account for $22,000. McCoy caused that check to be deposited into another client’s account, using the funds for the purchase of a 1968 Chevrolet Camaro. In total, McCoy admitted that he took approximately $532,395.59 of monies from Chase Bank. The actual loss to Chase Bank, after accounting for funds that the defendant deposited into client accounts and other funds that the bank was able to recover, is $447,784.45. At sentencing, the Court ordered the defendant to pay $447,784.45 in restitution. The investigation was conducted by the U.S. Secret Service. Assistant United States Attorney Meredith George Thomas handled the prosecution. The sentence was imposed by United States District Judge Irene Berger.
Q: How to turn off "Break when exception is thrown" for custom exception types I'm doing some debugging where I really want to have the "break when exception is thrown" option turned on. There's a third party assembly I rely on that regularly throws exceptions. Some of them, like SynchronizationLockException I can turn off via Debug -> Exceptions menu. The problem is they also have some custom exception types. Is there anyway to turn those off? A: In the Debug > Exceptions dialog, click Add, select Common Language Runtime exceptions, and enter the full name (not the assembly-qualified name) of the exception. Then uncheck the Thrown checkbox for this exception. A: In Visual Studio 2019, when the exception occurs, there will be an information dialog. Just un-check "Break when this exception type is user-unhandled".
The development of a work-oriented day center program. A community-based day center for former psychiatric patients developed a new work-oriented pilot program for members who want to change and become more self-directed and independent in their living situations. After a year the pilot program was evaluated. On the basis of the evaluation recommendations, the program became a permanent and expanded part of the center's activities. The expansion included a strong occupational therapy component and a Transitional Employment Program.
Apple Lets Mobile Trackers Have a Field Day, Alleges Consumer Lawsuit Apple and several app creators have been passing along mobile device users' personal information to advertisers without their permission or knowledge, alleges Jonathan Lalo of Los Angeles in a lawsuit filed in Northern California's federal district court. App creators named in the suit include Pandora, Dictionary.com, Toss It, Text4Plus, The Weather Channel, Talking Tom Cat, and Pimple Popper Lite. The tracking is done via a Unique Device Identifier that is special to each device. Using the UDID, advertisers can tell which apps have been downloaded to which devices, as well as which ads have been viewed. The suit claims that using UDIDs or geolocation information to send personal data to advertisers violates computer and business fraud laws. Apple is culpable because it is aware of the devices' ability to transmit this data, claims the plaintiff, who is seeking class-action status for the suit. MacNewsWorld was unable to reach Apple immediately for comment. 'Do Not Track' for Mobile Too The Wall Street Journal highlighted this issue earlier this month in an article that raised eyebrows among consumers and privacy advocates, and apparently was the driver behind this lawsuit. "It is clear that we need some kind of 'do not track' legislation for smartphones as well as online," John M. Simpson, a consumer advocate with Consumer Watchdog, told MacNewsWorld. This transmission of information was described as common in the Journal article, he noted -- and consumers have no recourse. "At least in the wired or online world, the consumer has some kind of privacy policy on which to rely," said Simpson. "If he or she wants to wade through it, at least it will give some kind of idea of what is happening with your information -- but in the mobile environment, there is zero transparency." Not surprisingly, Simpson said it's "great" a consumer has filed suit, and he expects to see more. "Something has to be done to hold these companies accountable." Privacy Is an Illusion Despite the uproar caused by the Journal article, it is surprising that a consumer would assume there were privacy safeguards associated with mobile apps, Rob Walch, host of Today in iPhone, told MacNewsWorld. "It is a free third-party app so -- regardless of the manufacturer -- why would any company provide it for free if they weren't getting something in return?" he asked. "Of course information is getting passed along." For the most part, though, it's unlikely there have been widespread egregious violations of privacy -- such as the passing along of email addresses or bank passwords, in Walch's view. The information that is being transmitted is no doubt more benign -- largely designed to help advertisers tailor their ads, he said. "There is great value for an advertiser to know if someone is in, say, Kansas City, and likes football." Apple's "walled garden" approach to the Internet will be of help here, added Walch. Unlike Google, Apple has a mechanism in place to yank apps that violate its rules. "Sooner or later, someone is going to break the rules and pass along information that they shouldn't if they haven't already," he acknowledged. "At least Apple has the means to stop it when it is brought to its attention." The Do-Not-Track Specter It is not clear such fine distinctions will resonate with consumers -- or the government. There has been heightened interest in this issue on Capitol Hill and in Washington. Earlier this month, hearings were held on the pros and cons of Do Not Track legislation. The Federal Trade Commission recently released a report outlining how such a plan could be implemented. Essentially the agency called for any company collecting data about consumers online to promote privacy throughout their organizations -- as well as inform people when data is being collected. For the most part, the focus has been online activities, but as news of mobile practices continues to make headlines, Washington's attention could expand to include smartphones, said Consumer Watchdog's Simpson. "This is an issue that everyone can understand and that impacts anyone who carries a smartphone," he noted.
Fitness cost of resistance to cadmium in the least killifish (Heterandria formosa). Fitness costs constrain the evolution of resistance to environmental stress in populations. We earlier reported on a rapid response to laboratory selection for cadmium resistance in the least killifish (Heterandria formosa). By the sixth generation, the three selection populations were threefold more resistant to cadmium than the control populations. Here, we report the fitness costs and trade-offs associated with this evolution of resistance. In the F3 and F4 generations, the selection populations produced smaller-sized offspring than the control populations. A comprehensive life-history traits study in the F7 generation showed that the selection populations had, on average, an 18% decrease in fecundity. The selection populations also had a smaller brood size, longer time to first reproduction, and shorter female life expectancy than the control populations. Our results strongly suggest that fitness costs and trade-offs were associated with the evolution of resistance to cadmium in the least killifish. The fitness costs and trade-offs may result from maintenance of the underlying resistance mechanisms, leading to changes in resource allocation in the cadmium-adapted fish.
VoyeurWeb.com - All Amateur Site Sometimes amateur girls can be a nice change from all of the model types we feature. VoyeurWeb.com is devoted to strictly amateur content and once in a while a cute Asian girl shows up there. Check out the full gallery of the cutie above. I'm sure there's far prettier filipinas out there. I just got back from the PI myself and saw many gorgeous girls, but I have to disagree with you on this one. She's absolutely gorgeous!! Just look at those breasts and those LIPS.....I LIKE!!! ALOT!!!!! no offense but i guess my taste run a little different. she reminds me too much of the typical Bangkok bar girls. Maybe it is the photographer but besides the petit body and nice perky boobs, I dont see her at exceptional. Posted by: LawBoy on Sep 22, 06 \| 5:50 am She has a pretty face, great boobs, and a slim body. And them lips are just luscious. Ooh, the possibilities. I wish I was lucky enough to be around hot ass filipinas everyday just so that I can say that she is nothing special.
Tag Archives: Fall Photography Tips Fall is quite possibly my favorite season. Perhaps it’s because the change in the air is so dramatic. Color, crispness, cooler temps–it’s allllll good. Fall pushes photographers everywhere to dig out both their camera and their personal commitment to creating meaningful imagery. It’s exciting to see the lanscape change so drastically, and quite honestly–there’s beauty in nearly every direction. Nothing fuels a photographer’s fire like gorgeous subject matter at a stone’s throw from nearly every canyon drive. I’ve had opportunity to get out quite a bit with several workshop students and shoot some of fall’s finest here in northern Utah. The weather, however, has been challenging for the most part, with clear skies and warm temperatures. It has forced us to get creative and really search for meaningful shots without dramatic skies. We did luck out one morning with fantastic storm clouds, and we took full advantage, knowing it was a gift. While gorgeous in their own right, colorful leaves don’t themselves a memorable image make. I imagine you, just as countless others, have come home from your fall photography forays only to find your images were flat and struggled to convey the sense of grandeur that you witnessed in person. The challenge, is depth. Conveying depth in our fall images is what really helps to take the viewer “there”. A flat mountainside with pretty leaves just won’t cut it. Sure, it’s pretty. But does it have impact? Probably not. Read below for a couple of tips on creating fall images with depth. 2. Search out broken light. Spotty clouds cast spotty or broken light. This random placement of lit and shaded areas carries viewers through the frame and creates that near/far perspective that helps to convey three dimensionality. 3. Use a polarizing filter. Even better, know where and how to use it most effectively. A polarizer will help to reveal full color in the foliage, by removing the natural sheen or reflection. Additionally, and perhaps more importantly (especially on those boring, crystal clear days), a polarizer will deepen skies, helping to add depth and interest to your fall photos. A polarizer is most effective when shot at 90 degrees to the sun–find those compositions that help the polarizer help you! Dawn light and fall color at Park City's iconic Osguthorpe Barn 4. Change your angle to the sun. Fall color takes on a completely different look, depending on your angle to the sun. Front lit aspens can appear dull and washed out, but as soon as place that light source behind them, they glow with life. This is a technique you can use to capture stunning imagery even into the mid-day hours. 5. Use Grad ND Filters. Not sure what they are? Search this blog or get on the Google. I use Singh Ray filters–the best! There’s absolutely no better tool out there for balancing difficult dynamic ranges and allowing you to capture dramatic skies. Storm clouds and lightning bolt at first light over Utah's Wasatch Mountains. 6. Get out there. The golden rule of landscape photography. Simply being there will allow you to make magic. It’s too easy to stay home and wait for what you think might be the perfect conditions to capture that five-star fall keeper. How do you know that you haven’t already missed it? Nothing helps to get the creative juices flowing like being out in nature. You’re sure to find something that floats your boat, and then some. Forget the boring weather forecasts or lackluster color-get out there and find a way to excel behind the lens. Interested in putting this into practice in the field with yours truly? Check out my workshop page for details.
All relevant data are within the paper and its Supporting Information files. Introduction {#sec001} ============ Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCR) that mediate the central and peripheral effects of noradrenaline (NA) and adrenaline \\[[@pone.0180319.ref001], [@pone.0180319.ref002]\\]. They are widely expressed throughout the body and play an important role in regulating multiple physiological processes including cardiac muscle contraction, airway reactivity, cognition, arousal, stress-related behavior, and inflammation \\[[@pone.0180319.ref002]--[@pone.0180319.ref005]\\]. Multiple subtypes of ADRs exist. Each subtype is expressed in distinct patterns and involved in multiple physiological processes \\[[@pone.0180319.ref002], [@pone.0180319.ref006]\\]. Therefore, ligands that selectively target one subtype will be valuable both as research tools to identify the roles of different ADR subtypes and as potential therapeutic agents for multiple diseases related to dysfunction of the NA and adrenaline systems. Among the many subtypes of ADRs, the beta-1 adrenergic receptor (ADRB1) is an important target in multiple therapeutic areas. For example, ADRB1 antagonists (beta-blockers) have been used to treat cardiovascular disease since the 1960s and remain one of the most commonly used drugs today \\[[@pone.0180319.ref007], [@pone.0180319.ref008]\\]. Our laboratory has also identified therapeutic potential of ADRB1 in the treatment of Alzheimer's disease (AD). For example, we previously demonstrated that activation of ADRB1 reverses AD-like cognitive deficits in transgenic mice overexpressing human amyloid beta protein precursor (APP) \\[[@pone.0180319.ref009]\\]. Similarly, we have shown that acute activation of ADRB1 rescues the contextual memory and spatial memory deficits observed in the Ts65Dn mouse model of Down syndrome, which displays an accelerated AD-like pathology \\[[@pone.0180319.ref010]\\]. In addition to the cognitive enhancing effects, we also observed that activation of ADRB1 attenuates pathological features of AD including beta-amyloid burden, tau pathology, and neuroinflammation \\[[@pone.0180319.ref011]\\]. Collectively, our discovery suggests that the ADRB1 agonist may have therapeutic potential for AD as it can address both cognitive symptoms and AD pathology. In addition to its involvement in AD, accumulating evidence suggests that the NA system and ADRB1 play a critical role in regulating neuroimmune responses \\[[@pone.0180319.ref012]--[@pone.0180319.ref014]\\]. By regulating the neuroinflammatory process, ADRB1 ligands may produce therapeutic benefits for the diseases associated with neuroinflammation. Thus, we have focused our attention on the development of ADRB1 agonists as potential therapeutic agents for AD and neuroinflammatory diseases. In the classical view of GPCR signaling, activation of ADRB1 leads to stimulation of two ubiquitous and generic mechanisms: G-protein signaling and β-arrestin signaling \\[[@pone.0180319.ref015]\\]. Recently, however, it has become clear that agonists can show biased activation of signaling pathways. The ability of ligands to activate a receptor and produce responses in a pathway-dependent manner has been termed "signaling bias" or "functional selectivity" \\[[@pone.0180319.ref016], [@pone.0180319.ref017]\\]. As G proteins and β-arrestins mediate distinct physiological processes, biased agonists are expected to provide improved therapeutic selectivity with reduced adverse effects. In search of compounds having therapeutic potential for AD and neuroinflammatory diseases, we sought to identify G protein-biased partial agonists of ADRB1. As partial agonists, these compounds would have more subtle effects in the periphery compared to full agonists, yet be efficacious enough to produce therapeutic benefits for AD and neuroinflammatory disease. By selectively activating ADRB1 G-protein signaling with minimal to no activity on β-arrestin signaling, these compounds would also specifically target the disease relevant signaling pathways without causing the agonist induced tolerance. Xamoterol (ICI118578) is one of the most selective agonists of ADRB1 reported to date ([Fig 1](#pone.0180319.g001){ref-type="fig"}). It is a partial agonist that produces approximately 50% efficacy compared to the full agonist isoproterenol, and was once used for the treatment of cardiovascular disease. However, xamoterol is an exceptionally polar compound (clogP = 0.4) with only 5% oral bioavailability in humans \\[[@pone.0180319.ref018]\\]. In addition, its central nervous system (CNS) penetration is low due to its polarity. Thus, the focus of our efforts was to develop ADRB1 ligands that (1) are partial agonists of ADRB1, (2) exhibit functional selectivity for the cAMP signaling cascade with minimal or no β-arrestin signaling, and (3) show improved brain penetration, using xamoterol as a lead compound. Here, we report the discovery of a series of compounds, including the highly potent and selective drug-like ADRB1 partial agonist STD-101-D1. ![Structure of (S)-xamoterol and two sites of modification.](pone.0180319.g001){#pone.0180319.g001} Materials and methods {#sec002} ===================== General chemistry and procedure for the preparation of compounds {#sec003} ---------------------------------------------------------------- All compounds were obtained at ≥ 95% purity as determined by HPLC/UV analyses. HPLC analyses were run on an Agilent 1100HPLC using a reverse phase Hypersil GOLD PFP 3μm column with a gradient mobile phase of acetonitrile and water containing 0.01% trifluoroacetic acid. LCMS analyses were run on a Shimadzu LC-10ATvp-API 150EX with an Agilent ZORBAX Eclipse XDB-C18 3.5uM column with a gradient mobile phase of acetonitrile and water containing 0.02% formic acid. Compounds were fully characterized with ^1^HNMR. ^1^HNMR spectra were recorded on a Varian 400 MHz machine. Samples were run in DMSO-d6 after removal of the exchangeable protons by D2O exchange with tetramethylsilane as an internal standard. The chemical shifts are expressed in δ (ppm) values, and coupling constants are expressed in hertz (Hz). s = singlet, d = doublet, t = triplet, m = multiplet, and brs = broad singlet. HPLC/UV and ^1^HNMR spectra for all of the compounds are shown in the Supporting Information. The synthesis of (R)- and (S)-xamoterol is shown in [Fig 2](#pone.0180319.g002){ref-type="fig"}. Reaction of 4-(benzyloxy)phenol with (R)-epichlorohydrin, (R)-5, gave the epoxide (S)-6. Ring opening of this epoxide with the morpholino amine, 4, and reductive removal of the benzyl group with Pd on charcoal then gave (S)-xamoterol. In a similar fashion (R)-xamoterol was prepared using (S)-epichlorohydrin. ![Synthesis of (R)- and (S)-xamoterol.](pone.0180319.g002){#pone.0180319.g002} ### Experimental procedure for tert-Butyl 2-(morpholine-4-carboxamido)ethylcarbamate (3) {#sec004} To a solution of tert-butyl 2-aminoethylcarbamate 1 (50 g, 312.09 mmol) in CH~2~Cl~2~ (300mL) was added triethylamine (94.74 g, 936.3 mmol), and morpholine-4-carbonyl chloride 2 (46.7 g, 312.09 mmol) in CH~2~Cl~2~ (200mL) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred at ambient temperature overnight. The reaction mixture was then concentrated under reduced pressure and, after extractive work up, the residue was purified by silica gel column (CH~2~Cl~2~: MeOH = 10:1) to give tert-butyl 2-(morpholine-4-carboxamido)ethylcarbamate 3 (75g, 87.9%) as a white solid. ### Experimental procedure for N-(2-aminoethyl) morpholine-4-carboxamide (4) {#sec005} A solution of tert-butyl 2-(morpholine-4-carboxamido)ethylcarbamate 3 (75 g, 274.39 mmol) in CH~2~Cl~2~ (500mL) was treated dropwise at 0°C with TFA (156.0 g, 1.37 mol). The reaction mixture was stirred for 1.5 hrs and then concentrated under reduced pressure. The resulting residue was dissolved in CH~2~Cl~2~ and 6M NaOH was added to adjust to pH 8. This mixture was extracted with CH~2~Cl~2~ and the organic solution was washed with water, dried over Na~2~SO~4~ and evaporated under reduced pressure to give N-(2-aminoethyl) morpholine-4-carboxamide 4 (43 g, 91%) as a yellow oil. Some of the free base was converted to 4-(N-beta-aminoethylcarbamoyl)morpholine hydrogen sulfate (mp. 168--169°C). ### Experimental procedure for (S)-2-((4-(benzyloxy)phenoxy)methyl)oxirane ((S)-6) {#sec006} CsF (113.79 g, 749.14 mmol) was added with stirring to a mixture of 4-(benzyloxy)phenol, (50 g, 249.71 mmol) and (R)-2-(chloromethyl)oxirane, (R)-5 (69.31 g, 749.14 mmol) in DMF (500mL). The reaction mixture was stirred at 50°C for 3 days. The reaction mixture was then partitioned between water (1 L) and EtOAc (2 L). The organic layer was washed with water (3x900 mL), brine, and then dried over Na~2~SO~4~. The filtered organic extract was concentrated under reduced pressure and purified by silica column (pet ether:EtOAc, 4:1) to give (S)-2-((4-(benzyloxy)phenoxy)methyl)oxirane, (S)-6 (47 g, 73.4%) as a white solid. ### Experimental procedure for (S)-N-(2-(3-(4-(benzyloxy)phenoxy)-2-hydroxypropylamino)ethyl)morpholine-4-carboxamide ((S)-7) {#sec007} A mixture of N-(2-aminoethyl)morpholine-4-carboxamide, 4 (30 g, 104.11 mmol) in isopropanol (120mL) was slowly added to a solution of (S)-2-((4-(benzyloxy)phenoxy)methyl)oxirane, (S)-6 (19.72 g, 156.66 mmol) in isopropanol (230mL) below 50°C over 5 hrs. The reaction mixture was then cooled to room temperature and thoroughly extracted with ethyl acetate. The organic layer was washed with water, brine, and then dried over Na~2~SO~4~. The ethyl acetate extract was concentrated under reduced pressure and purified by silica gel column (CH~2~Cl~2~: MeOH, 10:1) to give (S)-N-(2-(3-(4-(benzyloxy)phenoxy)-2-hydroxypropylamino)ethyl)morpholine-4-carboxamide, (S)-7 (20.8 g, 63%) as a white solid. ### Experimental procedure for (S)-xamoterol {#sec008} A mixture of (S)-N-(2-(3-(4-(benzyloxy)phenoxy)-2-hydroxypropylamino)ethyl)morpholine-4-carboxamide, (S)-7 (20 g, 46.56 mmol) in 200mL of EtOH containing 2mL of acetic acid was added Pd(OH)~2~/C (5g). The resulting reaction mixture was subjected to hydrogenation at 55 psi overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH, and converted to hemifumarate with fumaric acid. The hemifumarate salt was recrystallized with EtOH to give (S)-xamoterol hemifumarate (12.3 g, 91.7%) as an off-white solid. ### Experimental procedure for (R)-2-((4-(benzyloxy)phenoxy)methyl)oxirane ((R)-6) {#sec009} This compound was prepared following the procedure as described for (S)-6 from 4-(benzyloxy)phenol (8 g, 41.9 5mmol) and (S)-2-(chloromethyl)oxirane, (R)-5, to give (R)-2-((4-(benzyloxy)phenoxy)methyl)oxirane, (R)-6 (6.3 g, 24.6 mmol, 61%) as a white solid. ### Experimental procedure for (R)-N-(2-(3-(4-(benzyloxy)phenoxy)-2-hydroxypropylamino)ethyl)morpholine-4-carboxamide ((R)-7) {#sec010} This compound was prepared following the procedure as described for the preparation of (S)-7 from 6.3 g, (24.6 mmol) of (R)-6 and 12.77 g (73.80 mmol) of 4 to afford 3 g, (6.98 mmol, 30%) of (R)-7. ### Experimental procedure for (R)-xamoterol {#sec011} (R)-7 (3g, 6.98mmol) was converted to (R)-xamoterol hemifumarate following the procedure as described above to give (R)-xamoterol hemifumurate (2.5g, 6.8mmol) as an off-white solid. The general method for the synthesis of compounds STD-101-B1 to B8 is shown in [Fig 3](#pone.0180319.g003){ref-type="fig"}. Reaction of phenols 8-B1 to B8 with (R)-2-(chloromethyl)oxirane and CsF in iPrOH for 48 hrs at 50°C gave the coupled epoxides 9-B1 to B8 in good yield. Epoxide opening with an excess of N-(2-aminoethyl)morpholine-4-carboxamide in iPrOH at 50°C then provided the benzyl ethers 10-B1 to B8. Reductive removal of the benzyl protecting group with Pd/C then gave the free phenols, STD-101-B1 to B8 and E which were isolated either as the hemifumarate salts, STD-101-B1, B2, B3, B5 and B7 or as the free base, STD-101-B4, B6, B8 and E. Experimental procedure for the representative example STD-101-B1 is shown below. ![General method for the synthesis of compounds STD-101-B1 to B8.](pone.0180319.g003){#pone.0180319.g003} ### Experimental procedure for (S)-2-((4-(benzyloxy)-3-methylphenoxy)methyl)oxirane (9-B1) {#sec012} To a solution of 4-(benzyloxy)-3-methylphenol (1.95 g, 9.10 mmol) in DMF (20 mL) was added (R)-2-(chloromethyl)oxirane (2.53 g, 27.30 mmol),CsF (4.15 g, 27.30 mmol). The reaction mixture was stirred for 48 hrs at 50°C. The reaction mixture was cooled to room temperature and poured to ice water and extracted with EtOAc (3X20 mL).The combined organic layers were washed with brine, dried over Na~2~SO~4~, filtered, concentrated under reduced pressure and purified by flash silica column chromatography to give (S)-2-((4-(benzyloxy)-3-methylphenoxy)methyl)oxirane (2.1 g, 84.5%) as a yellow oil. ### Experimental procedure for (S)-N-(2-(3-(4-(benzyloxy)-3-methylphenoxy)-2-hydroxypropylamino)ethyl)morpholine-4-carboxamide (10-B1) {#sec013} To a solution of (S)-2-((4-(benzyloxy)-3-methylphenoxy)methyl)oxirane (0.6 g, 2.22 mmol) in iPrOH (20 mL) was added N-(2-aminoethyl)morpholine-4-carboxamide (0.77 g, 4.44 mmol). The reaction mixture was stirred for 18 hrs at 50°C. The reaction mixture was cooled to room temperature and poured to ice water and extracted with EtOAc (3X20 mL). The combined organic layers were washed with brine, dried over Na~2~SO~4~, filtered, concentrated under reduced pressure and purified by flash silica column chromatography to give (S)-N-(2-(3-(4-(benzyloxy)-3-methylphenoxy)-2-hydroxypropylamino)ethyl)morpholine-4-carboxamide (0.5 g, 50.8%) as a yellow oil. ### Experimental procedure for STD-101-B1, hemifumarate {#sec014} To a solution of (S)-N-(2-(3-(4-(benzyloxy)-3-methylphenoxy)-2-hydroxypropylamino)ethyl)morpholine-4-carboxamide (0.5 g, 2.22 mmol) in MeOH(15 mL) was added Pd/C. The reaction mixture was subjected to H~2~ for 4 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH(15 mL), fumaric acid(0.5eq) was added and solvent removed under reduced pressure to give STD-101-B1, hemifumarate (0.35 g, 75.5%) as a pink solid. The synthesis of STD-101-B9 is shown in [Fig 4](#pone.0180319.g004){ref-type="fig"}. Reaction of 2-fluoro-5-hydroxybenzaldehyde with (R)-2-(chloromethyl)oxirane and CsF in iPrOH gave the coupled epoxide 12, which was then treated with sodium borohydride to reduce the aldehyde to the hydroxymethylene, 13. Ring opening with N-(2-aminoethyl) morpholine-4-carboxamide gave STD-101-B9, which was isolated as the hemifumarate salt. ![Synthesis of STD-101-B9.](pone.0180319.g004){#pone.0180319.g004} ### Experimental procedure for (S)-2-fluoro-5-(oxiran-2-ylmethoxy)benzaldehyde (12) {#sec015} A mixture of 2-fluoro-5-hydroxybenzaldehyde (1.0 g, 7.14 mmol), (R)-2-(chloromethyl) oxirane (1.98 g, 21.41mmol) and CsF(3.25 g,21.41mmol) in DMF (10 ml) was stirred at 0°C and then heated at 50°C for 48 hrs. The reaction mixture was then portioned between water and ethylacetate (2:1 ratio), the organic layer was washed with water, brine, dried over Na~2~SO~4~, filtered, concentrated under reduced pressure and purified by silica column chromatography, to give (S)-2-fluoro-5-(oxiran-2-ylmethoxy)benzaldehyde (1.1 g, 78.6%) as a light yellow oil. ### Experimental procedure for (S)-(2-fluoro-5-(oxiran-2-ylmethoxy)phenyl)methanol (13) {#sec016} To a solution of (S)-2-fluoro-5-(oxiran-2-ylmethoxy)benzaldehyde (1.2 g, 6.14 mmol) in THF (10 ml) was added NaBH~4~(0.23 g, 6.12 mmol) and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was quenched with water and extracted with EtOAc (3X30mL). The combined organic layers were washed with water, brine, dried over Na~2~SO~4~, filtered, concentrated under reduced pressure and purified by silica column chromatography, to give (S)-(2-fluoro-5-(oxiran-2-ylmethoxy)phenyl)methanol (0.57 g, 47%) as yellow oil. ### Experimental procedure for (S)-N-(2-(2-hydroxy-3-(3-methyl-1H-indazol-4-yloxy)propylamino)ethyl)morpholine-4 (STD-101-B9) {#sec017} To a solution of (S)-(2-fluoro-5-(oxiran-2-ylmethoxy) phenyl) methanol (0.57 g, 2.88mmol) in iPrOH (20 ml), was added N-(2-aminoethyl) morpholine-4-carboxamide (1.0g, 5.75mmol). The reaction mixture was stirred at 50°C for 5 hrs, and then evaporated under reduced pressure. Water was added to the residue and the product was extracted into ethyl acetate. The organic layer was washed with water, brine, dried over Na~2~SO~4~, filtered, concentrated under reduced pressure and purified by silica column chromatography to give (S)-N-(2-(2-hydroxy-3-(3-methyl-1H-indazol-4-yloxy)propylamino)ethyl)morpholine-4-carboxamide (0.23 g, 18.6%) as a solid. The general method for the synthesis of compounds STD-101-D1 to D6 is shown in [Fig 5](#pone.0180319.g005){ref-type="fig"}. The starting material (S)-1-(4-(benzyloxy)phenoxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol (15) was prepared by treating 4-benzyloxyphenol with (R)-epichlorohydrin as described above. Opening of the epoxide ring of 15 with 2-(2-methoxyphenoxy)ethanamine gave the benzyl ether 16 which was then deprotected by catalytic reduction to give the desired product STD-101-D1. Compounds STD-101-D2 to D6 were prepared in a similar fashion using the appropriate amine reagent and isolated as the hemifumarate salts. Experimental procedure for the representative example compound STD-101-D1 is shown below. ![General method for the synthesis of compounds STD-101-D1 to D6.](pone.0180319.g005){#pone.0180319.g005} ### Experimental procedure for (S)-1-(4-(benzyloxy)phenoxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol (16) {#sec018} To a solution of (S)-2-((4-(benzyloxy)phenoxy)methyl)oxirane (1.0 g, 3.9mmol) in iPrOH (40 ml), was added 2-(2-methoxyphenoxy)ethanamine (0.98 g, 5.8mmol) in iPrOH dropwise under 50°C for 5h. The reaction mixture was cooled to room temperature, and removed the solution, water was added, extracted with EA. The organic layer was washed with water, brine, dried over Na~2~SO~4~, concentrated under reduced pressure and purified by silica column, to give (S)-1-(4-(benzyloxy)phenoxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol (0.52 g, 1.228mmol). ### Experimental procedure for (S)-4-(2-hydroxy-3-(2-(2-methoxyphenoxy)ethylamino)propoxy)phenol (STD-101-D1) {#sec019} A solution of (S)-1-(4-(benzyloxy)phenoxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol (0.52 g, 1.2mmol) and Pd/C (0.1 g) in MeOH (20ml), was stirred under a H~2~ atmosphere at RT for 2h. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica column to give (S)-4-(2-hydroxy-3-(2-(2-methoxyphenoxy)ethylamino)propoxy)phenol (0.35g, 1.05mmol). The syntheses of the amine components for STD-101-D5 and D6 are shown in [Fig 6](#pone.0180319.g006){ref-type="fig"}. ![Syntheses of the amine components for STD-101-D5 and D6.](pone.0180319.g006){#pone.0180319.g006} NMR spectral data {#sec020} ----------------- NMR spectral results for STD-101-B1 to B9, D1 to D6 and E are shown below. It is important to highlight that the H-signals for the fumaric acid in the hemifumarate salts are not recorded. ### (S)-N-(2-((2-hydroxy-3-(4-hydroxy-3-methylphenoxy)propyl)amino)ethyl)morpholine-4-carboxamide hemifumarate (STD-101-B1) {#sec021} MS(m/z), 354(M+1); ^1^HNMR (400 MHz, DMSO, after D2O): 2.04 (3H, s), 2.91(2H, m), 3.06(1H, m), 3.21 (4H, m), 3.25 (1H,m), 3.50(4H, m), 3.75 (1H,m), 4.0 (1H, m), 6.5 (1H,s), 6.66(2H, m). ### (S)-N-(2-((3-(3-chloro-4-hydroxyphenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide hemifumarate (STD-101-B2) {#sec022} MS(m/z), 374(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange, whenever as salt signals for fumaric acid are not shown): 2.96 (4H, m), 3.25 (4H, m), 3.37 (2H, m), 3.50 (4H, m), 3.84 (2H, m), 4.08 (1H, m), 6.73 (1H, dd, J = 8,4Hz); 6.76 (1H, d, J = 8Hz), 6.94 (1H, d, J = 4Hz.) ### (S)-N-(2-((3-(3-ethyl-4-hydroxyphenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide hemifumarate (STD-101-B3) {#sec023} MS(m/z), 368(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange); 1.05(3H,t J = 7.8 Hz), 2.48 (2H, q, J = 7.8Hz), 2.90(2H, m),2.95--3.22 (10H, m), 3.48 (4H,m), 4.01(1H, m), 6.41(1H, s), 6.55--6.65(2H,m). ### (S)-N-(2-((3-(5-chloro-2-fluoro-4-hydroxyphenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide (STD-101-B4) {#sec024} MS(m/z), 392(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 3.19(2H, m),3.25--3.36(6H, m), 3.48 (2H,m), 3.64(4H, m), 3.99 (2H, m) 4.03(1H, m), 6.72(1H, d, J = 12.2Hz), 7.14(1H,d, J = 8.72Hz). ### (S)-N-(2-((3-(2,5-difluoro-4-hydroxyphenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide hemifumarate (STD-101-B5) {#sec025} MS(m/z), 376(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.85--3.10 (4H, m),3.23 (4H, m), 3.48 (2H,m), 3.54--3.70 (6H, m), 3.91(2H, m) 4.13(1H, m), 6.82(1H, d, J = 8Hz), 7.10(1H,d, J = 12Hz). ### (S)-N-(2-((3-(3-cyano-4-hydroxyphenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide (STD-101-B6) {#sec026} MS(m/z), 365(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.48--2.54 (4H, m), 3.07(2H, m), 3.22 (4H, m), 3.50 (4H,m), 3.81 (2H, m), 3.88 (1H, m), 6.89(1H, d, J = 8.8 Hz), 7.08(1H, d J = 8.8Hz), 7.13(1H,s). ### (S)-N-(2-((3-(3,5-difluoro-4-hydroxyphenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide hemifumarate (STD-101-B7) {#sec027} MS(m/z), 376(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange: 2.72--2.86(4H, m), 3.13(4H, m), 3.49 (4H, m), 3.50 (4H,m), 3.60 (2H, m), 3.75 (2H, m), 3.85 (1H,m), 6.68(2H, d, J = 7.2 Hz). ### (S)-N-(2-((3-(5-cyano-2-fluoro-4-hydroxyphenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide (STD-101-B8) {#sec028} MS(m/z), 383(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.85--3.15(4H, m), 3.23--3.34 (4H, m), 3.46(6H, m), 3.98 (2H,m), 4.12(1H, m), 6.86(1H, d, J = 13 Hz), 7.45 (1H, d, J = 9Hz). ### (S)-N-(2-((3-(4-fluoro-3-(hydroxymethyl)phenoxy)-2-hydroxypropyl)amino)ethyl)morpholine-4-carboxamide hemifumarate (STD-101-B9) {#sec029} MS(m/z), 372(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange: 2.98 (4H, m), 3.12(4H, m), 3.30 (2H, m), 3.51 (4H, m), 3.89(2H, m), 4.12(1H,m), 4.47(2H,s), 6.80 (1H,m), 7.02 (2H,m). ### (S)-4-(2-hydroxy-3-((2-(2-methoxyphenoxy)ethyl)amino)propoxy)phenol hemifumarate (STD-101-D1) {#sec030} MS(m/z), 334(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.81 (2H, m), 2.95 (2H, m), 3.07 (2H, t, J = 4Hz), 3.71 (3H, s), 3.96 (1H, m), 4.08 (2H, t, J = 4Hz), 6.64 (2H, d, J = 8,4Hz); 6.73 (2H, d, J = 8Hz), 6.94 (4H, m) ### (S)-4-(3-((2-(3,4-dimethoxyphenethoxy)ethyl)amino)-2-hydroxypropoxy)phenol hemifumarate (STD-101-D2) {#sec031} S(m/z), 392(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.70 (2H, m), 2.96 (2H, m), 3.63 (3H, s), 3.66 (3H, s), 3.75 (2H, m), 3.97 (3H, m), 6.64 (2H, d, J = 8,4Hz); 6.73 (2H, d, J = 8Hz), 6.63--6.79 (7H, m). ### (S)-4-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)-1-morpholinobutan-1-one hemifumarate (STD-101-D3) {#sec032} MS(m/z), 339(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 1.73 (2H, m), 2.34 (2H, t, J = 7Hz), 2.75 (2H, m), 2.88 (1H, m), 3.39 (4H, m), 3.55 (4H, m), 3.80 (2H, m), 3.97 (1H, m), 6.65 (2H, d, J = 8Hz), 6.75 (2H, d, J = 8Hz). ### (S)-3-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)-1-morpholinopropan-1-one hemifumarate (STD-101-D4) {#sec033} MS(m/z), 325(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.71 (2H, m), 2.88 (1H, m), 3.08 (3H, m), 3.40 (4H, m), 3.60 (4H, m), 3.78 (2H, m), 4.08 (1H, m), 6.66 (2H, d, J = 8Hz), 6.75 (2H, d, J = 8Hz). ### (S)-3-hydroxy-N-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)azetidine-1-carboxamide hemifumarate (STD-101-D5) {#sec034} MS(m/z), 326(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.98 (4H, m), 3.20 (2H, m), 3.54 (2H, m), 3.81 (2H, m), 3.93 (2H, m), 4.10 (1H, m), 4.37 (1H, m), 6.66 (2H, d, J = 8Hz), 6.75 (2H, d, J = 8Hz). ### (S)-N-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-3-(hydroxymethyl)azetidine-1-carboxamide hemifumarate (STD-101-D6) {#sec035} MS(m/z), 340(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.57 (1H,m), 3.00 (3H, m), 3.18 (1H, m), 3.31 (2H, m), 3.50 (4H, m), 3.80 (4H, m), 4.12 (1H, m), 6.66 (2H, d, J = 8Hz), 6.75 (2H, d, J = 8Hz). ### (S)-N-(2-((2-hydroxy-3-((5-hydroxynaphthalen-1-yl)oxy)propyl)amino)ethyl)morpholine-4-carboxamide (STD-101-E) {#sec036} MS(m/z), 390(M+1); ^1^HNMR (400 MHz, DMSO, after D2O exchange): 2.77--2.84 (4H, m), 3.21 (6H, m), 3.47 (4H, m), 4.08 (3H, m), 6.87(2H, m), 7.23 (2H, m), 7.65 (2H, d, J = 8Hz). cAMP assay {#sec037} ---------- Pharmacological effects of compounds at the cAMP pathway mediated by ADRB1 were evaluated by measuring cAMP production using the homogenous time-resolved fluorescence detection method with HEK-293 cells stably expressing human recombinant ADRB1. Briefly, cells were suspended in HBSS buffer completed with 20 mM HEPES (pH 7.4) and 500 μM IBMX (3-isobutyl-1-methylxanthine) and distributed at a density of 3x10^3^ cells/well. Subsequently, cells were incubated with HBSS (basal control), the full agonist isoproterenol hydrochloride (I5627; Sigma-Aldrich Corp., MO), xamoterol (Santai Labs; <http://www.santailabs.com/index.asp>), or test compounds for 30 min. Following incubation, the cells were lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) were added. After a 60 min incubation with the fluorescence donor and acceptor at room temperature, the fluorescence transfer was measured at 337 nm (excitation) and 620 and 665 nm (emission) using a microplate reader. The cAMP concentration was determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results were expressed as a percent of the maximum efficacy achieved with isoproterenol. Pharmacological effects of compounds at the cAMP pathway mediated by ADRB2 and ADRB3 were measured as described above using CHO cells stably expressing human recombinant ADRB2 and human SK-N-MC neurotumor cells endogenously expressing ADRB3, respectively. β-arrestin assay {#sec038} ---------------- Pharmacological activity of compounds in the β-arrestin pathway mediated by ADRB1 were evaluated using an enzyme fragment complementation method with a β‐galactosidase functional reporter. An engineered CHO-K1-ADRB1 PathHunter cell line (DiscoveRx) was used in the assay. In this cell line, the enzyme acceptor (β‐galactosidase fragment) is fused to β-arrestin and the enzyme donor (β‐galactosidase fragment) is fused to the ADRB1. Thus, activation of the ADRB1 stimulates binding of β-arrestin to the ProLink-tagged ADRB1 and forces complementation of the two enzyme fragments, resulting in the formation of an active β‐galactosidase enzyme. Briefly, CHO-K1-ADRB1 PathHunter cell lines were plated in a total volume of 20 μL cell plating reagent (DiscoveRx, 93-0563R0A) at a density of 2,500 cells/well into 384 well microplates and incubated overnight at 37°C in 5% CO~2~. The following day, 5 μL of the full agonist isoproterenol, xamoterol (S), or test compounds was added to cells and incubated at 37°C for 90 min. After the 90 min incubation, 15 μL of PathHunter Detection reagent cocktail (DiscoveRx, 93--0001) was added, followed by a 60 min incubation at room temperature. Chemiluminescent signal was then read with a PerkinElmer Envision (Perkin Elmer, Inc., MA) instrument. The results were expressed as a percent of the maximum efficacy achieved with isoproterenol. Crystal structure modeling {#sec039} -------------------------- Ligands were docked to the binding pocket of PDB: 2YCZ, constrained to a 25 Angstrom box size surrounding the orthosteric pocket. Docking was performed using Schrödinger Glide, with SP precision and after using LigPrep to prepare all ligands with a maximum of 32 stereoisomers and 6 low energy ring conformations. The docking and analysis were facilitated by the open source software: (<https://github.com/evanfeinberg/conformation/blob/master/grids.py>)). In vitro primary microglia tumor necrosis factor α (TNFα) assay {#sec040} ----------------------------------------------------------------- Mixed glial cells were obtained from the cerebral cortex of Sprague Dawley rat pups at postnatal days 1--3. Briefly, neonates were euthanized by decapitation and their brain tissues were collected for cortex isolation. The isolated cortex was then trypsinized, triturated, and placed into tissue culture flasks in DMEM supplemented with 10% fetal bovine serum and 1% Penicillin/Streptomycin. After 10 days in vitro, microglia were harvested by gentle shaking of the growth flask, plated in a 96 well plate at a density of 30,000 cells/well, and incubated at 37°C overnight. The next day, microglia were stimulated with lipopolysaccharides (LPS) (10 ng/ml) along with isoproterenol, xamoterol (S), or STD-101-D1 at the concentration of 10 μM for 4 hrs at 37°C. Following the 4 hr incubation, cell media was collected and the concentration of TNFα was measured by ELISA (Invitrogen, KRC3011) according to the manufacturer's instruction. Microsomal stability assay {#sec041} -------------------------- The test compound was pre-incubated with pooled mouse, rat, or human microsomes in 100 mM potassium phosphate buffer (pH 7.4) containing 10 mM MgCl~2~ for 5 min in a 37°C shaking waterbath. After the preincubation, the reaction was initiated by adding freshly prepared NADPH to a final concentration of 1mM. Aliquots of the reaction samples were collected at 0 min, 15 min, 30 min, 45 min, and 60 min after the initiation of the reaction, and quenched with equal volume of acetonitrile. Samples were then mixed and centrifuged, and supernatants were diluted with equal volume of water and used for LC-MS/MS analysis to determine the concentrations of STD-101-D1. Analyte peak areas at different time points were recorded, and the compound remaining was calculated by comparing the peak area at each time point to time zero. The half-life was calculated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first order kinetics. Animals {#sec042} ------- For the in vivo LPS study, a total of 45 male C57Bl/6J mice at the age of 10--12 weeks (Jackson Laboratory, Bar Harbor, ME, USA) were used. For the pharmacokinetic study, a total of 36 Sprague-Dawley male rats (Charles River, Wilmington, MA, USA) weighing 280--380 g were used. All animals were kept under a reverse light-dark cycle with lights off at 8:30 AM and on at 8:30 PM in a temperature- and humidity-controlled environment and given food and water ad libitum. All animal experiments were conducted in accordance with the U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80--23). All experimental protocols were reviewed and approved by the Stanford University Institutional Animal Care and Use Committee (IACUC) (Protocol \\#---18466). In vivo LPS assay {#sec043} ------------------- C57Bl/6J mice (10--12 weeks old) were injected with xamoterol (3 mg/kg; subcutaneous; n = 11), STD-101-D1 (3 mg/kg; intraperitoneal; n = 4) or vehicle (5% DMSO/20%PEG400/water; intraperitoneal; n = 12) 15 min prior to LPS (50 ug/kg; intraperitoneal). A control group was injected with vehicle 15 minutes prior to saline (n = 18). Following injections, mice were single-housed. At 90 min post-LPS/saline, mice were deeply anesthetized with isoflurane and blood was collected from the right ventricle via cardiac puncture (23 g needle) into lithium heparin-containing vials (BD microtainer plasma tubes). Subsequently, brains were collected after perfusion with phosphate-buffered saline. Plasma was separated by centrifugation (11,000 rpm for 3 minutes) within 60 min of collection and stored at -80°C until analysis. The concentration of TNFα in the collected plasma was measured by ELISA (Invitrogen, KMC3012) according to the manufacturer's instruction. The LPS-induced inflammatory response in the CNS was assessed by measuring mRNA expression for genes related to neuroimmune activation in brain tissue according to the previously reported method \\[[@pone.0180319.ref011]\\]. Briefly, total RNA was extracted from hippocampus containing coronal sections using the RNeasy Lipid Tissue Mini Kit (Qiagen), and transcribed into cDNA (Superscript III, Invitrogen). PCR was performed in duplicate using TaqMan gene expression assays, TNFα (Mm00443258_m1), IL1b (Mm00434228_m1), IL6 (Mm00446190_m1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Mm99999915_g1). Fold changes of expression relative to control were determined after normalization to GAPDH. Relative quantification and fold change were calculated by the comparative CT method \\[[@pone.0180319.ref019]\\]. Brain uptake of STD-101-D1 was determined in brain tissue. Brain tissues were homogenized in distilled water at a ratio of 1:3 (weight of tissue:volume of water) and homogenates were analyzed using LC-MS/MS. Pharmacokinetic studies {#sec044} ----------------------- Two cohorts of Sprague-Dawley rats were used in two independent studies. All animals were fasted overnight before the experiment with free access to water. In study 1, a total of 18 rats were used for a 4 hr time course pharmacokinetic (PK) study. Rats were anesthetized with 3% isoflurane and catheters were implanted into the jugular and/or portal veins for compound administration and/or blood sampling at 1 to 2 days prior to the experiments as previously described \\[[@pone.0180319.ref020], [@pone.0180319.ref021]\\]. On the day of the experiment, xamoterol was freshly prepared in saline. STD-101-D1 was freshly prepared in 5% DMSO, 20% PEG, and 75% distilled water. The prepared xamoterol or STD-101-D1 was administered to the cannulated rats at a dose of 10 mg/kg intravenously (IV), intraperitoneally (IP), or orally (PO) (n = 3 per route). For IV and IP groups, approximately 150 μL aliquot of blood samples were collected via jugular vein catheters before drug administration, and at 1, 5, 10, 45, 60, 90, 120, and 180 min after drug administration. For the PO group, approximately 150 μL aliquot of blood samples were collected via jugular and portal vein catheters before drug administration, and at 1, 5, 10, 45, 60, 90, 120, and 180 min after drug administration. Four hours post-dose, rats were deeply anesthetized with isoflurane and blood samples were collected by cardiac puncture. In study 2, a total of 18 rats were used for a 20 min post-dose collection study. Xamoterol and STD-101-D1 were freshly prepared as described above and administered to rats at a dose of 10 mg/kg via IV, IP, or PO routes (n = 3 per route). At 20 min post-dose, rats were deeply anesthetized with isoflurane and blood samples were collected by cardiac puncture. Brains were collected after perfusion with phosphate buffered saline. All plasma samples were immediately separated after collection by centrifugation (11,000 rpm for 3 minutes) and stored at −80°C until analysis. The brain tissue samples were homogenized in distilled water at a ratio of 1:3 (weight of tissue:volume of water), and the homogenates were stored at −80°C until analysis. The concentrations of xamoterol and STD-101-D1 in plasma and brains were determined using LC-MS/MS (AB SCIEX QTRAP 4000 mass spectrometer coupled to a Shimadzu UFLC system). For xamoterol, LC separation was carried out on an Agilent Zorbax SB-Phenyl column (5 μm, 2.1×50 mm) with isocratic elution using a mobile phase composed of 30% methanol and 70% water with 0.1% of formic acid. Tulobuterol was used as the internal standard. The flow rate was set to 0.45 ml/min. Column temperature was 25°C. The analysis time was 2.2 min. The injection volume was 20 μl. The mass spectrometer was operated in the positive mode with multiple-reaction monitoring (MRM). The m/z 340.2→253.2 and 228.1→154.1 transitions were used for Xamoterol and the internal standard, respectively. For STD-101-D1, LC separation was carried out on a Phenomenex Synergi Polar-RP column (2.5 μm, 2 mm × 50 mm) with a flow rate of 0.25 ml/min at room temperature. Mobile phase A consisted of 10 mM ammonium acetate and 0.1% formic acid in LCMS grade water. Mobile phase B consisted of 10 mM ammonium acetate and 0.1% formic acid in LCMS grade acetonitrile:water 90:10% (v/v). The HPLC elution program was as follows: 35% B (0.3 min)→85% B (linear increase in 1.2 min)→35% B (linear decrease in 0.1 min)→35% B (0.9 min). Five μl of the extracted samples were injected. The mass spectrometer was operated in the positive mode with multiple-reaction monitoring (MRM) with the transition m/z 334.1→210.1 and 334.1→100.2. Data acquisition and analysis were performed using the Analyst 1.6.1 software (AB SCIEX, CA). Cardiovascular studies {#sec045} ---------------------- Effects of compounds on heart rate and blood pressure were measured in male Sprague-Dawley rats using a fluid filled catheter-transducer system with a disposable blood pressure transducer MLT 0699 connected to a PowerLab 8/30 recording unit with Quad Bridge Amp (AD instruments, CO). Briefly, rats were anesthetized with isoflurane (3--4% for induction and 1.5% for maintenance) and a 1 cm longitudinal incision was made on the ventral aspect of the tail exposing the tail artery. A polyethylene catheter (PE50) filled with heparinized saline was then inserted into the tail artery and connected to the blood pressure transducer system. After ensuring the absence of any air bubbles, 5--10 min of baseline systolic and diastolic blood pressure along with heart rate measurements were recorded using LabChart Pro (AD Instruments, CO). After establishing the baseline, xamoterol or STD-101-D1 was subcutaneously administered and changes in blood pressure and heart rate measurements were recorded for an additional 30 min. The effects of xamoterol or STD-101-D1 on heart rate were calculated as the difference between average values recorded during the baseline recording and average values recorded during 5 to 10 min after the administration of compound. The effects of xamoterol or STD-101-D1 on blood pressure were calculated as the difference between average values measured during the baseline recording and the lowest value measured during the 10 min period after administration of the compound. Calculation and statistics {#sec046} -------------------------- In vitro pharmacology data for the cAMP pathway represent 2--5 experiments performed singly or in duplicate. In vitro pharmacology data for the β-arrestin pathway represent technical replicates within a single experiment. Curve fitting was performed with GraphPad Prism 5.0 software (GraphPad Software, CA) using the equation for a single-site sigmoidal, dose-response curve with a variable slope. EC~50~ values were expressed as geometric means (95% confidence limits). Statistical analyses were performed with GraphPad Prism 5.0. One-way analyses of variance, followed by Dunnett's test for post-hoc analyses were performed on in vitro and in vivo TNFα data. Pharmacokinetic analyses were performed using the Phoenix WinNonlin Professional Edition computer software version 2.0 (Certara, NJ). Differences were considered to be significant at a level of p \\< 0.05. In all cases, outliers were excluded according to Grubbs' test and p \\< 0.05 was considered to be significant. Results {#sec047} ======= Structure-activity relationship of compounds at the cAMP pathway mediated by ADRB1 {#sec048} ---------------------------------------------------------------------------------- The β-aminoalcohol linking moiety is a crucial pharmacophoric element of most ADRB1 binding compounds, including xamoterol \\[[@pone.0180319.ref022]\\]. Consequently, structure-activity relationship (SAR) studies and drug discovery programs have focused upon making structural changes at the two terminal sites of ADRB1 binding molecules. We hypothesize that affinity and selectivity at ADRB1 can be significantly improved and manipulated by making the appropriate structural changes to xamoterol at the phenolic and morpholino subsites ([Fig 1](#pone.0180319.g001){ref-type="fig"}). As such, we prepared 18 analogs of xamoterol with the objective of (1) maintaining affinity and efficacy for ADRB1, and (2) increasing brain penetration. Pharmacological effects of the analogs on ADRB1 were then evaluated by measuring cAMP production. The major shortcomings of xamoterol for CNS indications are its poor oral bioavailability and rapid clearance \\[[@pone.0180319.ref018]\\]. Most of the absorbed drug in humans is excreted in the urine unchanged, with a substantial amount also excreted as the sulfate after first pass by the liver. We therefore envisioned that structural modifications of the phenol group could enhance PK properties of the molecules. In the first series of compounds, the phenol group in xamoterol is substituted with a variety of electron donating and electron withdrawing groups ([Fig 7](#pone.0180319.g007){ref-type="fig"}). These diverse structural modifications also alter the lipophilicity of the compounds and modulate other molecular properties, such as tPSA, which should enhance oral absorption. As the (S)-enantiomer of xamoterol was more potent and efficacious than the (R)-enantiomer, all structural modifications were made on the (S)-enantiomer ([Fig 7](#pone.0180319.g007){ref-type="fig"} and [Fig 8A](#pone.0180319.g008){ref-type="fig"}). As demonstrated by the data shown in Figs [7](#pone.0180319.g007){ref-type="fig"} and [8B](#pone.0180319.g008){ref-type="fig"}, the introduction of methyl, chlorine, and ethyl residues (STD-101-B1, B2, and B3) to sterically crowd the phenolic OH abolished the ADRB1 agonist activity. These analogs produced no pharmacological effects up to concentrations of 100 μM ([Fig 7](#pone.0180319.g007){ref-type="fig"} and [Fig 8B](#pone.0180319.g008){ref-type="fig"}). On the other hand, introduction of cyanide to this position (STD-101-B6) led to a decrease in both potency and efficacy compared to xamoterol (S) ([Fig 7](#pone.0180319.g007){ref-type="fig"} and [Fig 8B](#pone.0180319.g008){ref-type="fig"}). The addition of fluorines at C2 and C5 with respect to phenolic OH (STD-101-B5) resulted in an approximately 2-fold efficacy decrease. A fluorine substitution at C3 and C5 (STD-101-B7) abolished the agonist activity completely ([Fig 7](#pone.0180319.g007){ref-type="fig"} and [Fig 8B](#pone.0180319.g008){ref-type="fig"}) as did substitution of the larger substituents, chlorine or cyano, ortho to the phenolic OH group (STD-101-B4, STD-101-B8). Compounds (STD-101-B9) and STD-101-E ([Fig 7](#pone.0180319.g007){ref-type="fig"} and [Fig 8B](#pone.0180319.g008){ref-type="fig"}) were also inactive. ![Effects of structural modifications of the phenolic OH moiety of xamoterol on the cAMP pathway mediated by ADRB1.\\ clogP^a^, Calculated with ChemDraw Pro Version 16.0 (PerkinElmer Health Sciences, CT; EC~50~ (nM)^b^, Geometrical mean of EC50 values from at least two independent experiments; % Iso max^c^, Percent efficacy compared to the maximum response achieved with isoproterenol; \\~^d^, Could not be determined.](pone.0180319.g007){#pone.0180319.g007} ![Concentration-response effects of compounds on the cAMP pathway via ADRB1.\\ Data are expressed as a percentage of maximum efficacy obtained with the full agonist isoproterenol. Values represents means ± S.E.M.s (1--2 experiments with n = 1--2).](pone.0180319.g008){#pone.0180319.g008} In the second series of compounds, analogs incorporated structural modifications of the morpholino urea moiety of xamoterol ([Fig 9](#pone.0180319.g009){ref-type="fig"}). Replacement of morpholine-4-carboxamide moiety in xamoterol (S) by (2-methoxyphenoxy)ethanamine (STD-101-D1) led to an approximately 7-fold decrease in potency and approximately 30% increase in efficacy ([Fig 8C](#pone.0180319.g008){ref-type="fig"} and [Fig 9](#pone.0180319.g009){ref-type="fig"}). Substitution with \\[2-(3,4-dimethoxyphenyl)ethoxy\\]ethanamie (STD-101-D2) resulted in an approximately 80-fold decrease in potency and an approximately 10% increase in efficacy. Similarly, analogs where the NH of the urea was replaced with methylene (STD-101-D3) or completely excised (STD-101-D4) led to approximately 26- and 73-fold decreases in potency, respectively. However, these modifications in STD-101-D3 and STD-101-D4 led to approximately 20% increases in efficacy ([Fig 8C](#pone.0180319.g008){ref-type="fig"} and [Fig 9](#pone.0180319.g009){ref-type="fig"}). Substitution of the morpholine group in xamoterol (S) with smaller ring systems, 3-hydroxyazetidine (STD-101-D5) and 3-hydroxymethylazetidine (STD-101-D6) led to more than approximately 40-fold decreases in potency. Interestingly, these changes in STD-101-D5 and STD-101-D6 only marginally affected their efficacies. Substitution of the morpholine group in xamoterol (S) with 1,2-dimethoxybenzene (RO363) led to an approximately 3-fold decrease in potency and an approximately 2-fold increase in efficacy ([Fig 8C](#pone.0180319.g008){ref-type="fig"} and [Fig 9](#pone.0180319.g009){ref-type="fig"}). Importantly, none of the second series of compounds having partial agonist activity on the cAMP pathway via ADRB1 show activity on cAMP pathways via ADRB2 or ADRB3, suggesting that they are partial agonists selective for ADRB1 versus ADRB2 and ADRB3 (data not shown). ![Effects of structural modifications of the morpholino urea moiety of xamoterol on the cAMP pathway mediated by ADRB1.\\ clogP^a^, Calculated with ChemDraw Pro Version 16.0; EC~50~ (nM)^b^, Geometrical mean of EC50 values from at least two independent experiments; % Iso max^c^, Percent efficacy compared to the maximum response achieved with isoproterenol; \\~^d^, Could not be determined.](pone.0180319.g009){#pone.0180319.g009} Signaling bias of the key compound {#sec049} ---------------------------------- To identify G protein-biased agonists of ADRB1, we assessed the pharmacological activity of the compounds that showed significant agonistic activity at the cAMP pathway (e.g. STD-101-D1 through STD-101-D6 and RO363) on the ADRB1-mediated β-arrestin pathway. As a classical unbiased agonist, isoproterenol produced concentration-dependent responses at the β-arrestin pathway via ADRB1 with an EC~50~ value of 31.3 nM ([Fig 10](#pone.0180319.g010){ref-type="fig"}). In contrast, xamoterol (S) did not produce concentration-dependent responses up to 30 μM, indicating that it has a very high level of functional selectivity toward the cAMP pathway ([Fig 10](#pone.0180319.g010){ref-type="fig"}). The partial agonists STD-101-D1 through STD-101-D4 displayed very weak partial agonist activity at the β-arrestin pathway, producing less than 20% efficacy compared to the full agonist isoproterenol (Figs [9](#pone.0180319.g009){ref-type="fig"} and [10](#pone.0180319.g010){ref-type="fig"}). The other two compounds STD-101-D5 and STD-101-D6 did not produce concentration-dependent responses up to 30 μM ([Fig 9](#pone.0180319.g009){ref-type="fig"}). However, RO363, which showed full agonistic activity on the ADRB1-mediated cAMP pathway, produced partial agonistic activity on the ADRB1-mediated β-arrestin pathway, achieving 36.5% efficacy with an EC~50~ value of 32.2 nM. On the basis of potency and partial agonistic activity on the cAMP pathway and functional selectivity for the cAMP pathway over the β-arrestin pathway, the compound STD-101-D1 was selected for further in vitro and in vivo testing. ![Concentration-response effects of compounds on the β-arrestin pathway via ADRB1.\\ Data are expressed as a percentage of maximum efficacy obtained with the full agonist isoproterenol. Values represents means ± S.E.M.s (1--2 experiments with n = 1--2). Xamoterol^a^; data has been previously published \\[[@pone.0180319.ref011]\\].](pone.0180319.g010){#pone.0180319.g010} Crystal structure modeling {#sec050} -------------------------- In order to investigate the molecular mechanisms of xamoterol (S), xamoterol (R), and STD-101-D1, we used molecular docking to predict the binding poses of the three ligands ([Fig 11](#pone.0180319.g011){ref-type="fig"}). All three compounds are predicted to have a common set of characteristic interactions, including: 1) a salt bridge between the protonated secondary amine of the compound and the carboxylic acid of D121 of the receptor, 2) a hydrogen bond between the beta amino alcohol of the compound and D121 of the receptor, and 3) a hydrogen bond between the phenolic hydroxyl group of the compound and S211 of the receptor. Perceptible differences between the binding poses of the three compounds are qualitatively subtle and, in lieu of a fully active crystal structure of ARB1, are difficult to connect with differences in activity of the compounds. The carbon-nitrogen chain of xamoterol (S) packs much more closely to D121 and to the transmembrane (TM) domain 3 than xamoterol (R), likely owing to the difference in stereochemistry between the two compounds. In addition, whereas the phenolic moiety of all three drugs overlaps nearly exactly in the predicted pose, the six-membered heterocycle of both xamoterol enantiomers and the phenyl group of STD-101-D1 are predicted to adopt different positions in the extracellular portion of the binding pocket. These differences serve as potential mechanisms for the gap in affinity between the two chiral forms of xamoterol. ![Crystal structure of ADRB1 with xamoterol (S) (cyan, panel A), xamoterol (R) (blue, panel B), and STD-101-D1 (salmon, panel C) docked into the ligand-binding site. The transmembrane regions are shown as green ribbons, and. Putative interactions are displayed as yellow dashed lines with estimated distance in angstroms (Å). The carbon-nitrogen chain of xamoterol (S) is predicted to pack approximately 1.0 Angstroms closer to D121 and Transmembrane Helix 3 compared to xamoterol (R), and its morpholino ring rests in a rotated pose as well.](pone.0180319.g011){#pone.0180319.g011} Neuroimmuno-modulatory effects of the key compound {#sec051} -------------------------------------------------- The TNFα signaling pathway has been strongly implicated in AD pathology and neuroinflammatory diseases \\[[@pone.0180319.ref023]--[@pone.0180319.ref025]\\]. With the aim of identifying compounds that have therapeutic potential for AD and neuroinflammatory diseases, we assessed whether our key compound STD-101-D1 could modulate the TNFα signaling pathway. First, the effects of STD-101-D1 on the TNFα signaling pathway were assessed in vitro by stimulating primary microglia with the bacterial endotoxin LPS for 4 hrs in the absence or presence of the test compounds. Previous studies with this model have shown that the effects of xamoterol on the LPS-induced TNFα response are dependent on ADRB1; its effects were reversed by the selective ADRB1 antagonists CGP 20712A and betaxolol, but not by the selective ADRB2 antagonist ICI-118551 \\[[@pone.0180319.ref011]\\]. As shown in [Fig 12](#pone.0180319.g012){ref-type="fig"}, stimulation of primary microglia cells with LPS led to a significant increase in TNFα levels. Treatment with isoproterenol, the unbiased full agonist of ADRB1, inhibited the LPS-induced TNFα production by approximately 80%, whereas treatment with xamoterol (S) inhibited LPS-induced TNFα production by approximately 55%. The key compound STD-101-D1 reduced LPS-induced TNFα production by approximately 50%. In order to investigate whether STD-101-D1 could also inhibit the TNFα response in vivo, the effects of STD-101-D1 on mice exposed to LPS were also examined. Administration of LPS resulted in a peripheral inflammatory response as measured by increased levels of TNFα in plasma at 90 min post-LPS ([Fig 13A](#pone.0180319.g013){ref-type="fig"}). The LPS-induced systemic TNFα response was markedly inhibited by pre-treating mice with xamoterol (S) or STD-101-D1 at 3 mg/kg ([Fig 13A](#pone.0180319.g013){ref-type="fig"}). Administration of LPS also led to an inflammatory response in the CNS at 90 min post-LPS. Brain tissue from LPS-injected mice showed increased gene expression of proinflammatory cytokines TNFα, IL-1β, and IL-6 ([Fig 13B](#pone.0180319.g013){ref-type="fig"}). The LPS-induced inflammatory TNFα response in the brain was attenuated by pre-treating mice with STD-101-D1 at 3 mg/kg ([Fig 13B](#pone.0180319.g013){ref-type="fig"}). We observed a trend for attenuation of CNS IL-1β with STD-101-D1 and no effect at IL-6. Significant effects of xamoterol were not observed in CNS inflammatory markers at this time point, possibly due to timing of LPS response and differences in PK properties of xamoterol relative to STD-101-D1. The finding that 129.9 ± 28.2 ng/g (n = 5) of STD-101-D1 were detected at 105 min post-dose in brain homogenates from the mice pretreated with STD-101-D1 (3 mg/kg) indicates that it gets to the brain. ![Inhibitory effects of ADRB1 ligands on LPS-induced TNFα response in primary microglia.\\ Data are represented as mean ± S.E.M.s of four independent experiments (n = 3--18 per group, \\* p \\< 0.05, \\\\p \\< 0.01, \\\\\\* p \\< 0.001, one-way ANOVA followed by Dunnett's multiple comparison against LPS exposure alone).](pone.0180319.g012){#pone.0180319.g012} ![Inhibitory effects of ADRB1 ligands on LPS-induced TNFα response in mice.\\ (A) Plasma TNFα concentrations in control animals and animals pretreated with xamoterol or STD-101-D1 90 min after LPS injection. (B) TNFα, IL1β, and IL6 mRNA expression in homogenized cortical tissue from control mice and animals pretreated with xamoterol or STD-101-D1 90 min after LPS injection. Data are represented as mean ± S.E.M.s of three independent experiments. (n = 4--14 per group, \\* p \\< 0.05, \\\\p \\< 0.01, \\\\\\* p \\< 0.001, one-way ANOVA followed by Dunnett's multiple comparison).](pone.0180319.g013){#pone.0180319.g013} Pharmacokinetic properties of the key compound {#sec052} ---------------------------------------------- The findings that STD-101-D1 has potent partial agonistic activity on ADRB1 with functional selectivity for the cAMP pathway and produces anti-inflammatory effects suggested that it could be the promising drug-like lead compound. Toward evaluating this intriguing possibility, we profiled the PK properties of STD-101-D1 in an in vitro microsomal stability assay and in vivo pharmacokinetic studies. First, the metabolic stability of STD-101-D1 was assessed together with the reference compounds verapamil (a calcium channel blocker) and propranolol (a beta blocker) using microsomes from the mouse, rat, and human. In mouse microsomes, both verapamil and propranolol were readily metabolized, showing half-lives of less than 30 minutes ([Fig 14A](#pone.0180319.g014){ref-type="fig"}). In comparison, STD-101-D1 was stable in mouse liver microsomes, with 62.8% of the compound remaining after 60 min ([Fig 14A](#pone.0180319.g014){ref-type="fig"}). The rate of disappearance of verapamil, propranolol, and STD-101-D1 was greater in rat microsomes as compared to mouse microsomes ([Fig 14B](#pone.0180319.g014){ref-type="fig"}). Verapamil and propranolol were readily metabolized with half-lives of 20.9 min and 7 min, respectively. STD-101-D1 was metabolized with a half-life of 25.2 min in rat microsomes. In human microsomes, verapamil was metabolized with a half-life of 44.1 min; propranolol was stable with 72.2% of compound remaining after 60 min ([Fig 14C](#pone.0180319.g014){ref-type="fig"}). STD-101-D1 was very stable in human microsomes, with almost no reduction after 60 min. ([Fig 14C](#pone.0180319.g014){ref-type="fig"}). ![Metabolic stability in mouse, rat, and human microsomes.\\ STD-101-D1 and two reference compounds verapamil and propranolol were incubated at 0.1 uM in mouse (A), rat (B), or human (C) liver microsomes. Serial samples were removed up until 60 min. All experiments were performed in duplicate, and data are represented as mean ± S.E.M.](pone.0180319.g014){#pone.0180319.g014} In vivo pharmacokinetic properties of STD-101-D1 were also evaluated in male Sprague-Dawley rats in 4-hr time-course PK and 20-min post-dose collection studies after IV, IP, and PO administration of STD-101-D1. In comparison, the pharmacokinetic properties of xamoterol were also determined. The 4-hr time-course PK study revealed that xamoterol was cleared rapidly ([Fig 15A](#pone.0180319.g015){ref-type="fig"}, [Table 1](#pone.0180319.t001){ref-type="table"}). Consistent to what has been reported, xamoterol's oral bioavailability was low (1.7%). Concentrations of xamoterol in the jugular and portal veins were consistently low, indicating that the low absolute oral bioavailability of xamoterol is due to poor absorption. Compared to xamoterol, STD-101-D1 was cleared more slowly and remained in the system for a longer period of time ([Fig 15A](#pone.0180319.g015){ref-type="fig"}, [Table 1](#pone.0180319.t001){ref-type="table"}). Following IP injection, STD-101-D1 was rapidly and very significantly absorbed, as evidenced by the systemic plasma concentrations ([Fig 15A](#pone.0180319.g015){ref-type="fig"}). The maximum concentration (C~max~) of 762 ng/mL was achieved in systemic plasma after IP administration at 90 min post-dose ([Table 1](#pone.0180319.t001){ref-type="table"}). On the other hand, STD-101-D1 was minimally absorbed after oral administration, resulting in low oral bioavailability (6%) ([Fig 15A and 15B](#pone.0180319.g015){ref-type="fig"}). In the systemic (jugular vein) circulation, the C~max~ of STD-101-D1 was 116 ng/ml after oral administration. The corresponding C~max~ of STD-101-D1 in portal veins was 946 ng/ml ([Table 1](#pone.0180319.t001){ref-type="table"}). ![Pharmacokinetics of xamoterol and STD-101-D1.\\ Systemic (A) and portal vein (B) plasma concentrations of xamoterol and STD-101-D1 as a function of time after a single injection of xamoterol (10 mg/kg) or STD-101-D1 (10 mg/kg) via intravenous (IV), intraperitoneal (IP) and oral (PO) administration. Plasma and brain (C) concentrations of xamoterol and STD-101-D1 in rats collected 20 min after a single injection of xamoterol or STD-101-D1 (10 mg/kg) via IV, IP, and PO administration. Data are represented as mean ± SEM (n = 3 per route).](pone.0180319.g015){#pone.0180319.g015} 10.1371/journal.pone.0180319.t001 ###### Pharmacokinetic parameters of xamoterol and STD-101-D1 determined in the 4-hr time-course study. ![](pone.0180319.t001){#pone.0180319.t001g} Route C~max~ (ng/mL) AUC~inf~(h\\ng/mL) -------------- ------------- ---------------- -------------------- Xamoterol IV 22200 ± 4029 2446 ± 601 IP 7443 ± 730 2834 ± 517 PO--Systemic 23 ± 16 42.5 ± 29.5 PO--Portal 79.8 ± 23.8 175.9 ± 53.4 STD-101-D1 IV 3997 ± 1107 1796 ± 256 IP 762 ± 67 2159 ± 310 PO--Systemic 116 ± 78 101 ± 29 PO--Portal 946 ± 867 362 ± 367 The 20 min post-dose collection study revealed that systemic exposure to xamoterol was low after oral administration, in line with its low oral bioavailability. Plasma concentrations of xamoterol at 20 min after PO administration were 0.7% and 0.2% of the plasma concentrations achieved via IV and IP administration, respectively ([Fig 15C](#pone.0180319.g015){ref-type="fig"}, [Table 2](#pone.0180319.t002){ref-type="table"}). STD-101-D1 administration led to plasma concentrations comparables with those obtained from xamoterol administration. However, STD-101-D1 had higher CNS penetration, with 22-fold higher brain concentrations after IV treatment of STD-101-D1 compared to xamoterol ([Fig 15C](#pone.0180319.g015){ref-type="fig"}, [Table 2](#pone.0180319.t002){ref-type="table"}). 10.1371/journal.pone.0180319.t002 ###### Pharmacokinetic parameters of xamoterol and STD-101-D1 determined in the 20-min post-dose collection study. ![](pone.0180319.t002){#pone.0180319.t002g} ---------------------------------------------------------------------------------- Plasma concentration (ng/ml) Brain concentration\\ (ng/g) ------------ --------------- ------------------------------ ---------------------- Xamoterol IV 1121 ± 297.1 38.3 ± 9.3 IP 3113 ± 388.6 26.5 ± 8.4 PO 8.1 ± 2.0 15.8 ± 5.7 STD-101-D1 IV 1813 ± 67.41 838.7 ± 23.6 IP 597.7 ± 149.8 96.0 ± 22.6 PO 56.9 ± 29.2 41.7 ± 5.3 ---------------------------------------------------------------------------------- Pharmacological specificity of the key compound {#sec053} ----------------------------------------------- In light of its promising in vitro* pharmacology profiles and improved brain penetration, STD-101-D1 was screened against a panel of CNS relevant targets, including G protein-coupled receptors and transporters \\[[@pone.0180319.ref026]\\]. In comparison, off-target binding of xamoterol (S) was also determined. Xamoterol (S) displays a distinct preference for ADRB1 and shows low off-target affinity (Ki \\> 10 μM) for a broad range of neurotransmitter transporters, ion channels and other CNS proteins (including opioid, dopamine, serotonin, nicotinic acetylcholine, muscarinic acetylcholine, and N-methyl-D-aspartate receptors) ([S1 Table](#pone.0180319.s002){ref-type="supplementary-material"}). In contrast, STD-101-D1 displays a significant affinity for non-ADRB1 binding including 5-HT1A, 5-HT2B, α1A adrenergic, α1D adrenergic, and D3 dopaminergic receptors, while maintaining nominal affinity for several other CNS proteins including opioid, histamine, and muscarinic acetylcholine receptors ([S2 Table](#pone.0180319.s003){ref-type="supplementary-material"}). The fact that STD-101-D1 binds to non-ADRB1 CNS targets suggests that its neuroimmune-modulatory effects shown in in vitro and in vivo LPS studies should be interpreted cautiously. Cardiovascular effects of the key compound {#sec054} ------------------------------------------ ADRB1 is highly expressed in cardiac tissue and plays an important role in regulating cardiac function. To determine if xamoterol and STD-101-D1 has peripheral effects, we evaluated the effects of xamoterol or STD-101-D1 on heart rates and blood pressures in anesthetized rats. At a dose of 3 mg/kg, xamoterol and STD-101-D1 increased heart rates by 4% and 13%, respectively ([Fig 16A](#pone.0180319.g016){ref-type="fig"}). In addition, xamoterol and STD-101-D1 decreased blood pressures by 9% and 46%, respectively ([Fig 16B](#pone.0180319.g016){ref-type="fig"}). ![Effects of xamoterol and STD-101-D1 on heart rate and blood pressure.\\ Changes in heart rate (A) and blood pressure (B) following subcutaneous administration of xamoterol or STD-101-D1 at dose of 3 mg/kg. Date are represented as mean ± SEM (n = 3 per compound). (One-sample t-test vs. 0% theoretical mean, \\* p \\< 0.05).](pone.0180319.g016){#pone.0180319.g016} Discussion {#sec055} ========== In this study we established SARs for a novel chemotype targeting the ADRB1. The key compound, STD-101-D1, produced partial agonistic activity on G protein signaling with an EC~50~ value in the low nanomolar range, but engaged very little β-arrestin signaling compared to the unbiased agonist isoproterenol. This biased ligand represents a new mode for ADRB1 activation and is distinctly different compared to isoproterenol---a full and unbiased agonist. ADRB1 has been known to play an important role in learning and memory functions. For example, the ADRB1 selective antagonist betaxolol has been shown to induce contextual memory impairment in mice, which was reversed by the ADRB1 selective partial agonist xamoterol in a dose-dependent manner \\[[@pone.0180319.ref010]\\]. Similarly, the retrieval deficits exhibited by mice with NA deficiency have been rescued by the ADRB1 selective partial agonist xamoterol \\[[@pone.0180319.ref027]\\]. The involvement of ADRB1 in learning and memory has important clinical and therapeutic implications for AD, as severe neurodegeneration of the NA system begins in the early stages of AD. It is believed that loss of NA signaling and the resulting hypoactivation of ADRB1 may partially contribute to the cognitive symptoms in AD. Therefore, ADRB1 agonists may provide a promising therapeutic strategy to improve cognitive function in AD by restoring the lost NA signaling. Given the well-characterized role of protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling in learning and memory \\[[@pone.0180319.ref028], [@pone.0180319.ref029]\\], the cyclic adenosine monophosphate (cAMP) signaling pathway downstream of ADRB1 is believed to mediate the cognitive-enhancing effects of ADRB1 agonists. Toward our goal of modulating ADRB1 to produce therapeutic benefits in AD, we specifically sought to discover partial agonists; these would have more subtle effects in the periphery yet be efficacious enough to restore the decreased NA signaling found in AD. Indeed, human trials with ADRB1 partial agonists such as xamoterol were shown to be very safe, suggesting lack of toxicity with this class of compounds \\[[@pone.0180319.ref030], [@pone.0180319.ref031]\\]. Accordingly, we chose xamoterol, a known partial agonist of ADRB1, as our lead compound and exploited SAR around its analogs. The SAR studies described here showed that, in general, substitution of the phenol ring of xamoterol was not well tolerated. This was especially true for the ortho position to the phenolic OH group, where alkyl groups and Cl led to a complete loss of activity. This appeared to be largely a steric effect, as substitution with the small F atom ortho to the OH group gave a compound with only a small diminution in potency. In contrast, substitutions at the morpholino urea site were relatively well tolerated although all were less potent than xamoterol. Aside from the two azetidine urea analogs, all of the compounds showed greater efficacy at the cAMP pathway via ADRB1 compared to xamoterol (S). This effect did not correlate with lipophilicity (cLogP), nor any other obvious structural features of this subset of molecules. It is therefore interesting to speculate that the observed higher efficacy is due to the increased conformational flexibility of the side chains of the non-urea compounds and their consequent ability to fit more readily into the binding sites of the receptor. Biased agonism, the notion that ligands at GPCRs can preferentially stimulate one intracellular signaling pathway over another, is an emerging concept in GPCR signaling \\[[@pone.0180319.ref017], [@pone.0180319.ref032], [@pone.0180319.ref033]\\]. There is growing interest in the development of biased GPCR ligands, because biased ligands may provide safer and more efficacious therapeutic benefits compared to non-biased ligands by selectively targeting a subset of the receptor-mediated signaling \\[[@pone.0180319.ref034]\\]. As a result, the list of known biased agonists for GPCRs including the dopamine D2 receptor, serotonin 5-HT2A, cannabinoid CB1, and κ-opioid receptors, is growing and some have already progressed to clinical development \\[[@pone.0180319.ref035]--[@pone.0180319.ref040]\\]. A key property of xamoterol (S) and its analogs (STD-101-D1 through STD-101-D6) is the functional bias toward the G protein-mediated cAMP pathway. G protein-mediated signaling of ADRB1 is implicated in cognitive function and neuroinflammation, whereas β arrestin-mediated signaling is implicated in development of drug-induced tolerance. Therefore, the development of a G protein-biased agonist of ADRB1 may provide a means to optimally tune ADRB1 therapeutics that will ameliorate the cognitive deficits and pathology underlying AD, as well as other neuroinflammatory diseases, without producing significant tachyphylaxis. Biased ligands, such as those reported in this study, can be used as pharmacological tools to aid in the elucidation of ADRB1-mediated signaling cascades in cellular systems and in vivo. It will be of great interest to utilize these newly identified functionally selective G protein-biased ADRB1 agonists in additional in vitro and in vivo assays to determine the contribution of G-protein signaling to ADRB1-mediated effects. Computational modeling has enabled us to capture poses of the two enantiomers of xamoterol and the ADRB1 agonist STD-101-D1 consistent with experimental data. The docked poses feature polar contacts between the phenolic hydroxyl of xamoterol (S) and both S211 as well as with N310. Furthermore, the binding pocket residue D121 dually forms a salt bridge with the protonated secondary amine of xamoterol's backbone as well as a hydrogen bond with the beta amino alcohol of xamoterol. The experimental compound STD-101-D1 is predicted to form analogous sets of contacts, with the primary difference originating from the position of its methoxy phenyl ring compared to the heterocyclic ring of xamoterol. Previous studies have identified the contact with S211 as being important for mediating agonism \\[[@pone.0180319.ref041]\\]. Further insights into the structure-activity relationships of xamoterol and its derivatives, such as STD-101-D1, would benefit greatly from a fully active, G protein-bound or G protein-mimetic nanobody-bound crystal structure of ADRB1. Accumulating data suggest a close association between neuroinflammation and AD pathogenesis. Prominent activation of immune responses characterized by activated microglia, reactive astrocytes, and increased expression of complement factors and proinflammatory cytokines associated with Aβ deposits, have been observed in the brains of AD patients as well as in transgenic mouse models of AD \\[[@pone.0180319.ref042], [@pone.0180319.ref043]\\]. TNFα is one of the main proinflammatory cytokines known to be elevated in brains from AD patients and animal models of AD, and has been strongly implicated in AD pathology. For example, elevated levels of TNFα are observed in serum and cerebrospinal fluid from AD patients compared to age-matched controls \\[[@pone.0180319.ref044], [@pone.0180319.ref045]\\]. Similarly, overexpression of TNFα has been shown in several animal models of AD, including the 3xTg-AD and 5XFAD mouse models \\[[@pone.0180319.ref011], [@pone.0180319.ref046], [@pone.0180319.ref047]\\]. More importantly, increased TNFα in AD models has been correlated with disease progression \\[[@pone.0180319.ref048]\\]. At the molecular level, TNFα has been shown to exacerbate Aβ-induced apoptosis in neurons and increase Aβ production by upregulating both β-secretase expression and γ-secretase activity, as well as the expression of APP \\[[@pone.0180319.ref049]--[@pone.0180319.ref053]\\]. It has also been demonstrated that TNFα inhibits phagocytosis of toxic Aβ species, which might lead to hindering efficient plaque removal by brain resident microglia \\[[@pone.0180319.ref054]\\]. Taken together, these observations suggest that excessive expression of TNFα may contribute to and accelerate the progression of AD. Targeted inhibition of TNFα signaling in AD may be an effective therapeutic approach to halt or attenuate the progression of AD. In support of this idea, a recent study demonstrates that inhibition of TNFα signaling prevents pre-plaque amyloid-associated neuropathology and reduces plaque accumulation and tau phosphorylation in transgenic mouse models of AD \\[[@pone.0180319.ref055], [@pone.0180319.ref056]\\]. Relevant to the present study, the adrenergic system has been shown to be involved in the regulation of TNFα signaling as well as general peripheral inflammatory responses and CNS inflammatory responses \\[[@pone.0180319.ref057]--[@pone.0180319.ref059]\\]. In our previous in vitro study with primary microglia, we showed that the highly selective ADRB1 agonist xamoterol inhibited the LPS-induced TNFα response \\[[@pone.0180319.ref011]\\]. Its effects were reversed by the ADRB1 selective antagonists CGP 20712A and betaxolol, but not by the ADRB2 selective antagonist ICI-118551, suggesting that xamoterol produces its anti-inflammatory effects on the TNFα response via ADRB1. When chronically administered to the 5XFAD mouse model of AD, xamoterol also produced anti-inflammatory effects and attenuated increased expressions of proinflammatory markers, including TNFα, shown in the brains of the transgenic mice. This suggests that ADRB1 is an important player in regulating the immune response, and modulating ADRB1 activity has therapeutic potential for AD as well as other neuroinflammatory diseases. Notably, the key compound STD-101-D1 was found to suppress TNFα production in rat primary microglia challenged with LPS. When administered to mice prior to the LPS challenge at 3 mg/kg, STD-101-D1 also attenuated the acute peripheral and CNS TNFα response induced by LPS. Given the well-established suppressive effects of cAMP on LPS-induced transcriptional activation of the TNFα gene \\[[@pone.0180319.ref060]--[@pone.0180319.ref062]\\], we speculate that a G protein-biased agonist such as STD-101-D1 acts at the transcription level via a cAMP dependent mechanism. Our observations that the full ADRB agonist isoproterenol or the partial agonist STD-101-D1 did not produce anti-inflammatory effects when administered after the LPS challenge (data not shown), and that they require the pretreatment period to produce inhibitory effects on the LPS-induced inflammatory response, support this hypothesis. However, it should be noted that the current study measures the acute LPS-induced immune response. It will be intriguing to determine whether this class of compound produces anti-inflammatory effects when given after the LPS challenge in the long-term LPS exposure model. It is also important to note that STD-101-D1 has non-specific activity on other receptors and binds to several receptors such as 5-HT 1A and 5-HT 2B with comparable affinity to ADRB1. Thus, it is possible that its anti-inflammatory effects shown in vitro and in vivo could be mediated by non-ADRB1. Additional studies are necessary to validate that STD-101-D1 exerts its anti-inflammatory effects via ADRB1 and to identify more specific ADRB1 partial agonists. Regardless, identification of ADRB1 agonists with anti-inflammatory effects such as STD-101-D1 has important clinical implications. Xamoterol is a highly selective partial agonist of ADRB1 with functional bias for the cAMP pathway over the β-arrestin pathway \\[[@pone.0180319.ref011]\\]. However, its therapeutic utility as a CNS drug is limited, as it has very poor oral bioavailability and low CNS penetration ([Fig 15](#pone.0180319.g015){ref-type="fig"}). Despite this low penetration, however, xamoterol was shown to produce biological effects in the brain after systemic administration. For example, a systemic acute treatment with xamoterol led to increases in phosphorylation of CREB in the brain, an important event involved in learning and memory \\[[@pone.0180319.ref009]\\]. In multiple mouse models of AD, chronic systemic administration of xamoterol was also shown to enhance cognitive functions and attenuate pathological features of AD \\[[@pone.0180319.ref009], [@pone.0180319.ref011]\\]. Based on this observation, we hypothesized that we could maximize the therapeutic utility of this class of drugs for CNS indications by optimizing PK properties of xamoterol. With favorable CNS permeability, ADRB1 agonists can be administered at low doses, which will reduce systemic exposure and lower the peripheral effects, including cardiovascular effects. In order to evaluate the PK properties of STD-101-D1, we conducted in vitro microsomal stability tests and in vivo PK studies. In the in vitro microsome stability test, STD-101-D1 was shown to be very stable, with half-lives greater than 60 min, both in mouse and human microsomes. In rat microsomes, however, STD-101-D1 was relatively less stable and metabolized with a half-life of 25.2 min. This observation indicates a marked species difference in the metabolism of STD-101-D1. Given this faster rate of metabolism in rat liver microsomes compared to mouse liver microsomes, the in vivo PK study in rat uses a higher dose of STD-101-D1 (i.e. 10 mg/kg) compared to the dose used in the in vivo mouse LPS study (i.e. 3 mg/kg). In the in vivo PK study, STD-101-D1 was moderately cleared in Sprague-Dawley rat with a half-life of 2.7 hr after oral administration, in line with its moderate metabolic stability shown in rat microsomes. However, the oral bioavailability of STD-101-D1 remains low (6%), similar to xamoterol. The low oral bioavailability of STD-101-D1 could be due to poor absorption through the gut membrane and/or efflux through the P-glycoprotein. Obtaining compounds with good brain permeability is a major hurdle in CNS drug development. Importantly, STD-101-D1 shows greater CNS penetration compared to xamoterol ([Fig 15](#pone.0180319.g015){ref-type="fig"}). For example, when administered intravenously, STD-101-D1 achieved an approximately 22-fold higher brain concentration compared to xamoterol at 20 min post dose. With its improved CNS permeability, STD-101-D1 can be administered at lower doses for CNS indications, reducing systemic exposure and lowering cardiovascular effects. Of note, the brain concentrations achieved with STD-101-D1 are considered to be within the therapeutically relevant range. For example, when administered intravenously or intraperitoneally, acute single administration of STD-101-D1 at the dose of 10 mg/kg led to brain concentrations of 2.5 μM and 288 nM, respectively. As these values are up to 148-fold higher than its EC~50~ value (16.9 nM) for ADRB1 in vitro, we believe brain concentrations achieved with a single administration of STD-101-D1, even at lower doses, would be sufficient to induce the CNS target engagement needed for efficacy. This brain concentration is also in line with other drugs clinically used for AD, such as memantine and donepezil \\[[@pone.0180319.ref063], [@pone.0180319.ref064]\\]. Collectively, this suggests a possible beneficial therapeutic value of STD-101-D1 for CNS indications, although its overall PK properties remain to be improved. It is important to note that only a trace of STD-101-D1 was detected in the brain at 4 hrs post dose, indicating that most of the drug is cleared from brain within 4 hrs. Further medicinal chemistry efforts would be needed to identify new compounds that have improved oral bioavailability and longer half-lives. ADRB1 is highly expressed in a number of peripheral organs, and plays an important role in mediating multiple physiological processes. Thus, modulators of ADRB1 could possibly produce many unwanted peripheral adverse effects. Using a medicinal chemistry approach, our laboratory is developing partial agonists of ADRB1 with improved brain penetration and, as a result, we are seeking to decrease peripheral exposure with lower dosing, while achieving efficacious concentrations in the CNS. As our aim was to develop an ADRB1 partial agonist with minimal peripheral effects, we have evaluated the peripheral effects of the key compound STD-101-D1. Notably, at equivalent doses, both xamoterol and STD-101-D1 produced significant changes in heart rates and blood pressures of rats after an acute single administration. The effects of STD-101-D1 were more profound than those of xamoterol, possibility due to its higher efficacy on ADRB1. Importantly, higher brain permeability suggests that we can reduce the dose of STD-101-D1, thereby minimizing peripheral exposure. It has been previously shown that chronic administration of xamoterol (3 mg/kg, subcutaneous administration) does not lead to significant changes in cardiovascular function or cardiac structure in mice \\[[@pone.0180319.ref011]\\]. It will be important to determine whether chronic administration of STD-101-D1 at a lower dose leads to changes in cardiovascular function or cardiac structure. In summary, this study has described the rational design of a novel series of compounds with ADRB1 agonist activity. Our findings indicate that we have successfully identified biased ligands with unique pharmacology. Such biased ligands will be invaluable research tools to dissect out the G protein-coupled receptor signaling transduction mechanisms, and also act as potential lead compounds for further development to provide safer, more efficacious therapeutics. Supporting information {#sec056} ====================== ###### HPLC and NMR spectra for xamoterol (S), xamoterol (R), STD-101-B1 to B9, D1 to D6, and E. (PDF) ###### Click here for additional data file. ###### Binding affinity (K~i~, nM) of xamoterol (S) at non-ADRB1 binding sites. (PDF) ###### Click here for additional data file. ###### Binding affinity (K~i~, nM) of STD-101-D1 at non-ADRB1 binding sites. (PDF) ###### Click here for additional data file. Receptor binding profile was performed by the National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP). We thank the director of NIMH PDSP, Bryan L. Roth MD, PhD, at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. We thank Stanford Behavioral and Functional Neuroscience Laboratory for excellent technical support of in vivo pharmacokinetic and pharmacological studies. [^1]: Competing Interests:The authors have declared that no competing interests exist. [^2]: Conceptualization: BY AJ AE VP MS MG.Data curation: BY.Formal analysis: BY.Funding acquisition: MS.Investigation: BY DB KR JE EF AF WS JR.Methodology: EF AF.Project administration: BY MS.Resources: BY.Supervision: MS.Visualization: BY EF.Writing -- original draft: BY.Writing -- review & editing: MS.
Q: AngularJS - promises and error handling I'm trying to find out an answer to my question - does myFunction() .then(function (response) { }) .catch(function(error) { }); is the same as myFunction() .then(function (response) { }, function(error) {}); to handle errors from the promise? If so which one should be used as best practice? A: Yes, with they both you will get the same result. From $q service catch(errorCallback) – shorthand for promise.then(null, errorCallback) About to which one to use as a best practice... It's a matter of perspective: IMHO, you can use them both indistinctly.
Third Annual Pre-Thanksgiving Vegan Thanksgiving Potluck - Albany, NY It's that time again... before we're all thrown to the omni-wolves to stare at the sacrificial turkey, let's be thankful for delicious cruelty-free eats at the THIRD ANNUAL PRE-THANKSGIVING VEGAN THANKSGIVING POTLUCK!! And this year, I've got TWO gravy boats! What do I need to do??: Bring a vegan dish to share and let us know in advance what that will be so we have a good variety. Don't forget appetizers and desserts!! Also bring your own plate, silverware, and cup so we don't add more disposables to the landfills!
When you’re struggling under the weight of debt problems, it’s all too easy to lose perspective. But panicking about your situation isn’t going to help, no matter how understandable that may be. To stand a chance of overcoming your problems, you need to take a calm approach and decide which of your debts are the most urgent to deal with. Here’s how. Government Debt If you owe money to the government, whether it’s through outstanding taxes or unpaid fines, you need to deal with these as a priority. This doesn’t necessarily mean paying them in full, but you need to get in touch and make an arrangement of some kind. Ignoring these debts will land you in a serious amount of trouble, including legal action, and the authorities will never turn a blind eye to what you owe. Debts Which Impact Earnings Next, you need to take care of any debts which affect your ability to earn money. For example, if losing your car means you’ll lose your job, then making your auto loan payments should be high on your list. Without income, you have no chance of keeping on top of any of your other debts. Secured Debts If you have debts secured on your home, you need to take a long look at this situation. Pay what you can to prevent repossession proceedings, but also contact your lenders and try and restructure your debt to make things easier. In the long term, consider taking the decision to sell your home and move into cheaper rental accommodation. It’s better to do this in a controlled way rather than hanging on and losing everything. Life Essentials Next, try and pay something toward your essential debts such as energy bills. These may seem urgent, but in reality, so long as you don’t get too far behind you won’t have your supplies cut off. Energy companies are usually happy to come to an arrangement to clear old debts over time, so long as you make token repayments in the meantime. After all, they’d rather you pay something than nothing. Unsecured Debts At the bottom of the heap are unsecured debts, particularly credit cards. Card issuers will make a lot of noise if you owe them money and will send increasingly scary letters threatening all sorts of dire consequences. But the truth is, if you default on an unsecured debt, the only thing at risk is your credit rating. You can’t be sent to prison, and your possessions or home can’t be seized to clear what you owe. It’s important to keep your unsecured creditors in the loop and pay what you can, but don’t let them panic you into neglecting your other, more urgent debts. It’s a terrifying experience to be facing debts you can’t handle. But losing perspective is one of the worst things you can do if you want to come out the other side of your problems. Prioritizing your debts and keeping all your creditors informed gives you the breathing space to find expert help and start getting back on your feet. Share This Story, Choose Your Platform! After graduating from the University of Calgary with a Bachelor of Science degree in Computer Science, Gerald joined KPMG (Formerly Thorne Riddell) as a Computer Accounting Customer Service representative. In this position, Gerald installed accounting systems in over 200 different small to medium sized companies over a 6 year span. In 1989, Gerald left KPMG to continue to work with small business clients in his own corporation installing computer accounting systems. While in this role, he was engaged by the DeVry Institute of Technology in Calgary to teach various courses. In time, Gerald moved up through the ranks of DeVry until he attained the position of Director of Finance for the Calgary Campus. He also acquired his Masters of Business Administration from City University of Seattle, Washington in 2001. Gerald’s career has always been focused on small business, accounting and education. Padgett Business Services® is your local small business accounting, bookkeeping, tax, and payroll specialist, catering to the needs of small business owners through a network of local owner-operated offices. We provide a unique combination of business information and services to help small business owners succeed.
Q: Check if number is less than another number by a certain percentage I would like to check if $Price1 is less than $Price2 by 40% or more. $name = 'bob'; $price1 = '100'; $price2 = '300'; if($price1 < $price2) { echo $name; } The above code doesn't check if $price1 is less than by a percentage. A: $name = 'bob'; $price1 = '100'; $price2 = '300'; if($price1 < 0.6$price2) { echo $name; } You would like to echo 'bob' when $Price1 is less than $Price2 by 40% or more. In this case the 'or more' refers to the percentage. First thing we need to know is what 40% less than $Price2 is. This is 100% of $Price2 minus 40% of $Price2, in other words 100% minus 40% equals 60% of $Price2. That is the same as 0.6 times $Price2. Secondly we try an 'or more' case: Say that we need to know what what 45% less than $Price2 is. Analogous to the reasoning above this would be 0.55 times $Price2. So it is smaller than 0.6, hence the < operator between $Price1 and 0.6$Price2. Conclusion: We need to test when $Price1 < 0.6*$Price2 and then echo 'bob';
Q: What is the difference between append and addObject + Compare two date I am little bit confuse about, what is the difference between append and addObject. I am using both in my code but confuse what is the difference between them. addObject self.dateArrayServer.addObject(date as! String) append dateArrayCalendar.append(dateFormatatter.stringFromDate(dateStart)) And Second problem is Hi, I am try to compare two date- dateArrayForCompare, is the date which i get from NSDate and, dateArrayServer, is the date which i get from json response. var dateArrayServer = NSMutableArray() var dateArrayCalendar = NSMutableArray() var dateArrayForCompare = NSMutableArray() let dateHomework:NSArray = allAsign.valueForKey("date") as! NSArray let homeWork = allAsign.valueForKey("assignmenttype") as! NSArray for date in dateHomework{ self.dateArrayServer.addObject(date as! String) } let sys_date = NSDate() print("System Date: \\(sys_date)") let df = NSDateFormatter() df.dateFormat = "dd-MM-yyyy" let currentDate = df.stringFromDate(sys_date) print("String Date: \\(currentDate)") for dt in 0...self.dateArrayServer.count-1 { if(self.dateArrayServer.objectAtIndex(dt) .isEqualToString("\\(self.dateArrayForCompare)")) { print("Assignment on date: \\(self.dateArrayServer.objectAtIndex(dt)) are:\\n\\(allAsign.objectAtIndex(dt))") }else { print("\\(self.dateArrayServer.objectAtIndex(dt)) doesn't match with \\(self.dateArrayForCompare) ") } } But get this result- A: not a major different but i think i can explain it. in swift two data type declare first "let" and "var" this two type accept all type of data . but whenever you add array in "var" but not declare this is NSArray or NSMutableArray then you put any object on last position in it then you use append. appen is like "+=" operator so it add that value on last position var Array = ["1","2"] Array.append(["3"]) //Result :- "1","2","3" But you Declare as NSMutableArray or NSArray then you must use addObject like var Array = NSMutableArray() Array.addObject("1") Array.addObject("2") Array.addObject("3") //Result :- "1","2","3" And other different append is get that value and put on last index . addObject is get that Object and put on last index and value and object have different meaning.
Published/Revised June 8, 2015 By Roy Stevenson This post may contain promotional and affiliate links. EuropeUpClose may receive commissions for purchases made through links in this post. Please read our disclosure for more info. You’ll find an Eclectic Mix of Attractions in Erfurt: A Rich Religious History, Awesome Outdoor Operas, a Formidable Fortress, and an ancient Merchant Bridge. Oh Yes, . . . and a Puppet Maker and Delicious Dumplings. I’ll always remember the ancient city of Erfurt for its sheer variety of jaw dropping sights packed into a small area. One minute you’re crossing a medieval bridge with dozens ... Read Full Article Published/Revised June 12, 2014 By Sascha Matuszak This post may contain promotional and affiliate links. EuropeUpClose may receive commissions for purchases made through links in this post. Please read our disclosure for more info. Erfurt was reportedly described by Martin Luther as being in the "center of the center of Germany" and this might be one way of understanding this ancient city's charm. Being in the very middle of the country might have ironically insulated the city from the turmoil of Germany's long path from religious battleground to modern anchor-state. Erfurt was founded in the 8th century and is the ... Read Full Article Published/Revised January 23, 2016 By Terri Fogarty This post may contain promotional and affiliate links. EuropeUpClose may receive commissions for purchases made through links in this post. Please read our disclosure for more info. We love to travel and we love Europe, so as you can guess, our Best Kept Travel Secrets are Europe-Focused. Panzano in Chianti A few years ago, we came across Panzano in Chianti, a tiny Tuscan town with few tourist sights, but with some great places to eat and drink. If you are a foodie, you may have heard of its famous butcher, if not, here's the scoop: The town is built upon a long, narrow ... Read Full Article Published/Revised June 14, 2014 By Terri Fogarty This post may contain promotional and affiliate links. EuropeUpClose may receive commissions for purchases made through links in this post. Please read our disclosure for more info. Erfurt, the capital of Thuringia, is a beautiful town located in the center of Germany. It is one of the best preserved medieval towns in Germany. With more than 1,260 years of history, Erfurt has lots to offer those who love historic and architecturally rich towns. The following "postcards" offer just a small glimpse of this city's charms. The architecture in Erfurt runs from Gothic to ... Read Full Article Published/Revised June 14, 2014 By Terri Fogarty This post may contain promotional and affiliate links. EuropeUpClose may receive commissions for purchases made through links in this post. Please read our disclosure for more info. Germany has launched a great website for travelers who are interested in particular historic and cultural aspects of Germany. Historic Germany highlights thirteen smaller but historically important cities including Augsburg, Erfurt, Freiburg, Heidleberg, Koblenz, Lubeck, Muenster, Potsdam, Regensburg, Rostock, Trier, Weisbaden, and Wurzburg. The site also offers Dream Routes that focus on ... Read Full Article
Mamay (film) Mamay () is a 2003 Ukrainian language film. Based on ancient Ukrainian and Crimean Tatar folklore, this is a Ukrainian version of Romeo and Juliet. A fugitive Cossack falls in love with a stunningly beautiful Tatar woman who saves him from certain death. Their love defies age-old hatred between their respective peoples. The film features cinematography by Serhiy Mykhalchuk and a soundtrack by composer Alla Zahaykevych. It was directed by Oles Sanin. Mamay was Ukraine's 2003 submission for an Academy Award for Best Foreign Language Film. External links "Mamay" at Ukrainian Film Club of Columbia University (link inactive as of 2014.10.26) "Mamay" at Ukrainian Film Club of Columbia University (retrieved on 2014.10.26) Category:Ukrainian films Category:Ukrainian-language films Category:2003 films Category:Films based on Romeo and Juliet
Fractionation of mechanically sheared chromatin on ECTHAM-cellulose. Chromatography of chromatin on the weak ion-exchange resin ECTHAM-cellulose was re-examined using the combined salt-pH elution conditions of Stratling, W.H., Van, N.T. and O'Malley, B.W. (1976) Eur. J. Biochem. 66, 423-433. When mechanically sheared rat liver chromatin was chromatographed on ECTHAM-cellulose the histone composition of eluted fractions was very similar, whereas early eluting fractions were enriched in non-histone proteins, including certain high mobility group proteins, and in hnRNP particles, containing newly synthesised RNA. Later eluting fractions were depleted in all of these components. The majority of hnRNP particles in early eluting chromatin were shown to be physically associated with chromatin by centrifugation in metrizamide. Hen erythrocyte chromatin contained no early eluting material. Size of DNA fragments was not a significant factor in determining the elution position of chromatin fragments. Early eluting material was not generated by endogenous nuclease and protease action. The conditions of chromatin preparation, and of elution of early chromatin fractions caused no gross disruption of chromatin structure, or dissociation of chromatin proteins, although some nucleosome sliding may have occurred. The conditions required for elution of some of the later fractions are sufficient to cause dissociation of protein, and alteration of chromatin conformation.
Health minister Ben Bradshaw told the Guardian newspaper he hoped the scheme would work in the same way holidaymakers checked Trip Adviser before travelling or checked Amazon for reviews of books. "I would never think of going on holiday without cross-referencing at least two guide books and using Trip Adviser," the minister said. "We need to do something similar for the modern generation in healthcare. I can already learn a lot from the comments of people, both positive and negative, about a type of treatment or a hospital. We need to extend the service to cover GPs." The British Medical Association (BMA), however, criticised the plans for a website where people could "slander or praise irresponsibly". "Patients should be able to choose a doctor, but I don't think this is the way to do it," Laurence Buckman, chairman of the BMA's GPs committee, said. "I think this has everything to do with consumerism and it has not been thought through well. I am happy for people to praise or criticise their doctor, but this is not the way professionals should interact with their patients. "It has a great potential to be misleading." A DoH spokesman said at present it was hoped patients would be able to post comments by the end of the summer 2009.
Mt. Washington Auto Road ready for riding PINKHAM NOTCH -The Mount Washington Auto Road, the region's premier manmade attraction that climbs the Northeast's highest peak, opens for public travel up to treeline Saturday for the start of its 152nd season. It will be a beautiful ride up for those who venture about 4.5 miles, as the first soft green blush of spring spreads up from the valleys while the higher elevations are streaked with patches of white. "The northern Presidential Range is still covered with snow and the views are just spectacular at this time of year," Auto Road office manager Regina Ferriera said. She said the phone has been ringing off the hook as people have been calling to find out if they can drive up the mountain, and now the staff can answer that they can. It's just a little over a month since the attraction's SnowCoach made its last trip up the road, ceasing winter operations on March 31. That closure cleared the way for the road crew to start removing snow and ice. On Thursday, under deep-blue skies, road crew members worked to clear culverts at the seven-mile stretch. Their work has been aided by a week of warm weather, allowing them to clear and prepare the road's surface with the hope of opening the road to the summit within the next two weeks. The road will be open starting Saturday from 9 a.m. to 4 p.m. Vehicles cannot be left unattended, so those who are considering driving up to ski the snowfields should make alternative plans. Guided tours will be available later this month. For private vehicles, it's motorcycles only on June 10 during Laconia Bike Week. For the general public, guided tours will still run. A larger Bike Week event follows, with the Ride to the Sky on June 13, complete with expo and food at the base of the Auto Road. The Auto Road is offering guided Bicknell's Thrush tours on six dates in June. The birds prefer breeding and nesting above 3,000 feet in areas with low vegetation and abundant moisture in the Northeast. Other events coming up within the next couple of months are the Northeast Delta Dental Mount Washington Road Race June 15 and a bicycle hill climb July 6. All events are subject to the whims of the weather.
Anomalous diffusion and weak nonergodicity. Ergodic behavior of the class of G processes G(t)=∫(t(m))(t)du K(t,u)ξ(u)-∫(t(m))(0)du K(0,u)ξ(u), (ξ(t))=0, (ξ(t)ξ(s))=ϕ(\|t-s\|) is examined. Ergodicproperties are only G extensions of normal diffusion (K=1) and of Mandelbrot-Van Ness fractional diffusion [K(t,u)=K(t-u), t(m)→-∞]. Any deviation from these two types results in weak ergodicity breaking which thus is neither exceptional nor limited to some specific events but is typical for much wider class of processes. G processes driven by ξ(t) with nonvanishing correlations are important for describing transport in strongly nonequilibrium systems and may be responsible for peculiarities of diffusion found in biological, glassy, and nanoscale systems.
Q: Is there CDN for polymer elements? I would like to know if there are any CDNs for polymer elements, since you have to always download the elements and It would be more convinient to import it via cdn. Can't find any on google? Also are there any reasons that it does not exists or just because it is so new? A: There is now! I created this GitHub repository specifically for this purpose: download/polymer-cdn All GitHub repositories are automatically in CDN through RawGit. So, using that, we can now import Polymer elements using markup like this (for iron-icons in this case): <link rel="import" href="https://cdn.rawgit.com/download/polymer-cdn/1.0.1/lib/iron-icons/iron-icons.html"> The project structure was set up in such a way that imports from elements that you import (transitive dependencies) resolve correctly. The readme for the repository has a list of all elements it contains. Missing something? Let me know and I'll be happy to include it. Try it You can try it out right now by hacking on this Codepen: Polymer-CDN Example. Or you can run this code snippet: <base href="https://cdn.rawgit.com/download/polymer-cdn/1.5.0/lib/"> <script src="webcomponentsjs/webcomponents-lite.min.js"></script> <link rel="import" href="iron-icon/iron-icon.html"> <link rel="import" href="iron-icons/iron-icons.html"> <link rel="import" href="paper-button/paper-button.html"> <link rel="import" href="paper-checkbox/paper-checkbox.html"> <link rel="import" href="paper-tabs/paper-tabs.html"> <link rel="import" href="paper-toggle-button/paper-toggle-button.html"> <style is="custom-style"> :root { --paper-tabs-selection-bar-color: var(--paper-light-blue-900); --paper-tab-ink: var(--paper-light-blue-100); --paper-tabs: { color: white; background-color: var(--paper-light-blue-500); }; } </style> <div> <paper-button raised><iron-icon icon="check"></iron-icon>OK</paper-button> <paper-button raised><iron-icon icon="clear"></iron-icon>Cancel</paper-button> </div> <p><paper-checkbox>Checkbox</paper-checkbox></p> <p><paper-toggle-button></paper-toggle-button></p> <paper-tabs selected="0"> <paper-tab>TAB 1</paper-tab> <paper-tab>TAB 2</paper-tab> <paper-tab>TAB 3</paper-tab> </paper-tabs> A: You can also access polymer elements directly from polymer-project.org. Example: <link rel="import" href="https://www.polymer-project.org/0.5/components/core-ajax/core-ajax.html"> A: This is an old question, but there is a non-hacky solution now: http://polygit.org/ It uses rawgit behind the curtains but provides a much nicer api.
// ----------------------------------------------------------------------- // <copyright file="FunctionAuthorizationManagerBase.cs" company="OSharp开源团队"> // Copyright (c) 2014-2020 OSharp. All rights reserved. // </copyright> // <site>http://www.osharp.org</site> // <last-editor>郭明锋</last-editor> // <last-date>2020-02-26 23:05</last-date> // ----------------------------------------------------------------------- using System; using System.Collections.Generic; using System.Linq; using System.Linq.Expressions; using System.Threading.Tasks; using Microsoft.Extensions.DependencyInjection; using OSharp.Authorization.Dtos; using OSharp.Authorization.Entities; using OSharp.Authorization.Events; using OSharp.Authorization.Functions; using OSharp.Collections; using OSharp.Data; using OSharp.Entity; using OSharp.EventBuses; using OSharp.Exceptions; using OSharp.Extensions; using OSharp.Identity.Entities; using OSharp.Mapping; namespace OSharp.Authorization { /// <summary> /// 功能权限管理器基类 /// </summary> /// <typeparam name="TFunction">功能类型</typeparam> /// <typeparam name="TFunctionInputDto">功能输入DTO类型</typeparam> /// <typeparam name="TModule">模块类型</typeparam> /// <typeparam name="TModuleInputDto">模块输入类型</typeparam> /// <typeparam name="TModuleKey">模块编号类型</typeparam> /// <typeparam name="TModuleFunction">模块功能类型</typeparam> /// <typeparam name="TModuleRole">模块角色类型</typeparam> /// <typeparam name="TModuleUser">模块用户类型</typeparam> /// <typeparam name="TUserRole">用户角色类型</typeparam> /// <typeparam name="TUserRoleKey">用户角色编号类型</typeparam> /// <typeparam name="TRole">角色类型</typeparam> /// <typeparam name="TRoleKey">角色编号类型</typeparam> /// <typeparam name="TUser">用户类型</typeparam> /// <typeparam name="TUserKey">用户编号类型</typeparam> public abstract class FunctionAuthorizationManagerBase<TFunction, TFunctionInputDto, TModule, TModuleInputDto, TModuleKey, TModuleFunction, TModuleRole, TModuleUser, TUserRole, TUserRoleKey, TRole, TRoleKey, TUser, TUserKey> : IFunctionStore<TFunction, TFunctionInputDto>, IModuleStore<TModule, TModuleInputDto, TModuleKey>, IModuleFunctionStore<TModuleFunction, TModuleKey>, IModuleRoleStore<TModuleRole, TRoleKey, TModuleKey>, IModuleUserStore<TModuleUser, TUserKey, TModuleKey> where TFunction : IFunction where TFunctionInputDto : FunctionInputDtoBase where TModule : ModuleBase<TModuleKey> where TModuleInputDto : ModuleInputDtoBase<TModuleKey> where TModuleFunction : ModuleFunctionBase<TModuleKey>, new() where TModuleRole : ModuleRoleBase<TModuleKey, TRoleKey>, new() where TModuleUser : ModuleUserBase<TModuleKey, TUserKey>, new() where TModuleKey : struct, IEquatable<TModuleKey> where TUserRole : UserRoleBase<TUserRoleKey, TUserKey, TRoleKey> where TUserRoleKey : IEquatable<TUserRoleKey> where TRole : RoleBase<TRoleKey> where TUser : UserBase<TUserKey> where TRoleKey : IEquatable<TRoleKey> where TUserKey : IEquatable<TUserKey> { private readonly IServiceProvider _provider; /// <summary> /// 初始化一个 SecurityManager 类型的新实例 /// </summary> /// <param name="provider">服务提供程序</param> protected FunctionAuthorizationManagerBase(IServiceProvider provider) { _provider = provider; } #region 属性 /// <summary> /// 获取事件总线 /// </summary> protected IEventBus EventBus => _provider.GetService<IEventBus>(); /// <summary> /// 获取功能仓储 /// </summary> protected IRepository<TFunction, Guid> FunctionRepository => _provider.GetService<IRepository<TFunction, Guid>>(); /// <summary> /// 获取模块仓储 /// </summary> protected IRepository<TModule, TModuleKey> ModuleRepository => _provider.GetService<IRepository<TModule, TModuleKey>>(); /// <summary> /// 获取模块功能仓储 /// </summary> protected IRepository<TModuleFunction, Guid> ModuleFunctionRepository => _provider.GetService<IRepository<TModuleFunction, Guid>>(); /// <summary> /// 获取模块角色仓储 /// </summary> protected IRepository<TModuleRole, Guid> ModuleRoleRepository => _provider.GetService<IRepository<TModuleRole, Guid>>(); /// <summary> /// 获取模块用户仓储 /// </summary> protected IRepository<TModuleUser, Guid> ModuleUserRepository => _provider.GetService<IRepository<TModuleUser, Guid>>(); /// <summary> /// 获取用户角色仓储 /// </summary> protected IRepository<TUserRole, TUserRoleKey> UserRoleRepository => _provider.GetService<IRepository<TUserRole, TUserRoleKey>>(); /// <summary> /// 获取角色仓储 /// </summary> protected IRepository<TRole, TRoleKey> RoleRepository => _provider.GetService<IRepository<TRole, TRoleKey>>(); /// <summary> /// 获取用户仓储 /// </summary> protected IRepository<TUser, TUserKey> UserRepository => _provider.GetService<IRepository<TUser, TUserKey>>(); #endregion #region Implementation of IFunctionStore<TFunction,in TFunctionInputDto> /// <summary> /// 获取功能信息查询数据集 /// </summary> public IQueryable<TFunction> Functions => FunctionRepository.QueryAsNoTracking(); /// <summary> /// 检查功能信息是否存在 /// </summary> /// <param name="predicate">检查谓语表达式</param> /// <param name="id">更新的功能信息编号</param> /// <returns>功能信息是否存在</returns> public virtual Task<bool> CheckFunctionExists(Expression<Func<TFunction, bool>> predicate, Guid id = default(Guid)) { return FunctionRepository.CheckExistsAsync(predicate, id); } /// <summary> /// 更新功能信息 /// </summary> /// <param name="dtos">包含更新信息的功能信息DTO信息</param> /// <returns>业务操作结果</returns> public virtual async Task<OperationResult> UpdateFunctions(params TFunctionInputDto[] dtos) { Check.Validate<TFunctionInputDto, Guid>(dtos, nameof(dtos)); OperationResult result = await FunctionRepository.UpdateAsync(dtos, (dto, entity) => { if (dto.IsLocked && entity.Area == "Admin" && entity.Controller == "Function" && (entity.Action == "Update" \|\| entity.Action == "Read")) { throw new OsharpException($"功能信息“{entity.Name}”不能锁定"); } if (dto.AuditEntityEnabled && !dto.AuditOperationEnabled && !entity.AuditOperationEnabled && !entity.AuditEntityEnabled) { dto.AuditOperationEnabled = true; } else if (!dto.AuditOperationEnabled && dto.AuditEntityEnabled && entity.AuditOperationEnabled && entity.AuditEntityEnabled) { dto.AuditEntityEnabled = false; } if (dto.AccessType != entity.AccessType) { entity.IsAccessTypeChanged = true; } return Task.FromResult(0); }); if (result.Succeeded) { //功能信息缓存刷新事件 FunctionCacheRefreshEventData clearEventData = new FunctionCacheRefreshEventData(); EventBus.Publish(clearEventData); //功能权限缓存刷新事件 FunctionAuthCacheRefreshEventData removeEventData = new FunctionAuthCacheRefreshEventData() { FunctionIds = dtos.Select(m => m.Id).ToArray() }; EventBus.Publish(removeEventData); } return result; } #endregion Implementation of IFunctionStore<TFunction,in TFunctionInputDto> #region Implementation of IModuleStore<TModule,in TModuleInputDto,in TModuleKey> /// <summary> /// 获取模块信息查询数据集 /// </summary> public IQueryable<TModule> Modules => ModuleRepository.QueryAsNoTracking(); /// <summary> /// 检查模块信息是否存在 /// </summary> /// <param name="predicate">检查谓语表达式</param> /// <param name="id">更新的模块信息编号</param> /// <returns>模块信息是否存在</returns> public virtual Task<bool> CheckModuleExists(Expression<Func<TModule, bool>> predicate, TModuleKey id = default(TModuleKey)) { return ModuleRepository.CheckExistsAsync(predicate, id); } /// <summary> /// 添加模块信息 /// </summary> /// <param name="dto">要添加的模块信息DTO信息</param> /// <returns>业务操作结果</returns> public virtual async Task<OperationResult> CreateModule(TModuleInputDto dto) { const string treePathItemFormat = "${0}$"; Check.NotNull(dto, nameof(dto)); if (dto.Name.Contains('.')) { return new OperationResult(OperationResultType.Error, $"模块名称“{dto.Name}”不能包含字符“-”"); } var exist = Modules.Where(m => m.Name == dto.Name && m.ParentId != null && m.ParentId.Equals(dto.ParentId)) .SelectMany(m => Modules.Where(n => n.Id.Equals(m.ParentId)).Select(n => n.Name)).FirstOrDefault(); if (exist != null) { return new OperationResult(OperationResultType.Error, $"模块“{exist}”中已存在名称为“{dto.Name}”的子模块，不能重复添加。"); } exist = Modules.Where(m => m.Code == dto.Code && m.ParentId != null && m.ParentId.Equals(dto.ParentId)) .SelectMany(m => Modules.Where(n => n.Id.Equals(m.ParentId)).Select(n => n.Name)).FirstOrDefault(); if (exist != null) { return new OperationResult(OperationResultType.Error, $"模块“{exist}”中已存在代码为“{dto.Code}”的子模块，不能重复添加。"); } TModule entity = dto.MapTo<TModule>(); //排序码，不存在为1，否则同级最大+1 var peerModules = Modules.Where(m => m.ParentId.Equals(dto.ParentId)).Select(m => new { m.OrderCode }).ToArray(); if (peerModules.Length == 0) { entity.OrderCode = 1; } else { double maxCode = peerModules.Max(m => m.OrderCode); entity.OrderCode = maxCode + 1; } //父模块 string parentTreePathString = null; if (!Equals(dto.ParentId, default(TModuleKey))) { var parent = Modules.Where(m => m.Id.Equals(dto.ParentId)).Select(m => new { m.Id, m.TreePathString }).FirstOrDefault(); if (parent == null) { return new OperationResult(OperationResultType.Error, $"编号为“{dto.ParentId}”的父模块信息不存在"); } entity.ParentId = dto.ParentId; parentTreePathString = parent.TreePathString; } else { entity.ParentId = null; } if (await ModuleRepository.InsertAsync(entity) > 0) { entity.TreePathString = entity.ParentId == null ? treePathItemFormat.FormatWith(entity.Id) : GetModuleTreePath(entity.Id, parentTreePathString, treePathItemFormat); await ModuleRepository.UpdateAsync(entity); return new OperationResult(OperationResultType.Success, $"模块“{dto.Name}”创建成功"); } return OperationResult.NoChanged; } /// <summary> /// 更新模块信息 /// </summary> /// <param name="dto">包含更新信息的模块信息DTO信息</param> /// <returns>业务操作结果</returns> public virtual async Task<OperationResult> UpdateModule(TModuleInputDto dto) { const string treePathItemFormat = "${0}$"; Check.NotNull(dto, nameof(dto)); if (dto.Name.Contains('.')) { return new OperationResult(OperationResultType.Error, $"模块名称“{dto.Name}”不能包含字符“-”"); } var exist1 = Modules.Where(m => m.Name == dto.Name && m.ParentId != null && m.ParentId.Equals(dto.ParentId) && !m.Id.Equals(dto.Id)) .SelectMany(m => Modules.Where(n => n.Id.Equals(m.ParentId)).Select(n => new { n.Id, n.Name })).FirstOrDefault(); if (exist1 != null) { return new OperationResult(OperationResultType.Error, $"模块“{exist1.Name}”中已存在名称为“{dto.Name}”的子模块，不能重复添加。"); } var exist2 = Modules.Where(m => m.Code == dto.Code && m.ParentId != null && m.ParentId.Equals(dto.ParentId) && !m.Id.Equals(dto.Id)) .SelectMany(m => Modules.Where(n => n.Id.Equals(m.ParentId)).Select(n => new { n.Id, n.Name })).FirstOrDefault(); if (exist2 != null) { return new OperationResult(OperationResultType.Error, $"模块“{exist2.Name}”中已存在代码为“{dto.Code}”的子模块，不能重复添加。"); } TModule entity = await ModuleRepository.GetAsync(dto.Id); if (entity == null) { return new OperationResult(OperationResultType.Error, $"编号为“{dto.Id}”的模块信息不存在。"); } entity = dto.MapTo(entity); if (!Equals(dto.ParentId, default(TModuleKey))) { if (!entity.ParentId.Equals(dto.ParentId)) { var parent = Modules.Where(m => m.Id.Equals(dto.ParentId)).Select(m => new { m.Id, m.TreePathString }).FirstOrDefault(); if (parent == null) { return new OperationResult(OperationResultType.Error, $"编号为“{dto.ParentId}”的父模块信息不存在"); } entity.ParentId = dto.ParentId; entity.TreePathString = GetModuleTreePath(entity.Id, parent.TreePathString, treePathItemFormat); } } else { entity.ParentId = null; entity.TreePathString = treePathItemFormat.FormatWith(entity.Id); } return await ModuleRepository.UpdateAsync(entity) > 0 ? new OperationResult(OperationResultType.Success, $"模块“{dto.Name}”更新成功") : OperationResult.NoChanged; } /// <summary> /// 删除模块信息 /// </summary> /// <param name="id">要删除的模块信息编号</param> /// <returns>业务操作结果</returns> public virtual async Task<OperationResult> DeleteModule(TModuleKey id) { TModule entity = await ModuleRepository.GetAsync(id); if (entity == null) { return OperationResult.Success; } if (await ModuleRepository.CheckExistsAsync(m => m.ParentId.Equals(id))) { return new OperationResult(OperationResultType.Error, $"模块“{entity.Name}”的子模块不为空，不能删除"); } //清除附属引用 await ModuleFunctionRepository.DeleteBatchAsync(m => m.ModuleId.Equals(id)); await ModuleRoleRepository.DeleteBatchAsync(m => m.ModuleId.Equals(id)); await ModuleUserRepository.DeleteBatchAsync(m => m.ModuleId.Equals(id)); OperationResult result = await ModuleRepository.DeleteAsync(entity) > 0 ? new OperationResult(OperationResultType.Success, $"模块“{entity.Name}”删除成功") : OperationResult.NoChanged; if (result.Succeeded) { //功能权限缓存刷新事件 Guid[] functionIds = ModuleFunctionRepository.QueryAsNoTracking(m => m.Id.Equals(id)).Select(m => m.FunctionId).ToArray(); FunctionAuthCacheRefreshEventData removeEventData = new FunctionAuthCacheRefreshEventData() { FunctionIds = functionIds }; EventBus.Publish(removeEventData); } return result; } /// <summary> /// 获取树节点及其子节点的所有模块编号 /// </summary> /// <param name="rootIds">树节点</param> /// <returns>模块编号集合</returns> public virtual TModuleKey[] GetModuleTreeIds(params TModuleKey[] rootIds) { return rootIds.SelectMany(m => ModuleRepository.QueryAsNoTracking(n => n.TreePathString.Contains($"${m}$")).Select(n => n.Id)).Distinct() .ToArray(); } private static string GetModuleTreePath(TModuleKey currentId, string parentTreePath, string treePathItemFormat) { return $"{parentTreePath},{treePathItemFormat.FormatWith(currentId)}"; } #endregion Implementation of IModuleStore<TModule,in TModuleInputDto,in TModuleKey> #region Implementation of IModuleFunctionStore<TModuleFunction> /// <summary> /// 获取模块功能信息查询数据集 /// </summary> public IQueryable<TModuleFunction> ModuleFunctions => ModuleFunctionRepository.QueryAsNoTracking(); /// <summary> /// 检查模块功能信息是否存在 /// </summary> /// <param name="predicate">检查谓语表达式</param> /// <param name="id">更新的模块功能信息编号</param> /// <returns>模块功能信息是否存在</returns> public virtual Task<bool> CheckModuleFunctionExists(Expression<Func<TModuleFunction, bool>> predicate, Guid id = default(Guid)) { return ModuleFunctionRepository.CheckExistsAsync(predicate, id); } /// <summary> /// 设置模块的功能信息 /// </summary> /// <param name="moduleId">模块编号</param> /// <param name="functionIds">要设置的功能编号</param> /// <returns>业务操作结果</returns> public virtual async Task<OperationResult> SetModuleFunctions(TModuleKey moduleId, Guid[] functionIds) { TModule module = await ModuleRepository.GetAsync(moduleId); if (module == null) { return new OperationResult(OperationResultType.QueryNull, $"编号为“{moduleId}”的模块信息不存在"); } Guid[] existFunctionIds = ModuleFunctionRepository.QueryAsNoTracking(m => m.ModuleId.Equals(moduleId)).Select(m => m.FunctionId).ToArray(); Guid[] addFunctionIds = functionIds.Except(existFunctionIds).ToArray(); Guid[] removeFunctionIds = existFunctionIds.Except(functionIds).ToArray(); List<string> addNames = new List<string>(), removeNames = new List<string>(); int count = 0; foreach (Guid functionId in addFunctionIds) { TFunction function = await FunctionRepository.GetAsync(functionId); if (function == null) { continue; } TModuleFunction moduleFunction = new TModuleFunction() { ModuleId = moduleId, FunctionId = functionId }; count = count + await ModuleFunctionRepository.InsertAsync(moduleFunction); addNames.Add(function.Name); } foreach (Guid functionId in removeFunctionIds) { TFunction function = await FunctionRepository.GetAsync(functionId); if (function == null) { continue; } TModuleFunction moduleFunction = ModuleFunctionRepository.QueryAsNoTracking() .FirstOrDefault(m => m.ModuleId.Equals(moduleId) && m.FunctionId == functionId); if (moduleFunction == null) { continue; } count = count + await ModuleFunctionRepository.DeleteAsync(moduleFunction); removeNames.Add(function.Name); } if (count > 0) { //功能权限缓存刷新事件 FunctionAuthCacheRefreshEventData removeEventData = new FunctionAuthCacheRefreshEventData() { FunctionIds = addFunctionIds.Union(removeFunctionIds).Distinct().ToArray() }; EventBus.Publish(removeEventData); return new OperationResult(OperationResultType.Success, $"模块“{module.Name}”添加功能“{addNames.ExpandAndToString()}”，移除功能“{removeNames.ExpandAndToString()}”操作成功"); } return OperationResult.NoChanged; } #endregion Implementation of IModuleFunctionStore<TModuleFunction> #region Implementation of IModuleRoleStore<TModuleRole> /// <summary> /// 获取模块角色信息查询数据集 /// </summary> public IQueryable<TModuleRole> ModuleRoles => ModuleRoleRepository.QueryAsNoTracking(); /// <summary> /// 检查模块角色信息是否存在 /// </summary> /// <param name="predicate">检查谓语表达式</param> /// <param name="id">更新的模块角色信息编号</param> /// <returns>模块角色信息是否存在</returns> public virtual Task<bool> CheckModuleRoleExists(Expression<Func<TModuleRole, bool>> predicate, Guid id = default(Guid)) { return ModuleRoleRepository.CheckExistsAsync(predicate, id); } /// <summary> /// 设置角色的可访问模块 /// </summary> /// <param name="roleId">角色编号</param> /// <param name="moduleIds">要赋予的模块编号集合</param> /// <returns>业务操作结果</returns> public virtual async Task<OperationResult> SetRoleModules(TRoleKey roleId, TModuleKey[] moduleIds) { TRole role = await RoleRepository.GetAsync(roleId); if (role == null) { return new OperationResult(OperationResultType.QueryNull, $"编号为“{roleId}”的角色信息不存在"); } TModuleKey[] existModuleIds = ModuleRoleRepository.QueryAsNoTracking(m => m.RoleId.Equals(roleId)).Select(m => m.ModuleId).ToArray(); TModuleKey[] addModuleIds = moduleIds.Except(existModuleIds).ToArray(); TModuleKey[] removeModuleIds = existModuleIds.Except(moduleIds).ToArray(); List<string> addNames = new List<string>(), removeNames = new List<string>(); int count = 0; foreach (TModuleKey moduleId in addModuleIds) { TModule module = await ModuleRepository.GetAsync(moduleId); if (module == null) { return new OperationResult(OperationResultType.QueryNull, $"编号为“{moduleId}”的模块信息不存在"); } TModuleRole moduleRole = new TModuleRole() { ModuleId = moduleId, RoleId = roleId }; count = count + await ModuleRoleRepository.InsertAsync(moduleRole); addNames.Add(module.Name); } foreach (TModuleKey moduleId in removeModuleIds) { TModule module = await ModuleRepository.GetAsync(moduleId); if (module == null) { return new OperationResult(OperationResultType.QueryNull, $"编号为“{moduleId}”的模块信息不存在"); } TModuleRole moduleRole = ModuleRoleRepository.GetFirst(m => m.RoleId.Equals(roleId) && m.ModuleId.Equals(moduleId)); if (moduleRole == null) { continue; } count = count + await ModuleRoleRepository.DeleteAsync(moduleRole); removeNames.Add(module.Name); } if (count > 0) { //功能权限缓存刷新事件 moduleIds = addModuleIds.Union(removeModuleIds).Distinct().ToArray(); Guid[] functionIds = ModuleFunctionRepository.QueryAsNoTracking(m => moduleIds.Contains(m.ModuleId)) .Select(m => m.FunctionId).Distinct().ToArray(); FunctionAuthCacheRefreshEventData removeEventData = new FunctionAuthCacheRefreshEventData() { FunctionIds = functionIds }; EventBus.Publish(removeEventData); if (addNames.Count > 0 && removeNames.Count == 0) { return new OperationResult(OperationResultType.Success, $"角色“{role.Name}”添加模块“{addNames.ExpandAndToString()}”操作成功"); } if (addNames.Count == 0 && removeNames.Count > 0) { return new OperationResult(OperationResultType.Success, $"角色“{role.Name}”移除模块“{removeNames.ExpandAndToString()}”操作成功"); } return new OperationResult(OperationResultType.Success, $"角色“{role.Name}”添加模块“{addNames.ExpandAndToString()}”，移除模块“{removeNames.ExpandAndToString()}”操作成功"); } return OperationResult.NoChanged; } /// <summary> /// 获取角色可访问模块编号 /// </summary> /// <param name="roleId">角色编号</param> /// <returns>模块编号集合</returns> public virtual TModuleKey[] GetRoleModuleIds(TRoleKey roleId) { TModuleKey[] moduleIds = ModuleRoleRepository.QueryAsNoTracking(m => m.RoleId.Equals(roleId)).Select(m => m.ModuleId).Distinct().ToArray(); return GetModuleTreeIds(moduleIds); } #endregion Implementation of IModuleRoleStore<TModuleRole> #region Implementation of IModuleUserStore<TModuleUser> /// <summary> /// 获取模块用户信息查询数据集 /// </summary> public IQueryable<TModuleUser> ModuleUsers => ModuleUserRepository.QueryAsNoTracking(); /// <summary> /// 检查模块用户信息是否存在 /// </summary> /// <param name="predicate">检查谓语表达式</param> /// <param name="id">更新的模块用户信息编号</param> /// <returns>模块用户信息是否存在</returns> public virtual Task<bool> CheckModuleUserExists(Expression<Func<TModuleUser, bool>> predicate, Guid id = default(Guid)) { return ModuleUserRepository.CheckExistsAsync(predicate, id); } /// <summary> /// 设置用户的可访问模块 /// </summary> /// <param name="userId">用户编号</param> /// <param name="moduleIds">要赋给用户的模块编号集合</param> /// <returns>业务操作结果</returns> public virtual async Task<OperationResult> SetUserModules(TUserKey userId, TModuleKey[] moduleIds) { TUser user = await UserRepository.GetAsync(userId); if (user == null) { return new OperationResult(OperationResultType.QueryNull, $"编号为“{userId}”的用户信息不存在"); } TModuleKey[] existModuleIds = ModuleUserRepository.QueryAsNoTracking(m => m.UserId.Equals(userId)).Select(m => m.ModuleId).ToArray(); TModuleKey[] addModuleIds = moduleIds.Except(existModuleIds).ToArray(); TModuleKey[] removeModuleIds = existModuleIds.Except(moduleIds).ToArray(); List<string> addNames = new List<string>(), removeNames = new List<string>(); int count = 0; foreach (TModuleKey moduleId in addModuleIds) { TModule module = await ModuleRepository.GetAsync(moduleId); if (module == null) { return new OperationResult(OperationResultType.QueryNull, $"编号为“{moduleId}”的模块信息不存在"); } TModuleUser moduleUser = new TModuleUser() { ModuleId = moduleId, UserId = userId }; count += await ModuleUserRepository.InsertAsync(moduleUser); addNames.Add(module.Name); } foreach (TModuleKey moduleId in removeModuleIds) { TModule module = await ModuleRepository.GetAsync(moduleId); if (module == null) { return new OperationResult(OperationResultType.QueryNull, $"编号为“{moduleId}”的模块信息不存在"); } TModuleUser moduleUser = ModuleUserRepository.GetFirst(m => m.ModuleId.Equals(moduleId) && m.UserId.Equals(userId)); if (moduleUser == null) { continue; } count += await ModuleUserRepository.DeleteAsync(moduleUser); removeNames.Add(module.Name); } if (count > 0) { //功能权限缓存刷新事件 FunctionAuthCacheRefreshEventData removeEventData = new FunctionAuthCacheRefreshEventData() { UserNames = new[] { user.UserName } }; EventBus.Publish(removeEventData); if (addNames.Count > 0 && removeNames.Count == 0) { return new OperationResult(OperationResultType.Success, $"用户“{user.UserName}”添加模块“{addNames.ExpandAndToString()}”操作成功"); } if (addNames.Count == 0 && removeNames.Count > 0) { return new OperationResult(OperationResultType.Success, $"用户“{user.UserName}”移除模块“{removeNames.ExpandAndToString()}”操作成功"); } return new OperationResult(OperationResultType.Success, $"用户“{user.UserName}”添加模块“{addNames.ExpandAndToString()}”，移除模块“{removeNames.ExpandAndToString()}”操作成功"); } return OperationResult.NoChanged; } /// <summary> /// 获取用户自己的可访问模块编号 /// </summary> /// <param name="userId">用户编号</param> /// <returns>模块编号集合</returns> public virtual TModuleKey[] GetUserSelfModuleIds(TUserKey userId) { TModuleKey[] moduleIds = ModuleUserRepository.QueryAsNoTracking(m => m.UserId.Equals(userId)).Select(m => m.ModuleId).Distinct().ToArray(); return GetModuleTreeIds(moduleIds); } /// <summary> /// 获取用户及其拥有角色可访问模块编号 /// </summary> /// <param name="userId">用户编号</param> /// <returns>模块编号集合</returns> public virtual TModuleKey[] GetUserWithRoleModuleIds(TUserKey userId) { TModuleKey[] selfModuleIds = GetUserSelfModuleIds(userId); TRoleKey[] roleIds = UserRoleRepository.QueryAsNoTracking(m => m.UserId.Equals(userId)).Select(m => m.RoleId).ToArray(); TModuleKey[] roleModuleIds = roleIds .SelectMany(m => ModuleRoleRepository.QueryAsNoTracking(n => n.RoleId.Equals(m)).Select(n => n.ModuleId)) .Distinct().ToArray(); roleModuleIds = GetModuleTreeIds(roleModuleIds); return roleModuleIds.Union(selfModuleIds).Distinct().ToArray(); } #endregion Implementation of IModuleUserStore<TModuleUser> } }
Q: python variable assignment using time slices This is more of a newbie python question. I have a pandas dataframe tmp_df, which I slice using 3 datetime inputs as follows to extract different time ranges of data: tmp_daily_df = tmp_df.loc[idx[daily[1]:daily[2]],:] tmp_weekly_df = tmp_df.loc[idx[weekly[1]: weekly[2]],:] tmp_monthly_df = tmp_df.loc[idx[monthly[1]: monthly[2]],:] Then I pass the resulting 3 dataframes to a function called compute_stats(), which calculates various statistics and performs some manipulations to the input dataframe (i.e. tmp_daily_df). One such manipulation is adding several new columns to tmp_daily_df etc. final_daily_df = compute_stats(tmp_daily_df, 'M','').reset_index(drop=True) final_weekly_df = compute_stats(tmp_weekly_df, 'M','').reset_index(drop=True) final_monthly_df = compute_stats(tmp_monthly_df, 'M','').reset_index(drop=True) My question is since python variable assignment operates more like a linkage than a copy I'm wondering will the 2nd and 3rd calls to compute_stats be corrupted by manipulations to tmp_daily_df, which is a time slice of tmp_df which is referenced by tmp_weekly_df and tmp_monthly_df. A: Slicing a list creates a copy, in other words : new_list = l[:] is equivalent to : new_list = list(l) DataFrames work a bit differently though. Take a look at this post : dataframes copies vs views DataFrame.loc will return a view when used with scalar indexing/slicing. According to this : Whenever an array of labels or a boolean vector are involved in the indexing operation, the result will be a copy. With single label / scalar indexing and slicing, e.g. df.ix[3:6] or df.ix[:, 'A'], a view will be returned. you will get a view unless you use an array of labels or a boolean vector. Using the copy method would give you the desired result.
Fuzzy’s Taco Shop Officially Closed Well, after only being in business for less than a year, Fuzzy’s Taco Shop on University Boulevard has officially closed it's doors. It was announced on their Facebook page earlier today which read: “We regret to announce that Fuzzy’s Taco Shop Tuscaloosa is now permanently closed due to renovations and an HVAC issue. We hope you all understand. Thank you all for the support!” Fuzzy’s opened back on November 15, 2016 downtown at the old Cafe Venice location. The restaurant chain describes itself as "Baja-style Mexican restaurant", with a menu that included tacos, burritos, nachos, quesadillas and other Mexican specialties. According to their website, there are around 150 Fuzzy's locations throughout the country, with the original Fuzzy's being located in Fort Worth, Texas. I had the opportunity to eat there on a few occasions, and always had a pleasant dining experience. The food was good, the prices were reasonable, and their frozen drink concoctions in the bar were quite tasty as well. Wish they could've stuck around longer because I enjoyed them.
TSPluginInit() must be defined by all plugins. Traffic Server calls this initialization routine when it loads the plugin and sets argc and argv appropriately based on the values in plugin.config. argc is a count of the number of arguments in the argument vector, argv. The count is at least one because the first argument in the argument vector is the plugins name, which must exist in order for the plugin to be loaded. TSPluginRegister() registers the appropriate SDK version specific in sdk_version for your plugin. Use this function to make sure that the version of Traffic Server on which your plugin is running supports the plugin.
```ocaml # let empty = 0;; val empty : int = 0 # let satisfies_identity_law = 10 + empty = 10;; val satisfies_identity_law : bool = true # let satisfies_associative_law = 1 + (2 + 3) = (1 + 2) + 3;; val satisfies_associative_law : bool = true ```
CORE test.c --show-vcc main::1::node1!0@1#2\\.\\.data = main::1::node2!0@1#2\\.\\.data = ^EXIT=0$ ^SIGNAL=0$ -- main::1::node1!0@1#[3-9]\\.\\.children\\[\\[[01]\\]\\] = -- This checks that mixed array and field accesses are executed using a field-sensitive symbol (main::1::node1!0@1#2..data) rather than by assigning the whole struct and expanding into field symbols (which would assign main::1::node1!0@1#3..children\\[\\[[01]\\]\\])
World reports Stocks to watch AAP 2012-12-31 Australian shares closed almost half a per cent lower on the final trading day of 2012, as investors locked in profits following a negative lead from Wall Street. The benchmark S&P/ASX200 index closed a shortened session down 22.4 points, or 0.48 per cent, at 4,648.9 points on Monday, while the broader All Ordinaries index fell 20.7 points, or 0.44 per cent, to 4,664.6 points. On the ASX 24, the March 2013 share price index futures contract was 30 points lower at 4,616 points, on volume of 14,233 contracts traded. The Australian stock market closed early on New Year's Eve and will resume trade on Wednesday, January 2, 2013. The prospect of no deal being reached between US president Barack Obama and legislators in the US Congress over a looming budget deadline caused investors to offload stocks during Friday night's (AEDT) US session. CommSec economist Craig James said local investors now appeared to be more optimistic about the US situation, and took heart from stronger-than-expected Chinese manufacturing figures released at 1230 AEDT. "It was short-lived strength, but there was a degree of strength when the Chinese data came through," Mr James said. "What we're seeing now is some of the late book squaring and profit-taking by a number of the professional investors and some retail-type investors." Australia had again outperformed European and US markets, with most people optimistic that an agreement would be reached in the US.
--- title: Notes from the Road author: tjfontaine date: 2014-06-11T16:00:00.000Z status: publish category: Uncategorized slug: notes-from-the-road layout: blog-post.hbs --- ## Notes from the Road As Project Lead for Node.js, I was excited to have the opportunity to go on the road and bring production stories to all of our users. We've had amazing speakers and turn out in San Francisco, Seattle, Portland, Boston, and New York. But I wanted to make sure we reached more than just our coasts, so soon we'll be in [Minneapolis](http://www.joyent.com/noderoad/cities/minneapolis-6-17-2014) and I'll be returning to my home state of Ohio and doing an event in [Cincinnati](http://www.joyent.com/noderoad/cities/cincinnati-6-19-2014). The Node.js community is all over the world, and hopefully Node on the Road can reach as many of you as it can. Nominate your city to be a future stop on the Node.js on the Road series [here](http://www.joyent.com/noderoad/cities/suggest). These Node on the Road events are successful because of the incredible support from the community and the existing meetup organizations in their respective cities. But the biggest advantage is that the project gets to solicit feedback directly from our users about what is and isn't working for them in Node.js, what modules they're using, and where they need Node to do better. ## Release schedules Some of the feedback we've received has been about the upgrade process for Node. Veteran Node.js alums will occasionally sit around campfires and tell the stories of when things would break every release, or how long they stayed on 0.4 before upgrading to 0.6. Some production companies are still out there running on 0.8 afraid to make the jump to 0.10. While other companies advise people to avoid upgrading to a new release of a Node version until the patch number hits double digits. It's those sorts of stories that make it important for us to get the release for 0.12 right, from the get go. Node is in a fantastic place right now, it's maturing quickly and finding its footing in new environments with new users and new use cases. The expectation for Node is getting higher each day with every release. There are multiple interests at stake, keeping Node lean, keeping it up to date with languages and standards, keeping it fast, and balanced with keeping it stable such that we don't upset the adoption rate. That means Node needs to make the right choices that balance the needs of all of our users without closing the doors to others. All of these conversations are helping to shape the release process going forward, and helping to scope just what does go into a release and how fast people want to see those happen. In fact something we've been considering is eliminating the confusion around our Stable/Unstable branches, and instead moving to releases that are always stable. But it's important that the features and changes that go into a release are shaped by user feedback, which is why events like Node on the Road are vital. ## Better Documentation Another key piece of feedback has consistently been around our documentation. Users need us to clean up our API reference documentation, there are lots of undocumented and under-documented methods and properties that are being used or should be used. Node needs to include what errors may be delivered as part of the operation of your application, as well as what methods will throw and under what circumstances. But mostly users are looking for more general purpose documentation that can help both new and veteran Node.js users be more productive with Node. And the people who are most equipped to provide that documentation are the users themselves who've already been successful. ## Easier Contribution Aside from soliciting feedback from users of Node.js and bringing production stories to our users, Node on the Road has also been about highlighting the various ways you as a member of the community can contribute. There are many ways you can contribute from meetups and conferences, to publishing modules, to finding issues in modules or core, to fixing issues in modules or core, or even adding features to modules or core. Where ever you are passionate about Node.js there are ways you can contribute back to Node. Node.js has inherited many things from our largest dependency V8, we've adopted their build system GYP, we use their test runner (which is unfortunately in python), and when we were structuring the project we brought along the Contributor License Agreement (CLA) that Google uses to manage contributions for Chromium and V8. The CLA is there as a way for a project to audit itself and to give itself the opportunity to relicense itself in the future if necessary. Node.js though is distributed under the venerable [MIT](http://opensource.org/licenses/MIT) license, and that's not going to change. The MIT license is one of the most permissible open source licenses out there, and has fostered a ton of development with Node.js and we want that to continue. In an effort to make it easier for users to contribute to Node.js the project has decided to lift the requirement of signing the CLA before contributions are eligible for integration. Having to sign the CLA could at times be a stumbling block for a contribution. It could involve a long conversation with your legal department to ultimately contribute typo corrections. I'm excited to see what contributions will be coming from the community in the future, excited to see where our users take Node.js, and excited to be participating with all of you on this project.
Acceptable quality limit The acceptable quality limit (AQL) is the worst tolerable process average (mean) in percentage or ratio that is still considered acceptable; that is, it is at an acceptable quality level. Closely related terms are the rejectable quality limit and rejectable quality level (RQL). In a quality control procedure, a process is said to be at an acceptable quality level if the appropriate statistic used to construct a control chart does not fall outside the bounds of the acceptable quality limits. Otherwise, the process is said to be at a rejectable control level. In 2008 the usage of the abbreviation AQL for the term "acceptable quality limit" was changed in the standards issued by at least one national standards organization (ANSI/ASQ) to relate to the term "acceptance quality level". It is unclear whether this interpretation will be brought into general usage, but the underlying meaning remains the same. An acceptable quality level is a test and/or inspection standard that prescribes the range of the number of defective components that is considered acceptable when random sampling those components during an inspection. The defects found during an electronic or electrical test, or during a physical (mechanical) inspection, are sometimes classified into three levels: critical, major and minor. Critical defects are those that render the product unsafe or hazardous for the end user or that contravene mandatory regulations. Major defects can result in the product's failure, reducing its marketability, usability or saleability. Lastly, minor defects do not affect the product's marketability or usability, but represent workmanship defects that make the product fall short of defined quality standards. Different companies maintain different interpretations of each defect type. In order to avoid argument, buyers and sellers agree on an AQL standard, chosen according to the level of risk each party assumes, which they use as a reference during pre-shipment inspection. See also Acceptance sampling Statistical process control Control limits References Further reading Category:Statistical process control Category:Sampling (statistics)
Virulence regulators RfaH and YaeQ do not operate in the same pathway. The expression of virulence factors such as hemolysin and lipopolysaccharides in Proteobacteria is regulated by the transcription elongation factor RfaH. RfaH reduces pausing and termination at intergenic sites, and thus allows RNA polymerase to conclude transcription of the distal genes in long virulence operons. The yaeQ gene of Salmonella enterica sv. Typhimurium has been identified as a high-copy-number suppressor of the hemolytic defect in an rfaH deletion strain, leading to speculation regarding a direct role of YaeQ in the transcriptional control of bacterial virulence. In order to evaluate this hypothesis, yaeQ genes from Escherichia coli and S. enterica sv. Typhimurium were cloned and expressed. Their products, purified YaeQ proteins, displayed no antitermination effects in in-vitro transcription assays over a wide range of concentrations, neither by themselves nor in competition with RfaH. When overexpressed in vivo, plasmid-borne E. coli and S. enterica sv. Typhimurium yaeQ genes also failed to restore hemolytic activity in an rfaH deletion strain under conditions in which episomal E. coli rfaH and its orthologs exhibited full complementation of the genomic rfaH deletion. Taken together, our findings do not support the hypothesis of YaeQ involvement in RfaH-dependent regulation of virulence, even in stoichiometric excess in vitro or upon overexpression in vivo.
Bulk Actin Dynamics Drive Phase Segregation in Zebrafish Oocytes. Segregation of maternal determinants within the oocyte constitutes the first step in embryo patterning. In zebrafish oocytes, extensive ooplasmic streaming leads to the segregation of ooplasm from yolk granules along the animal-vegetal axis of the oocyte. Here, we show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the oocyte. This wave functions in segregation by both pulling ooplasm animally and pushing yolk granules vegetally. Using biophysical experimentation and theory, we show that ooplasm pulling is mediated by bulk actin network flows exerting friction forces on the ooplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. Our study defines a novel role of cell-cycle-controlled bulk actin polymerization waves in oocyte polarization via ooplasmic segregation.
// Copyright 2015 The Prometheus Authors // Licensed under the Apache License, Version 2.0 (the "License"); // you may not use this file except in compliance with the License. // You may obtain a copy of the License at // // http://www.apache.org/licenses/LICENSE-2.0 // // Unless required by applicable law or agreed to in writing, software // distributed under the License is distributed on an "AS IS" BASIS, // WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. // See the License for the specific language governing permissions and // limitations under the License. // Package expfmt contains tools for reading and writing Prometheus metrics. package expfmt // Format specifies the HTTP content type of the different wire protocols. type Format string // Constants to assemble the Content-Type values for the different wire protocols. const ( TextVersion = "0.0.4" ProtoType = `application/vnd.google.protobuf` ProtoProtocol = `io.prometheus.client.MetricFamily` ProtoFmt = ProtoType + "; proto=" + ProtoProtocol + ";" // The Content-Type values for the different wire protocols. FmtUnknown Format = `<unknown>` FmtText Format = `text/plain; version=` + TextVersion + `; charset=utf-8` FmtProtoDelim Format = ProtoFmt + ` encoding=delimited` FmtProtoText Format = ProtoFmt + ` encoding=text` FmtProtoCompact Format = ProtoFmt + ` encoding=compact-text` ) const ( hdrContentType = "Content-Type" hdrAccept = "Accept" )
Glide Ranger Station The Glide Ranger Station in Umpqua National Forest near Glide, Oregon was built in 1938 by the Civilian Conservation Corps. It served historically as a government office. It was listed on the National Register of Historic Places in 1986 for its architecture. It was designed by architects of the United States Forest Service in Rustic and other architecture. In 1986 the station building was in excellent condition. It is a one-story wood frame building on a concrete foundation, with gables, timbers, and stone steps. Decorative features include pine tree shaped cutouts in shutters and pine tree designs centered in each gable end. References Category:United States Forest Service ranger stations Category:Civilian Conservation Corps in Oregon Category:Park buildings and structures on the National Register of Historic Places in Oregon Category:Government buildings completed in 1938 Category:Buildings and structures in Douglas County, Oregon Category:Rustic architecture in Oregon Category:National Register of Historic Places in Douglas County, Oregon Category:1938 establishments in Oregon
Creating Localizable App Builds (OS X) Got a localization question? Creating Localizable App Builds (OS X) Certain app localizers (inc. Applingua) allow you to send entire app builds in order to see the inner workings of an app and to make sure all text, images and supporting html files are discovered and translated. In the case of OS X apps, it also allows localizers to translate and test on the fly. When you now create a build of your app, localizers can now extract strings using IBTOOL or a string extraction tool themselves. On OS X, they can also reimport the strings using IBTOOL again and run the app in their native language for testing. iOS This also works for the NIBs within an iOS application bundle. Unfortunately the more important Localizable.strings file is compressed on build so it is not possible for a localizer to extract all the necessary text this way. The best thing is to send the raw XIBs and .strings files from your Xcode project manually and send a build of the app to the localizer for testing. Important: If a localizer translates a NIB file, then these NIBs have to be imported into your Xcode project. Since Xcode 3 the default format has been XIB. Although this will have no effect on the operation of your app, some developers might not like to have two different interface builder formats within their project. In these cases, you will need to send the raw XIBs from your Xcode project, then build the app for yourself in order for the translator to test their localization. We’d really appreciate it if you could rate this post to let us know how useful you found it! :) Thanks! Leave a Reply Welcome This Knowledge Base (KB) is brought to you by Applingua, the friendly app localization agency that knows its tap from its click. It’s designed to help you find answers to all your localization questions. If you need help or would like to get a quote to localize your app feel free to get in touch!
Marked as glass cabinet door replacements discussion or glass door kitchen cabinet subject along with kitchen cabinets glass doors area of interest with seedy glass for kitchen cabinets object and reface kitchen cabinets object or floor cabinet with glass doors topic as well as Furniture, So don't forget to check out the main article in Tips For Cleaning The Glass Door Cabinet Hi-Res Wallpaper Photos
Discordances in the temporal pattern of the ACTH/beta-endorphin releasing effects of synthetic CRFs and partially purified bovine CRF in a superfusion system. Temporal characteristics of ACTH and beta-endorphin secretion induced by bovine hypothalamic CRF-A (void volume) and CRF-B (Kav = 0.583) separated by Sephadex G-100 were compared to those of synthetic ovine or rat CRF, sauvagine and vasopressin. Dispersed cells or minced fragments of rat adenohypophyses perifused in a column were exposed to various secretagogues, and ACTH and/or beta-endorphin concentrations of the effluent were measured by radioimmunoassays. CRF-A or CRF-B induced an immediate brisk rise of ACTH and beta-endorphin within 1 min after initiation of CRF perifusion. The maximum rate of ACTH or beta-endorphin secretion was reached 1-2 min later. Hormone secretion persisted throughout a 10-min exposure to these secretagogues. More than 80% of the total ACTH or beta-endorphin secretion induced by 10-min perifusion with bovine CRF occurred during exposure to CRF. With 10-min perifusion with 300 ng/ml ovine or rat CRF, the onset of the major CRF-stimulated ACTH or beta-endorphin secretion was markedly delayed compared to that following bovine CRF. During perifusion with ovine or rat CRF, a modest slow increase in ACTH or beta-endorphin secretion was observed. More than 60-70% of the total ACTH or beta-endorphin secretion induced by 10-min perifusion with rat or ovine CRF occurred after CRF withdrawal. The ACTH secretory patterns for sauvagine were very similar to those for synthetic rat or ovine CRF. These results suggest some qualitative differences between partially purified bovine CRF and synthetic ovine or rat CRF.
Q: How do I decode/parse the Access and ID tokens returned to me by Cognito? I have gotten to the following two lines in my javascript code: alert(result.getAccessToken().getJwtToken()); alert(result.getIdToken().getJwtToken()); I now want to get the family_name value from the payload of th ID token, as well as the expiration time of the token, but am a little confused. I know the tokens are JSON Web Tokens but I am still a little confused as to how to easily access these values (eg family_name) that are part of the JSON Web Token payload?! thanks A: See this example, a function in AWS Cognito JS SDK; it parses JWT to read token expiry. A JWT has three parts (header, payload and signature - in that order), which are separated by ".". The payload is encoded as UTF-8 chars in base 64. To read the claims from the payload, extract the payload and convert it into a JSON object. Read the claims that you are interested in from the JSON object, for e.g. get expiry by payloadJsonObject.exp.
Friday, October 22, 2010 You said: “I’ll go to another country, go to another shore,find another city better than this one.Whatever I try to do is fated to turn out wrongand my heart lies buried as though it were something dead.How long can I let my mind moulder in this place?Wherever I turn, wherever I happen to look,I see the black ruins of my life, here,where I’ve spent so many years, wasted them, destroyed then totally.” You won’t find a new country, won’t find another shore.This city will always pursue you. You will walkthe same streets, grow old in the same neighborhoods,will turn gray in these same housesYou will always end up in this city. Don’t hope for things elsewhere:there is no ship for you, there is no road.As you’ve wasted your life here, in this small corner,you’ve destroyed it everywhere else in the world.
The drive from Sukhothai to Lampang was a pleasant 3/4 hours. The roads weren't particularly bumpy and greenery of the central Thai countryside was slowly transformed into more mountainous terrain as we moved north. Lampang is one of Thailand's relatively untouched cities. Locals refer to it as the 'last paradise' in their country. Tourism has brought a significant amount of benefits for the north of the country, but with tourist money has come new developments. The traditional cities of Chiang Mai and Chiang Rai have been transformed into cities with skyscrapers, catering to the tourism industry. Lampang stands out in this development. The cityscape has remained broadly the same, and tourism is still in its infancy. Those tourists that do stay, tend only to stop off for a lunch break. I fell into a third category, staying slightly longer to explore the surrounding area. Animal tourism The city is built in the valley of the Wang River and its northerly latitude gives it a relatively dry climate. The city has perpetually been in the shadow of its northern powerhouse rivals, Chiang Mai and Chiang Rai and has therefore escaped some of the changes and tourism. However, on the flip side, this isolation has also left it less developed. Lampang's economy is focused on rice paddy farming, the cultivation of pineapples and sugarcane as well as logging. The name of the city means 'city of the horse carriage cart', and horse drawn carriages are the typical form of transportation. The first stop I made was in the city's elephant conservation centre with some travelers I had met on the way north. They were an amazing group of people, and I still stay in touch with many of them today. I like a good picture. My personal Instagram account is full of pictures that I am very proud to have taken. However, there is always a line. The safety and happiness of myself and others around is key. Sikhi teaches compassion and empathy, with selfishness and ego seen as evils. There is no way I would ever take a picture that would cause suffering to others. I see a lot of pictures with people sitting on elephants or lying with tigers. I'm sure this is an amazing experience. However, on my travels I was taught that these animals are drugged, beaten and emotionally broken until they become docile. Others are deprived of sleep. I think its important to take into account cultural differences. What's acceptable in Thailand may not always be acceptable in the UK. I didn't want to take an anglocentric view point and act like 'my way' was better or gave me some moral high ground. However, I made a commitment to myself early on that I would avoid experiences where animals are harmed. The Friends of the Asian Elephant Hospital is one of the places in Thailand that actively takes care of its elephants. These are elephants that have been rescued from abusive owners/companies and are rehabilitated. I was told there are two elephant centres in Lampang, and this is the one that has a good ethical record. You have the option to ride elephants while they take a bath, but again, the group I was with decided it wasn't the most ethical thing to do. However, if its something you are comfortable with, it looks fun and I'm told the elephants don't mind in this particular centre. They take the elephants for a bath in a lake in the middle of the centre, if you don't want to ride them, you can still walk closely with them. Following this the elephants parade up a road leading to the entrance before they turn into their enclosures. After leaving the elephant hospital, we headed into the countryside, not far from Lampang and we were welcomed by a rural family to stay at their house. The family put on quite a show, playing traditional Thai instruments and cooking an amazing dinner. After dinner we got some massages and headed outside to light a Chinese lantern. We then just lounged around, getting to know each other better and playing card games. One of the children at the house, a 7 year old boy had a little football so I spent a lot of time kicking the ball around with him. Village life That night I slept in a small shed, just outside the main living quarters. The shed was literally big enough for just my mattress, and the mosquito net was covered in holes at the side, while the top had hundreds of dead bugs on it. I decided to plaster on the mosquito repellent. As soon as I turned the lights off, the noises started. It was pitch black in the middle of the countryside with no outdoor lighting. I heard noises I have never heard before from grasshoppers, to dogs, to what I can only describe as a satan like deep bellow. Other than some devil like monster possibly loitering outside my shed, the other noises were oddly relaxing. It's one thing I never hear back in England, and is similar to what I heard in rural India, although here there seemed to be thousands of animals and insects, everywhere. It was genuinely one of my favourite nights of the whole trip. Despite the cast of the Lion King doing their best to keep me awake, I actually had a really good nights sleep. I woke up the next day and took a bucket bath in freezing water, with large ants crawling on the walls of the open area. It was the quickest morning routine of my life. As I got ready I walked out and the young boy was waiting, football in hand, so I obliged with a round two. After about 20 minutes, it was time for him to do his homework and for me to take my leave. I headed out and joined the others for an early morning cooking class. The ingredients were all sourced from surrounding farms and we spent an hour cooking a breakfast rice dish that is popular in Northern Thailand, although the name escapes me now. It was a spicy breakfast, a world away from Coco Pops. The cooking class was fun, and these classes are available all over the country. I would definitely recommend attending at least one of these. The food is delicious, and most of these ingredients are available back home, should you get a craving for a genuine Thai meal. The first Monk Following this we headed out to a local temple, taking some offerings with us. After a short wait we were greeted by a Buddhist Monk who took a good look at all of us. Through a local interpreter he specifically asked about me, no doubt as I stood out just a little. I inquired what he asked and she said he wanted to know what religion I was as he had never come across this appearance before. I replied that I am a Sikh. He seemed satisfied with the response. We all went up, one by one, and he tied a little string around our hand for protection and luck. He was very friendly, welcoming and open. During my time in Thailand, I ended up getting this same ritual from two different monks. Both were inquisitive about my background and both seemed happy with the response I had given. Whether they knew what a Sikh or not, I am unsure, but I do know the two faiths share a tremendous amount of similarities in their belief systems; especially around meditation, reincarnation and different energies. Cycle through the countryside After the temple we headed off to a local bike shop and rented some cycles for the day, and so began possibly my favourite day of all my trips in SE Asia. We began by riding through the village and then crossed into the surrounding countryside, The route we took was breathtakingly scenic, surrounded by lush greenery with mountains in the distance. We stopped off at a small farmhouse that grew mushrooms. It was a small family business and all members of the family were involved in the enterprise. We were taken to a small place in their farm where the mushrooms are put into a small warm room to mature. The area was very hot, but it was cool seeing how the process worked, at least in northern Thailand. We actually stayed a fair amount of time as the farmer talked us through the process. We rode for about half an hour, with a nice cool breeze a welcome element on a very hot day. We decided to go to the local village school and disembarked. As soon as we got off all the kids started shouting from the balconies. These were a rowdy group of kids. We went into one of the classrooms and taught English for a short while which was quite fun. What made the experience even better is that even though most of us (bar two) had English as a first language, our pronunciations were very different as there were Aussies and Kiwi's too. The teacher suggested we all sing our national anthems. There were four of us from England and I watch England football matches so that was no problem for me. I ended the anthem with a little slide along the floor that got the kids laughing. The Japanese girl was on her own, but as soon as she opened her mouth, the rest of us were left jaw dropped. She had an absolutely stunning voice. We then headed outside with the kids for their breaktime. They wanted to play the hokey cokey which seemed fine. But they didn't play it like we do. I should have known something was up when a lot of the boys ran over to me and another guy who was also quite well built. I didn't think anything of it until I realised the bigger you are, the further you can throw these kids. They literally wanted us to throw them whilst they fly kicked each other in the faces. Not one to disappoint, I picked up a few kids and threw them across the corridors like they were my own personal missiles. Pretty sure I had more fun than they did. Following our school visit we headed out to a factory that processes some of the rice. They still have a manual mill that I got to have a go on. To say its hard work is an absolute understatement, so after a while I decided to keep myself occupied by chasing some of the chickens instead. I've worked in a farm back home, and catching chickens is a lot easier than it sounds. After this we headed on a 20 minute ride to our next stop, a sewing factory. We were shown around by one of the ladies. The room was quite large, but covered in sewing machines, not too dissimilar to factories in the UK. They showed us some of the clothes that were produced and it was a wide range of goods, from jackets to purses. We were heading into the late afternoon now, and after a cold drink we hit the road once again. We rode another hour or so, slowly back to the village, through amazing, postcard like scenery. Most of the journey was on dirt road but there were parts where there was just no road at all. At times there were large gaps in the road so we had to get off our bikes and walk through fields to find the road again. We rode past locals working on their rice paddies, knee deep in irrigation, waving to us as we went past. At one point I had to just stop for a few minutes and really take in my surroundings. It all felt like a dream.
In the production of filter tow for use in making filter rods for the cigarette industry, the tow is laid in so-called “filling cans”. During this process, the filter tow is distributed in uniform layers over the cross-sectional area of the can by the movements of a laying unit, which moves alternately in the lengthwise and crosswise direction. As a result, a large number of layers are laid on top of each other until the filter tow package has reached the desired weight and height in the can. Package weights of several hundred kilograms are conventional in this area. A highly compressed bale and a process for the optimal filling of a can for the purpose of avoiding consequent processing problems is described in WO 02/32,238 A2. The content of the can which has been filled in this way is then compressed in the direction in which the layers were superimposed. After it has been compressed, the filter tow package is wrapped with packaging material while still inside the pressing device and therefore still under compressive stress. The pressing device is then opened completely, so that the filter tow package, now called the “bale”, is held together by the packaging material. Conventional packaging materials include cardboard, which is held mechanically together by strapping or by an adhesive, and synthetic fabric, which is closed by, for example, a Velcro fastening. An example of a glued package is described in German Utility Patent No. 76-35,849.1. Information on a filter tow package wrapped with synthetic fabric can be found in the company prospectus “Some Useful Information about the Reusable Packaging for Rhodia Filter Tow”, published by RHODIA Acetow GmbH, Engesserstrasse 8, D-79108 Freiburg. The two latter types of packaging require no additional strapping. The types of packaging described above which do not make use of any strapping suffer from the problem that, after the pressure on the bale has been released at the end of the pressing operation, the elastic restoring force of the compressed filter tow leads to a pressure on the packaging, this pressure being exerted primarily in the direction opposite that in which the bale was compressed. This leads to an increase in the volume of the package and thus to undesirable bulges at the top and bottom of the bale. If the measures described in WO 02/32,238 A2 are taken, these bulges do not interfere with the intended use of the filter tow, but they do prevent the filter tow packages from being stacked securely. This problem is solved in the state of the art either by stacking the bales on their sides or by the use of special pallets, such as those described in the Rhodia publication cited above. Problems associated with the bursting-open of the packages because of excessive internal pressure also occur frequently. A solution to the difficulties associated with strapping is described in U.S. Pat. No. 4,577,752. In cases where filter tow which has been packaged with straps is used as intended, the bulges are less of a problem than the constrictions, which cause the variations in puff resistance described in WO 02/32,238 A2. And even strapped bales can burst open. It is also standard practice in the packaging of filter tow to use liners between the filter tow and the above-mentioned mechanically supportive packaging materials. The liner protects the filter tow from contamination, especially from odor contamination, and from the diffusion of water vapor into and out of the package. The liner usually consists of three pieces, which are laid loosely inside the external packaging. The disadvantages of the transport packaging normally used today have already been discussed above in the description of the state of the art. It is especially the bulges at the top and bottom of the bales which interfere with transport of multiple layers. This problem has been solved in the past by transporting the bales not in their so-called working position but rather in a sideways storage position. Two additional work steps are required to do this, however; namely, the bale must be turned 90° before transport and then turned back into the working position after transport. The constrictions which are formed by strapping are also a source of trouble. Even when the bale is used as intended, these constrictions cause considerable variations in the puff resistance of the filter rods produced from the filter tow. More than 5% of the filter rods produced from a bale are affected by these variations. The greater the packing density of the bale, the greater the severity of these two problems. The problems occur as soon as the packing density exceeds 300 kg/m3.
Absolutely awesome in that it helps me with my menstral cramps. I was in agony for years and only had ibuprofen for relief. I still take ibuprofen for cramp relief now but much less and have NO pain left!(whereas it was just barely bearable with the tons of ibuprofen before). Added plus...the phyto-estrogen gives me a younger appearance and strengthens my immune system!
[Diverticulosis of the small intestine]. The authors describe a case of a patient who has reoperated for generalized peritonitis shortly after elective inguinal hernia repair. The cause of peritonitis was small bowel diverticulosis with a ruptured diverticulum.
I love it (07036, NJ, Union County) If you're hung and know how to use what you were given... If you're intelligent and turned on by a woman with a brain, a beautiful curvy size 8 body (natural tits & ass)... If you're able to host Monday morning and enjoy a mind boggling blow job (and I swallow) and are mature married dating able to recover quickly and pound a few out... You should reply to this post with a Picture asap. I'm looking to host a sexy discreet strip (07036, Linden, NJ) hey I'm looking to host a sexy discreet strip tease on this cold snowy day. we can Drink if u like. I wont to tease you until u cant take mature ladies anymore.you must be clean, 30& older, white to top of my list.wet your sweet potato, before thanksgiving
--- abstract: 'Monitoring with the Ryle Telescope at 15GHz of the Galactic X-ray transient source GRS1915+105 has revealed a remarkable range of rapid and extended flares which appear to be related to the X-ray emission as recorded by the [RXTE]{} all-sky monitor. Quasi-periodic oscillations in the range 20 – 40 min have been found and are probably related to oscillations in the soft X-ray flux.' author: - 'G. G. Pooley' - 'R. P. Fender' title: 'GRS1915+105: Flares, QPOs and other events at 15GHz' --- \\[poole\\] Introduction ============ The Galactic X-ray transient GRS1915+105 has proved to have a rich structure in its high- and low-energy X-ray emission. In the radio regime, it is no less remarkable: Mirabel & Rodríguez (1995) discovered a double-sided relativistic ejection for which they derive a velocity of 0.92$c$. The distance is estimated, from H[i]{} absorption measurements, to be 12.5 kpc. Radio monitoring had already shown the emission to be highly variable (Rodríguez et al. (1995), Foster et al. (1996)), and we started monitoring the source at 15 GHz in mid-1995. The observational details and further results are described by Pooley & Fender (1997). Results ======= Figure 1 shows the data for some 17 months. Individual observations lasted from less than 1 hour to about 6 hours. It can be seen that the variations are unpredictable and frequently very rapid; the flux density can increase from less than 1 mJy to 100 mJy and back in less than a day. The major flare event starting in 1996 July was characterised by relatively smooth variations during the first month or so; subsequently the source became highly variable and showed frequent examples of quasi-periodic variations. Quasi-periodic oscillations --------------------------- A characteristic form of the outbursts observed at 15 GHz is an event with a rise-time of less than 5 min, followed by a roughly exponential decay with time constant between 12 and 25 min. These may be isolated, they may recur with apparently random intervals, or they may repeat with some regularity; the QPOs seem to favour intervals near 25 and 40 minutes, although not exclusively so. Some examples are shown in Figure 2. Comparison with other wavebands ------------------------------- The pattern of radio emission is related in a rather complex way to that of the soft X-ray, as recorded by the [RXTE]{} all-sky monitor. Active (rapidly-varying) X-ray emission is usually, but not always, accompanied by radio emission. During the 1996 July radio flare, the X-ray emission was unusually constant. Obtaining simultaneous observations of the rapid QPO events is difficult, since they are very unpredictable, but we believe that these observations will be necessary for a better understanding of the source. Perhaps the most intriguing simultaneous observation is that on 1996 Oct 24, when the PCA on the [RXTE]{} satellite detected oscillations which appear, on the basis of only a few cycles, to be related in phase with the 15-GHz data. One observation with the VLBA at 8 GHz, on 1996 May 24, overlapped with a Ryle Telescope observation; the variations at 15 GHz appear about 4 minutes earlier than those at 8 GHz (Dhawan, , ). Fender et al. (1997) have observed outbursts in the infrared with time-scales and flux densities similar to those of the radio events. We do not yet have simultaneous IR and radio data for these flares. Fender, R. P. et al., 1997, submitted to Foster, R. S. et al., 1996, , [467]{}, L81–84. Mirabel, I. F. & Rodríguez, L. F., 1995, , [92]{} 11390–11392 Pooley, G. G. & Fender, R. P., 1997, submitted to Rodríguez, L. F. et al., 1995, , [101]{} 173–179
# List of Breaking Changes for 4.x
Q: MarionetteJS - Multiple nested side by side views I am looking at the example here http://davidsulc.github.io/backbone.marionette-nested-views/ it shows how you can create a list a superheroes and for each hero have an inner list of villains. How would one extend this to not only list villains for each hero, but also their top three favorite colors? for example. So I could have something like Batman ----------------------------------- Bane \| Black Ra's Al Ghul \| Blue The Joker \| Orange The Riddler \| =================================== Spiderman ----------------------------------- Green Goblin \| Red Venom \| Green \| Violet =================================== Wonder Woman ----------------------------------- Ares \| Silver Doctor Psycho \| Purple Silver Swan \| White =================================== In the composite view it is as if I need two sets of itemviews and itemcomtainers, something like HeroView = Backbone.Marionette.CompositeView.extend({ template: "#accordion-group-template", className: "accordion-group", itemView: VillainView, itemViewContainer: "#villainUL", itemView2: FavoriteColorView, itemViewContainer2: "#colorUL", ... But of course such a thing doesn't exist. Edit: this http://jsfiddle.net/derickbailey/AdWjU/ will probably serve as a solution, but I will have to wait until the morning to adapt it. A: First of all, hopefully you're aware of the blog post I wrote to go with the code: http://davidsulc.com/blog/2013/02/03/tutorial-nested-views-using-backbone-marionettes-compositeview/ Bad news: I think you'll actually need more work to achieve what you want... The jsFiddle you linked (http://jsfiddle.net/derickbailey/AdWjU/) displays a list of element that are sub-elements. What you want to do is display two separate lists! Here's what I'd try: you need to replace the VillainView (which is an ItemView) with a layout which we'll call HeroInfo, in this layout you need to declare 2 regions (one for the villain list, the other for the colors). This new layout also won't be rendered within a ul so you can remove the itemViewContainer from the view definition and the template. Note you might not be able to specify the layout regions as an object (you can't use ids in the template since they'll be repeated, and you might not yet have access to this.$el). If that's the case, you need to initialize them with something like this: initialize: function(){ // assuming you have an element with class "js-villain-region" in your layout template this.addRegion("villainRegion", this.$el.find(".js-villain-region").first()); } Next, you need to define a VillainView and a ColorView (both are collection views) to be displayed in the layout's regions on the "show" event (see example code using a layout here: https://github.com/davidsulc/marionette-gentle-introduction/blob/master/assets/js/apps/contacts/list/list_controller.js#L43 I hope this helps to set you on the right path! Also, as a side note: this seems to be more challenging than it looks at first glance. If you're doing this as a learning experience, don't get discouraged: you're attempting a challenging, complex view implementation, which will be tricky when first getting into Marionette.
I think it is Patton Oswald who has a bit about Bob Ross being a the ultimate sleeping pill. He's right, years ago I found a bunch of his DVDs at a garage sale, I digitized them and when I'm having trouble sleeping or I'm overly stressed out I put them on while I'm laying in bed. I rarely make it through one episode before I'm out.
Attached is the Additional list of GCP sign-offs on Clickpaper approval for 10-17-00 P.S. Counterparty is set up in GCP as "Bloch Lumber Company". Per counterparty Credit dept., D&B, and CP website, that is the correct name. From: Karen Lambert@ECT on 10/17/2000 02:31 PM To: Adnan Patel/Corp/Enron@ENRON, Samuel Schott/HOU/ECT@ECT cc: Mary G Gosnell/HOU/ECT@ECT Subject: Bloch Lumber amendmeny ---------------------- Forwarded by Karen Lambert/HOU/ECT on 10/17/2000 02:30 PM --------------------------- Walter Guidroz@ENRON 10/17/2000 12:17 PM To: Camille Gerard/Corp/Enron@ENRON, Tana Jones/HOU/ECT@ECT, Karen Lambert/HOU/ECT@ECT, Frank L Davis/HOU/ECT@ECT, Tom Moran/HOU/ECT@ECT cc: Subject: Bloch Lumber amendmeny Attached is an amendment to open Block Lumber Company, Inc. to trade both financial and physical. The original had them trading only within physical. Please call if you have any questions. Thanks. Walter
54 N.J. 151 (1969) 253 A.2d 814 CARDELL, INC., A CORPORATION OF THE STATE OF NEW JERSEY AND J. RICHARD HUDANICH, PLAINTIFFS-APPELLANTS, v. THE TOWNSHIP OF MADISON, A MUNICIPAL CORPORATION IN THE COUNTY OF MIDDLESEX, STATE OF NEW JERSEY, AND MANZO CONTRACTING CO., A CORPORATION OF THE STATE OF NEW JERSEY, DEFENDANTS-RESPONDENTS. The Supreme Court of New Jersey. Argued June 4, 1969. Decided June 6, 1969. *152 Mr. Stewart M. Hutt argued the cause for appellants (Messrs. Hutt and Berkow, attorneys). Mr. Marc J. Gordan and Mr. Mark L. Stanton argued the cause for respondents. PER CURIAM. The judgment is reversed for the reasons expressed in the dissenting opinion of Judge Labrecque in the Appellate Division. For reversal Chief Justice WEINTRAUB and Justices JACOBS, FRANCIS, PROCTOR, HALL, SCHETTINO and HANEMAN 7. For affirmance None.
Q: Typescript `Property is missing in type`, but the type is `never` What I want to achieve is to reference the original interface, and remove some attributes. This is my original interface: export interface IInvitations { parent: Parse.User; visitor: Visitors; dates: IInvitationDateAndPin[]; } When a user initiates the invitation, he should not give parent as a parameter. which will be auto-assigned before saving into the database. So I made a new interface to omit it: export interface ICInvitations extends IInvitations { parent: never; } But then I cannot successfully assign value to this interface. let data: ICInvitations = { visitor: Visitors, datas: [...] } It shows Property 'parent' is missing in type. But the type is never, which I failed to assign anything into it. A: As Jeff mentioned, while you can't remove the property from the interface, you can reuse most of it by doing something like this (Omit is shipped with TypeScript 3.5): export interface ICInvitations extends Omit<IInvitations, 'parent'> { parent?: never; } The parent?: never part is optional, but will let you get an error if anyone tries to construct something implementing this interface with a value set for parent.
The scintigraphic visualization of a lingual thyroid after excision of associated ectopic thyroid tissue. The scintigraphic findings in a 2-year-old boy with both a lingual thyroid and ectopic thyroid tissue in the neck are presented. One day following excision of the neck mass, no functioning thyroid tissue was seen. However, one month later, the lingual gland was well visualized. The possible reason for this is discussed.
Acetohydroxyacid synthase (AHAS) in vivo assay for screening imidazolinone-resistance in sunflower (Helianthus annuus L.). The objective of this work was to evaluate the in vivo acetohydroxyacid synthase (AHAS) activity response to imidazolinones and its possible use as a selection method for evaluating AHAS inhibitor resistance. In vivo AHAS assay and the comparison of parameters from dose-response curves have been used as a valid tool for comparing sunflower lines and hybrids differing in imidazolinone resistance. The sunflower resistant genotypes evaluated here were 100-fold and 20-fold more resistant compared with the susceptible line for imazethapyr and imazapyr, respectively. This assay also allowed discrimination of homozygous from heterozygous genotypes for I(mr1) locus that codify for the catalytic subunit of AHAS. The in vivo AHAS assay described in this study was useful for the selection of sunflower genotypes differing in herbicide resistance and could be a useful tool when breeding for imidazolinone resistance in sunflower.
package streamanalytics import ( "context" "fmt" "log" "time" "github.com/Azure/azure-sdk-for-go/services/streamanalytics/mgmt/2016-03-01/streamanalytics" "github.com/hashicorp/go-azure-helpers/response" "github.com/hashicorp/terraform-plugin-sdk/helper/schema" "github.com/hashicorp/terraform-plugin-sdk/helper/validation" "github.com/terraform-providers/terraform-provider-azurerm/azurerm/helpers/azure" "github.com/terraform-providers/terraform-provider-azurerm/azurerm/helpers/tf" "github.com/terraform-providers/terraform-provider-azurerm/azurerm/internal/clients" "github.com/terraform-providers/terraform-provider-azurerm/azurerm/internal/features" "github.com/terraform-providers/terraform-provider-azurerm/azurerm/internal/timeouts" "github.com/terraform-providers/terraform-provider-azurerm/azurerm/utils" ) func resourceArmStreamAnalyticsReferenceInputBlob() schema.Resource { return &schema.Resource{ Create: resourceArmStreamAnalyticsReferenceInputBlobCreate, Read: resourceArmStreamAnalyticsReferenceInputBlobRead, Update: resourceArmStreamAnalyticsReferenceInputBlobUpdate, Delete: resourceArmStreamAnalyticsReferenceInputBlobDelete, Importer: &schema.ResourceImporter{ State: schema.ImportStatePassthrough, }, Timeouts: &schema.ResourceTimeout{ Create: schema.DefaultTimeout(30 time.Minute), Read: schema.DefaultTimeout(5 * time.Minute), Update: schema.DefaultTimeout(30 * time.Minute), Delete: schema.DefaultTimeout(30 * time.Minute), }, Schema: map[string]schema.Schema{ "name": { Type: schema.TypeString, Required: true, ForceNew: true, ValidateFunc: validation.StringIsNotEmpty, }, "stream_analytics_job_name": { Type: schema.TypeString, Required: true, ForceNew: true, ValidateFunc: validation.StringIsNotEmpty, }, "resource_group_name": azure.SchemaResourceGroupName(), "date_format": { Type: schema.TypeString, Required: true, ValidateFunc: validation.StringIsNotEmpty, }, "path_pattern": { Type: schema.TypeString, Required: true, ValidateFunc: validation.StringIsNotEmpty, }, "storage_account_key": { Type: schema.TypeString, Required: true, Sensitive: true, ValidateFunc: validation.StringIsNotEmpty, }, "storage_account_name": { Type: schema.TypeString, Required: true, ValidateFunc: validation.StringIsNotEmpty, }, "storage_container_name": { Type: schema.TypeString, Required: true, ValidateFunc: validation.StringIsNotEmpty, }, "time_format": { Type: schema.TypeString, Required: true, ValidateFunc: validation.StringIsNotEmpty, }, "serialization": azure.SchemaStreamAnalyticsStreamInputSerialization(), }, } } func getBlobReferenceInputProps(ctx context.Context, d schema.ResourceData) (streamanalytics.Input, error) { name := d.Get("name").(string) containerName := d.Get("storage_container_name").(string) dateFormat := d.Get("date_format").(string) pathPattern := d.Get("path_pattern").(string) storageAccountKey := d.Get("storage_account_key").(string) storageAccountName := d.Get("storage_account_name").(string) timeFormat := d.Get("time_format").(string) serializationRaw := d.Get("serialization").([]interface{}) serialization, err := azure.ExpandStreamAnalyticsStreamInputSerialization(serializationRaw) if err != nil { return streamanalytics.Input{}, fmt.Errorf("Error expanding `serialization`: %+v", err) } props := streamanalytics.Input{ Name: utils.String(name), Properties: &streamanalytics.ReferenceInputProperties{ Type: streamanalytics.TypeReference, Datasource: &streamanalytics.BlobReferenceInputDataSource{ Type: streamanalytics.TypeBasicReferenceInputDataSourceTypeMicrosoftStorageBlob, BlobReferenceInputDataSourceProperties: &streamanalytics.BlobReferenceInputDataSourceProperties{ Container: utils.String(containerName), DateFormat: utils.String(dateFormat), PathPattern: utils.String(pathPattern), TimeFormat: utils.String(timeFormat), StorageAccounts: &[]streamanalytics.StorageAccount{ { AccountName: utils.String(storageAccountName), AccountKey: utils.String(storageAccountKey), }, }, }, }, Serialization: serialization, }, } return props, nil } func resourceArmStreamAnalyticsReferenceInputBlobCreate(d schema.ResourceData, meta interface{}) error { client := meta.(clients.Client).StreamAnalytics.InputsClient ctx, cancel := timeouts.ForCreateUpdate(meta.(clients.Client).StopContext, d) defer cancel() log.Printf("[INFO] preparing arguments for Azure Stream Analytics Reference Input Blob creation.") name := d.Get("name").(string) jobName := d.Get("stream_analytics_job_name").(string) resourceGroup := d.Get("resource_group_name").(string) if features.ShouldResourcesBeImported() && d.IsNewResource() { existing, err := client.Get(ctx, resourceGroup, jobName, name) if err != nil { if !utils.ResponseWasNotFound(existing.Response) { return fmt.Errorf("Error checking for presence of existing Stream Analytics Reference Input %q (Job %q / Resource Group %q): %s", name, jobName, resourceGroup, err) } } if existing.ID != nil && existing.ID != "" { return tf.ImportAsExistsError("azurerm_stream_analytics_reference_input_blob", existing.ID) } } props, err := getBlobReferenceInputProps(ctx, d) if err != nil { return fmt.Errorf("Error creating the input props for resource creation: %v", err) } if _, err := client.CreateOrReplace(ctx, props, resourceGroup, jobName, name, "", ""); err != nil { return fmt.Errorf("Error Creating Stream Analytics Reference Input Blob %q (Job %q / Resource Group %q): %+v", name, jobName, resourceGroup, err) } read, err := client.Get(ctx, resourceGroup, jobName, name) if err != nil { return fmt.Errorf("Error retrieving Stream Analytics Reference Input Blob %q (Job %q / Resource Group %q): %+v", name, jobName, resourceGroup, err) } if read.ID == nil { return fmt.Errorf("Cannot read ID of Stream Analytics Reference Input Blob %q (Job %q / Resource Group %q)", name, jobName, resourceGroup) } d.SetId(read.ID) return resourceArmStreamAnalyticsReferenceInputBlobRead(d, meta) } func resourceArmStreamAnalyticsReferenceInputBlobUpdate(d schema.ResourceData, meta interface{}) error { client := meta.(clients.Client).StreamAnalytics.InputsClient ctx, cancel := timeouts.ForCreateUpdate(meta.(clients.Client).StopContext, d) defer cancel() log.Printf("[INFO] preparing arguments for Azure Stream Analytics Reference Input Blob creation.") name := d.Get("name").(string) jobName := d.Get("stream_analytics_job_name").(string) resourceGroup := d.Get("resource_group_name").(string) props, err := getBlobReferenceInputProps(ctx, d) if err != nil { return fmt.Errorf("Error creating the input props for resource update: %v", err) } if _, err := client.Update(ctx, props, resourceGroup, jobName, name, ""); err != nil { return fmt.Errorf("Error Updating Stream Analytics Reference Input Blob %q (Job %q / Resource Group %q): %+v", name, jobName, resourceGroup, err) } return resourceArmStreamAnalyticsReferenceInputBlobRead(d, meta) } func resourceArmStreamAnalyticsReferenceInputBlobRead(d schema.ResourceData, meta interface{}) error { client := meta.(clients.Client).StreamAnalytics.InputsClient ctx, cancel := timeouts.ForCreateUpdate(meta.(clients.Client).StopContext, d) defer cancel() id, err := azure.ParseAzureResourceID(d.Id()) if err != nil { return err } resourceGroup := id.ResourceGroup jobName := id.Path["streamingjobs"] name := id.Path["inputs"] resp, err := client.Get(ctx, resourceGroup, jobName, name) if err != nil { if utils.ResponseWasNotFound(resp.Response) { log.Printf("[DEBUG] Reference Input Blob %q was not found in Stream Analytics Job %q / Resource Group %q - removing from state!", name, jobName, resourceGroup) d.SetId("") return nil } return fmt.Errorf("Error retrieving Reference Input Blob %q (Stream Analytics Job %q / Resource Group %q): %+v", name, jobName, resourceGroup, err) } d.Set("name", name) d.Set("resource_group_name", resourceGroup) d.Set("stream_analytics_job_name", jobName) if props := resp.Properties; props != nil { v, ok := props.AsReferenceInputProperties() if !ok { return fmt.Errorf("Error converting Reference Input Blob to a Reference Input: %+v", err) } blobInputDataSource, ok := v.Datasource.AsBlobReferenceInputDataSource() if !ok { return fmt.Errorf("Error converting Reference Input Blob to an Blob Stream Input: %+v", err) } d.Set("date_format", blobInputDataSource.DateFormat) d.Set("path_pattern", blobInputDataSource.PathPattern) d.Set("storage_container_name", blobInputDataSource.Container) d.Set("time_format", blobInputDataSource.TimeFormat) if accounts := blobInputDataSource.StorageAccounts; accounts != nil && len(accounts) > 0 { account := (accounts)[0] d.Set("storage_account_name", account.AccountName) } if err := d.Set("serialization", azure.FlattenStreamAnalyticsStreamInputSerialization(v.Serialization)); err != nil { return fmt.Errorf("Error setting `serialization`: %+v", err) } } return nil } func resourceArmStreamAnalyticsReferenceInputBlobDelete(d schema.ResourceData, meta interface{}) error { client := meta.(clients.Client).StreamAnalytics.InputsClient ctx, cancel := timeouts.ForCreateUpdate(meta.(*clients.Client).StopContext, d) defer cancel() id, err := azure.ParseAzureResourceID(d.Id()) if err != nil { return err } resourceGroup := id.ResourceGroup jobName := id.Path["streamingjobs"] name := id.Path["inputs"] if resp, err := client.Delete(ctx, resourceGroup, jobName, name); err != nil { if !response.WasNotFound(resp.Response) { return fmt.Errorf("Error deleting Reference Input Blob %q (Stream Analytics Job %q / Resource Group %q) %+v", name, jobName, resourceGroup, err) } } return nil }
Valkyrie Profile: Lenneth Arriving on Smartphones in Japan This SpringI am now convinced Square Enix has no desire to ever make me happy....03.09.18 - 9:34 PM Last week Square Enix released a teaser trailer and tweet about Valkyrie Profile: Lenneth. Enix fans from back in the day (yes, those pre-merger days) were thrilled at the prospect of reliving the odd classic again, especially if it was to be a re-release of the excellent PSP port. The world wide web went on to speculate about what platform Square might bring VP: Lenneth, but speculation is no longer needed: Valkyrie Profile: Lenneth will be coming to iOS and Android devices in Japan this Spring. Sorry... while writing that my vision turned to a dark crimson and I blanked out for about an hour. You can check out a teaser trailer for the newly announced port below: While I am being very unfair (for starters I just don't like playing any games on a phone or tablet), Square Enix hasn't had the best track record with their mobile versions of their classic back catalog. However their mobile ports of the original PlayStation Final Fantasy games have a slew of fans, so here is hoping this is at least a one-to-one of the 2006 PSP game with some of the convenience additions of previous Square Enix mobile ports.
----- Forwarded by Jeff Dasovich/NA/Enron on 02/02/2001 08:14 PM ----- Scott Govenar <sgovenar@govadv.com> 02/02/2001 01:46 PM To: Mike Day <MDay@GMSSR.com>, Sandra McCubbin <Sandra.McCubbin@enron.com>, Jeff Dasovich <jdasovic@enron.com> cc: Subject: Rate Freeze Edison has agreed to support Enron's legislative language regarding the rate freeze. I forwarded this information to Joe Lyons in Rod Wright's office.
The first is the 2018 AMG GT Roadster and the second is the more powerful GT C Roadster. Both come with a 4.0-liter twin-turbo V8 under the hood. The AMG GT is good for 469-horses and 465 pound-feet of torque. The AMG GT C Roadster bumps power up to 550-horses and 502 pound-feet of torque. 2018 Mercedes-AMG GT C Roadster 2018 Mercedes-AMG GT C Roadster The GT C’s rear end is also wider to fit the larger wheels and an active rear axle steering system carried over from the AMG GT R. Mercedes says it gives “significantly higher agility and increased driving pleasure with less steering input.” The GT C also features larger front brakes. There’s also an extra “RACE” mode for the seven-speed dual-clutch transmission for faster shifting. Both versions come with a fabric roof you can get in black, beige or red. It takes about 11 seconds to open or close it. And you can even do that going 30 mph. They also share front end styling and electronically controlled grille shutters. Keep them closed for better aerodynamics and open them for additional cooling. 2018 Mercedes-AMG GT C Roadster Inside the cabin you find typical Mercedes luxury. We’d definitely opt for the optional available AMG Performance seats. For the first time you can get them with a neck-level heating system and seat climate control. This is also the GT to buy if you’ve always wanted a light beige interior. It available on a GT for the first time. 2018 Mercedes-AMG GT Roadster Music lovers will love a newly designed subwoofer than transmits low notes throughout the entire car. It essentially uses the entire interior space as a bass box. The two 2018 AMG GT Roadsters are a year out. They’ll arrive next fall for a triple-digit pretty penny.
Q: 一文で書くfor loopとジェネレーターについてこのようにfor loopを1文で書けると思います。 l = [i for i in range(5)] # 結果　[0, 1, 2, 3, 4] あとは、このようにもできると思います。 x = '\\n'.join(" "i + "I" for i in range(n)) print(x) #　結果 # I # I # I # I 一番最初のものでlistではなくて、printを連続で行うような処理をしようとしたのですが、プリントできません。 print(i for i in range(5)) # 結果　<generator object <genexpr> at 0x000002A167A4C048> なぜ、joinはうまくできているのにprintはできないのでしょうか？ A: print() の場合は以下のようにします。 print((i for i in range(5))) 0 1 2 3 4 print() は渡されたオブジェクトをそのまま表示するのがその機能なので値を表示したければ値を渡さなければなりません。 print(i for i in range(5)) だと (i for i in range(5)) というジェネレータが渡されたことを意味します。アスタリスクを付けて *(i for i in range(5)) とすると、ジェネレータをアンパックします(評価した値を渡します)。
Treatment of Adults with Idiopathic Recurrent Pericarditis: Novel Use of Immunotherapy. Idiopathic recurrent pericarditis (IRP) can be challenging to treat. Even after guideline-directed first-line treatment consisting of aspirin (ASA) or a nonsteroidal antiinflammatory drug (NSAID) in combination with colchicine therapy, recurrences still occur in greater than 20% of patients. Many patients then require treatment with long-term corticosteroids, which is not a favorable option due to their short- and long-term adverse effects. Because it is theorized that the pathophysiology of IRP may possess autoimmune sequelae, the use of immunotherapy for the treatment of IRP has emerged. In this review, we describe the literature associated with immunotherapy used to treat IRP in an adult population as well as provide an overview of the safety and monitoring parameters for each agent. The most common immunotherapies used after patients have had multiple recurrences of IRP are anakinra, intravenous immunoglobulin (IVIG), and azathioprine. In most cases, these immunotherapies are adjunctive therapy, with the goal of tapering and discontinuing immunosuppressive corticosteroids. After reviewing the data, anakinra resulted in more patients discontinuing corticosteroids and prevented further recurrences of pericarditis. IVIG resulted in symptom resolution and no further recurrences in most of the patients. Azathioprine was associated with more than half of patients becoming recurrence free; however, many patients required a restart of corticosteroids due to recurrence. Clinicians should be aware of the adverse effects of immunotherapy, ranging from mild gastrointestinal events to risk of infection and serious blood dyscrasias that may require diligent monitoring. The use of immunotherapy for the treatment of adults with IRP should be restricted to patients who have multiple recurrences. Ideally, immunotherapy would be adjunctive to first-line combination therapy with ASA/NSAID plus colchicine, with the goal of tapering and discontinuing immunosuppressive corticosteroids. Furthermore, clinicians should consider cost, drug-drug and drug-disease interactions, and safety, as well as the quality of the retrospective evidence before considering any immunotherapy.
1. Introduction {#sec1-ijerph-16-01149} =============== The rapid development of China's economy in recent decades has caused serious environmental pollution, among which atmospheric pollution is particularly serious \\[[@B1-ijerph-16-01149],[@B2-ijerph-16-01149]\\]. The frequent haze weather across the country has seriously affected the urban environment \\[[@B3-ijerph-16-01149],[@B4-ijerph-16-01149]\\] and the physical and mental health of residents \\[[@B5-ijerph-16-01149],[@B6-ijerph-16-01149],[@B7-ijerph-16-01149]\\]. The main pollutant forming haze weather is fine particulate matter with a diameter of less than 2.5 μm (PM~2.5~). PM~2.5~ can reduce visibility. It is harmful to people's life, especially in health effects \\[[@B8-ijerph-16-01149],[@B9-ijerph-16-01149]\\], so PM~2.5~ pollution has become a research hotspot. The previous studies mainly involved two aspects, namely micro aspects and macro aspects. The micro aspects focus mainly on chemical components \\[[@B10-ijerph-16-01149],[@B11-ijerph-16-01149],[@B12-ijerph-16-01149]\\] and physical and mental health effects of PM~2.5~ \\[[@B13-ijerph-16-01149],[@B14-ijerph-16-01149],[@B15-ijerph-16-01149],[@B16-ijerph-16-01149]\\], etc. The macro aspects focus mainly on the influencing factors \\[[@B17-ijerph-16-01149],[@B18-ijerph-16-01149]\\], spatiotemporal variations and distribution about PM~2.5~ \\[[@B19-ijerph-16-01149],[@B20-ijerph-16-01149]\\], etc. Simultaneously, PM~2.5~ pollution has also hampered economic development \\[[@B21-ijerph-16-01149]\\]. Hence, a clear understanding of the PM~2.5~ pollution problem benefits from the research on the spatial relationships between PM~2.5~ and social economy, which can be assisted in adopting more effective methods to improve air quality. China's economy has entered a period of rapid development and various industries have witnessed rapid development since the "reform and opening up". Meanwhile, many pollution sources have been increased \\[[@B22-ijerph-16-01149],[@B23-ijerph-16-01149]\\]. Some human activities \\[[@B24-ijerph-16-01149]\\], such as industrial emissions, motor vehicle emissions, coal burning \\[[@B25-ijerph-16-01149]\\], fossil fuel burning and outdoor biomass burning and so on \\[[@B26-ijerph-16-01149],[@B27-ijerph-16-01149]\\], produced emissions of elemental carbon (EC), organic mass (OM), inorganic ions, metal elements and secondary aerosol precursors \\[[@B28-ijerph-16-01149]\\], resulting in increased PM~2.5~ concentration. So, reducing these human activities may be important for controlling China's PM~2.5~ levels, which in turn reduced the impact on the environment, economy and health caused by PM~2.5~ pollution \\[[@B29-ijerph-16-01149]\\]. Some socioeconomic factors can be used to reflect PM~2.5~ pollution and control pollution sources. For example, more energy consumption and emissions could be caused by higher population density \\[[@B30-ijerph-16-01149]\\], and motor vehicle exhaust (CO, NO, and SO~2~) also results in increased PM~2.5~ \\[[@B31-ijerph-16-01149]\\]. In this paper, four controllable socioeconomic factors are selected to quantify the relationships between socioeconomic development and PM~2.5~, namely GDP per capita, industrial added values, urban population density and private car ownership \\[[@B17-ijerph-16-01149],[@B18-ijerph-16-01149],[@B32-ijerph-16-01149]\\]. However, the imbalance of urbanization and economic development in China, in addition the influence of other natural factors, had resulted in spatial heterogeneity of PM~2.5~ pollution \\[[@B33-ijerph-16-01149],[@B34-ijerph-16-01149]\\]. Therefore, some scholars put forward policy suggestions that were appropriate to local conditions for reducing the emission of PM~2.5~ in different regions \\[[@B35-ijerph-16-01149]\\]. Some scholars pointed out that the influence of economic urbanization and coal consumption on PM~2.5~ concentration were greater than population urbanization \\[[@B36-ijerph-16-01149]\\]. In China, the relationships between PM~2.5~ concentration and economic development shows an environmental Kuznets curve (EKC) of inverted U-shape \\[[@B37-ijerph-16-01149]\\]. Industrial atmospheric pollutants, the proportion of primary and secondary industry to GDP, population density and meteorological condition had great contributed to PM~2.5~ concentration \\[[@B20-ijerph-16-01149],[@B38-ijerph-16-01149]\\]. PM~2.5~ of Asian and African countries had a significantly positive correlation with urbanization \\[[@B39-ijerph-16-01149]\\]. Although the relationship between PM~2.5~ and socioeconomic factors was investigated in many literatures, few literatures analyzed the spatial correlation between PM~2.5~ and socioeconomic factors by bivariate spatial correlation analysis method, especially from the perspective of long time series. The spatio-temporal variations of PM~2.5~ concentration and socioeconomic factors, their traditional statistical relationships, spatial statistical relationships and spatial spillover effect of PM~2.5~ concentration were examined in this research using the multisource data of 31 provinces in China from 1998 to 2016. The findings in this study will contribute to a thorough understanding of the spatial relationships between PM~2.5~ concentration and socioeconomic factors in China, and will provide auxiliary decision support for urban sustainability and policy efficiency. 2. Materials and Methods {#sec2-ijerph-16-01149} ======================== 2.1. Data {#sec2dot1-ijerph-16-01149} --------- At the website of Dalhousie University, the global surface PM~2.5~ concentration dataset that was estimated by GEOS-Chem chemical transport model combined with the aerosol optical depth (AOD) were provided by the Atmospheric Composition Analysis Group (<http://fizz.phys.dal.ca/~atmos/martin/?page_id=140>). The NASA MODIS, MISR, and SeaWIFS satellite instruments were used to retrieve the AOD. The global surface PM~2.5~ concentration dataset was calibrated based on global ground PM~2.5~ observations using geographically weighted regression (GWR) \\[[@B40-ijerph-16-01149],[@B41-ijerph-16-01149]\\]. The annual average PM~2.5~ data in 31 provinces of China at a resolution of 0.1° × 0.1° from 1998 to 2016 in this study were extracted from this dataset by ARCGIS10.3 software (ESRI Inc., Redlands, CA, USA). The socioeconomic data were obtained from the National Bureau of Statistics of the People's Republic of China (<http://data.stats.gov.cn/>). In this study, four major socioeconomic factors were collected in 31 provinces of Mainland China during 1998--2016, namely GDP per capita (GDPP), industrial added values (IVA), urban population density (UPD) and private car ownership (PCO). In order to eliminate the influence of dimension, z-scores were used to standard all factors and variables. 2.2. Methods {#sec2dot2-ijerph-16-01149} ------------ Five methods were used in this paper, namely unary linear regression model, Spearman's rank correlation analysis, univariate spatial autocorrelation, bivariate spatial correlation analysis and spatial regression analysis. The main methods were analyzed in detail below. ### 2.2.1. Unary Linear Regression Model {#sec2dot2dot1-ijerph-16-01149} In order to analyze the temporal trend, the slope of socioeconomic factors and PM~2.5~ concentration were calculated by using unary linear regression model. The slope is expressed as:$$Slope = \\frac{\\sum\\limits_{t = 1}^{T}{t \\cdot Y_{t} - \\frac{1}{T}\\left( {\\sum\\limits_{t = 1}^{T}t} \\right)\\left( {\\sum\\limits_{t = 1}^{T}Y_{t}} \\right)}}{\\sum\\limits_{t = 1}^{T}{t^{2} - \\frac{1}{T}\\left( {\\sum\\limits_{t = 1}^{T}t} \\right)^{2}}},$$ where slope is the trend gradient, $Y_{t}$ denotes the variable (PM~2.5~ concentration or GDPP or IVA or UPD or PCO) in the t-th year, $T$ is the study period of 1998--2016. A positive (negative) slope means that the variable increases (decreases) over the years. The greater the absolute value of the slope, the faster the increase or decrease of speed. ### 2.2.2. The Univariate Spatial Autocorrelation Analysis {#sec2dot2dot2-ijerph-16-01149} Moran's I, as the most commonly used indicator of global spatial autocorrelation, was initially suggested by Moran \\[[@B42-ijerph-16-01149]\\]. In essence, it represents the cross product statistics of a variable and its spatial lag. The degree to which the feature values of a position are similar or different from those of its spatial neighbors is measured by spatial autocorrelation. The global spatial association of PM~2.5~ concentration across China was explored by global Moran's I in this paper. To explore the local spatial association (spatial clustering or spatial dispersion) in adjacent provinces, we chose a local indicator of spatial association (LISA) \\[[@B43-ijerph-16-01149]\\] as the analysis method. The global Moran's I and local Moran's I are calculated by:$$I = \\frac{n}{\\sum\\limits_{i = 1}^{n}{\\sum\\limits_{j = 1}^{n}w_{ij}}}\\frac{\\sum\\limits_{i = 1}^{n}{\\sum\\limits_{j = 1}^{n}{w_{ij}\\left( {x_{i} - \\overline{x}} \\right)\\left( {x_{j} - \\overline{x}} \\right)}}}{\\sum\\limits_{i = 1}^{n}\\left( {x_{i} - \\overline{x}} \\right)^{2}}$$ $$I_{i} = \\frac{x_{i} - \\overline{x}}{\\sigma^{2}}{\\sum\\limits_{j = 1}^{n}w_{ij}}\\left( \\frac{x_{j} - \\overline{x}}{\\sigma} \\right),$$ where $I$ stands for global Moran's I for the whole study region, $I_{i}$ is the Moran's I for province i, $x_{i}$ donates PM~2.5~ concentration at province i, $x_{j}$ donates PM~2.5~ concentration at all the other provinces (where $$j \\neq i$$). Also, $\\overline{x}$ is the mean PM~2.5~ concentration of 31 provinces in China, $n$ represents the total number of provinces. $\\sigma$ is the standard deviation of the PM~2.5~ concentration of 31 provinces. $w_{ij}$ is the spatial weight matrix, representing province $i$ is adjacent to province $j$, neighboring provinces were 1 and non-adjacent provinces were 0. The values of $I$ or $I_{i}$ ranged from −1 to 1. A positive (negative) $I$ or $I_{i}$ value indicates positive (negative) spatial autocorrelation in the provinces. Positive autocorrelation indicates that provinces with similar PM~2.5~ concentration are closely distributed in space, whereas negative spatial autocorrelation indicates that PM~2.5~ concentration of neighboring provinces are dissimilar. A zero $I$ or $I_{i}$ value indicates a random spatial pattern. The size of the absolute value of $I$ or $I_{i}$ can reflect the strength of the spatial correlation. ### 2.2.3. The Bivariate Spatial Correlation Analysis {#sec2dot2dot3-ijerph-16-01149} The spatial correlation between PM~2.5~ and socioeconomic factors were examined by global bivariate Moran's I and local bivariate Moran's I. Global bivariate Moran's I reflects the global spatial associations between PM~2.5~ and another variable (GDPP, IVA, UPD or PCO) across the whole region, whereas local bivariate Moran's I explores the local spatial correlations within different provinces \\[[@B44-ijerph-16-01149],[@B45-ijerph-16-01149],[@B46-ijerph-16-01149]\\]. Global bivariate Moran's I and local bivariate Moran's I are given by:$$I_{xy} = \\frac{n{\\sum\\limits_{i = 1}^{n}{\\sum\\limits_{j \\neq i}^{n}{w_{ij}Z_{i}^{x}Z_{j}^{y}}}}}{\\left( {n - 1} \\right){\\sum\\limits_{i = 1}^{n}{\\sum\\limits_{j \\neq i}^{n}w_{ij}}}}$$ $$I_{xy}^{i} = Z_{i}^{x}{\\sum\\limits_{j = 1,j \\neq i}^{n}w_{ij}}Z_{j}^{y},$$ where $I_{xy}$ is the global bivariate Moran's I, and $I_{xy}^{i}$ is the local bivariate Moran's I in province $i$. $n$ is the total number of provinces, and $w_{ij}$ is the queen contiguity weight matrix. $Z_{i}^{x}$ is the standardized z-scores of PM~2.5~ concentration in the i-th province, $Z_{j}^{y}$ is the standardized z-scores of socioeconomic factors (GDPP, IVA, UPD or PCO) in the j-th province. The values of $I_{xy}$ or $I_{xy}^{i}$ is in the range \\[−1,1\\]. The values of $I_{xy}$ or $I_{xy}^{i}$ greater than 0, less than 0, equal to 0 indicate positive spatial correlation, negative spatial correlation, or no correlation between PM~2.5~ concentration and socioeconomic factors, respectively. The size of the absolute value of $I_{xy}$ or $I_{xy}^{i}$ can reflect the strength of the spatial correlation. ### 2.2.4. The Spatial Regression Model {#sec2dot2dot4-ijerph-16-01149} Spatial lag model (SLM) and spatial error model (SEM) were based on the ordinary least squares (OLS) \\[[@B47-ijerph-16-01149],[@B48-ijerph-16-01149]\\]. SLM can be used to explore whether PM~2.5~ concentration diffuses in one province, whereas SEM can be used to interpret the dependence of spatial error \\[[@B44-ijerph-16-01149]\\]. The SLM and SEM can be defined as follows:$$Y_{it} = \\alpha + \\rho wY_{it} + \\beta_{1}x_{GDPP} + \\beta_{2}x_{IVA} + \\beta_{3}x_{UPD} + \\beta_{4}x_{PCO} + \\varepsilon$$ $$Y_{it} = \\alpha + \\beta_{1}x_{GDPP} + \\beta_{2}x_{IVA} + \\beta_{3}x_{UPD} + \\beta_{4}x_{PCO} + \\lambda w_{\\mu} + \\varepsilon,$$ where $Y_{it}$ denotes PM~2.5~ concentration in province $i$ in the t-th year, $\\alpha$ represents a constant term. $\\beta_{1}$, $\\beta_{2}$, $\\beta_{3}$, and $\\beta_{4}$ are the parameters to reveal the correlations between PM~2.5~ and GDPP, IVA, UPD, and PCO, respectively. $wY_{it}$ is a spatial lag-dependent variable vector, it reflects the endogenous interaction effects among $Y_{it}$, $\\rho$ is a spatial regression coefficient that denotes the spatial dependence of the sample observations. $w_{\\mu}$ reflects the interaction effects among the disturbance term of different provinces. The spatial autoregressive coefficient $\\lambda$ denotes the spatial dependence of the residuals; $\\varepsilon$ is the random error term, $\\mu$ represents the spatially autoregressive error terms. In order to determine whether SLM or SEM is more suitable for the simulation of PM~2.5~, a Lagrange multiplier (LM) test and robust Lagrange multiplier (RLM) test should be estimated by the OLS. Anselin et al. proposed the criterion that if SLM-LM and SEM-LM are not significant, the OLS model was selected as the final model. If SLM-LM is significant and SEM-LM is not significant, SLM will be selected, and vice versa for SEM; if both SLM-LM and SEM-LM are insignificant, SLM-RLM is significant but SEM-RLM is not significant, SLM will be selected; if both SLM-LM and SEM-LM are insignificant, SEM-RLM is significant but SLM-RLM is not significant, SEM will be selected \\[[@B46-ijerph-16-01149]\\]. The univariate spatial autocorrelation analysis, the bivariate spatial correlation analysis and the spatial regression analysis were conducted in GeoDa software (GeoDa Press LLC, Chicago, IL, USA), and we chose queen contiguity weight matrix in GeoDa software. 3. Results {#sec3-ijerph-16-01149} ========== 3.1. The Spatial Distribution of Socioeconomic Factors and PM~2.5~ in China {#sec3dot1-ijerph-16-01149} --------------------------------------------------------------------------- From [Figure 1](#ijerph-16-01149-f001){ref-type="fig"}, 31 provinces in China were classified and mapped according to the values of PM~2.5~ and socioeconomic factors. From [Figure 1](#ijerph-16-01149-f001){ref-type="fig"}a, it could be found that PM~2.5~ concentration only in Tibet met the WHO Air Quality Guideline (AQG) level (10 μg/m^3^) in 1998. PM~2.5~ concentration in most provinces were observed between 10 μg/m^3^ and 35 μg/m^3^. Furthermore, PM~2.5~ concentration in some provinces, such as Tianjin, Anhui, Shandong, Gansu, Ningxia, and Xinjiang, were found to be higher than 35 μg/m^3^. From [Figure 1](#ijerph-16-01149-f001){ref-type="fig"}b, in 2016, obvious changes mainly occurred in some provinces of China. For example, PM~2.5~ concentration increased obviously (\\>35 μg/m^3^) in Liaoning, Beijing Hebei, Jiangsu, Shanghai and Henan; however, PM~2.5~ concentrations in Gansu and Ningxia were found to have fallen below 35 μg/m^3^. The distributions of socioeconomic factors were similar to the distribution of PM~2.5~ both in 1998 and 2016 generally. From [Figure 1](#ijerph-16-01149-f001){ref-type="fig"}c,d, provinces with GDPP below 10,000 yuan accounted for more than 80% in 1998. Obviously, GDPP in all provinces was higher than 10,000 yuan in 2016, some of which had a GDPP of more than 100,000 yuan, such as Shanghai, Beijing and Tianjin. [Figure 1](#ijerph-16-01149-f001){ref-type="fig"}e,f show that IVA increased rapidly in most provinces of China, especially in North China, East China, Central China and Northeast China. The UPD exceeded 2000 person/per square kilometer only in Shanghai, Jiangsu, Beijing and Qinghai in 1998 ([Figure 1](#ijerph-16-01149-f001){ref-type="fig"}g). In 2016, the UPD in most provinces was higher than 2000 person/per square kilometer, and some provinces even exceeded 3000 person/per square kilometer ([Figure 1](#ijerph-16-01149-f001){ref-type="fig"}h). From [Figure 1](#ijerph-16-01149-f001){ref-type="fig"}i,j, we could find that PCO in Mainland China was less than 1 million in 1998. PCO in 31 provinces was more than 1 million, except Tibet and Qinghai in 2016. 3.2. The Temporal Variation of Socioeconomic Factors and PM~2.5~ {#sec3dot2-ijerph-16-01149} ---------------------------------------------------------------- ### 3.2.1. The Temporal Variation of Socioeconomic Factors and PM~2.5~ in China {#sec3dot2dot1-ijerph-16-01149} Annual data on socioeconomic factors and PM~2.5~ concentration in 1998 and 2016 were counted in [Table 1](#ijerph-16-01149-t001){ref-type="table"}, and [Table 2](#ijerph-16-01149-t002){ref-type="table"} showed the temporal variation trend (the fitted slope) of 1998--2016. In 1998, PM~2.5~, GDPP, IVA, UPD and PCO in Mainland China were 23.97 μg/m^3^, 6860 yuan/person, 3413.49 billion, 459 person/per square kilometer and 4.24 million private cars, respectively; and reached to 29.68 μg/m^3^, 53,935 yuan/person, 24787.78 billion, 2408 person/per square kilometer and 163.3 million private cars in 2016, respectively. The fitted slope of PM~2.5~, GDPP, IVA, UPD and PCO in Mainland China were 0.138, 0.173, 0.174, 0.164 and 0.165, respectively. These indicated that GDPP, IVA, UPD, PCO and PM~2.5~ generally increased from 1998 to 2016, but the increased trend of IVA, GDPP, PCO and UPD was faster than the increased trend of PM~2.5~. [Figure 2](#ijerph-16-01149-f002){ref-type="fig"} showed their temporal variations intuitively. It could be found that GDPP, IVA, UPD and PCO in Mainland China showed an increase trend gradually in 1998--2016. The PM~2.5~ concentration also increased generally but began to fluctuate sharply from 2010. It indicated that the increasing trend of PM~2.5~ concentration was similar to that of GDPP, IVA, UPD and PCO in 1998--2016, and this increasing trend was significant, especially before 2006. ### 3.2.2. The Temporal Variation of Socioeconomic Factors and PM~2.5~ in the Seven Geographical Subareas {#sec3dot2dot2-ijerph-16-01149} The seven regions of China are showed in [Figure 3](#ijerph-16-01149-f003){ref-type="fig"}. From [Table 1](#ijerph-16-01149-t001){ref-type="table"}, in 1998, the GDPP and UPD in East China and North China, the IVA in East China, and the PCO in North China and Central China were far higher than other geographical subareas. The GDPP, IVA, UPD, and PCO in Northwest China were relatively lower. However, Northwest China had the highest PM~2.5~ concentration (35.26 μg/m^3^). In 2016, compared with other regions, GDPP in East China and North China, and IVA in East China were still relatively higher. Notably, East China had the most private cars. Central China was the most densely populated. North China became the region with the highest PM~2.5~ concentration, followed by East China. To better analyze the variation of PM~2.5~ (GDPP, IVA, UPD or PCO) in seven sub-regions, this slopegraph in [Figure 4](#ijerph-16-01149-f004){ref-type="fig"} can be used to show the increases/decreases between just two fixed points (1998 and 2016) for different factors. Most importantly, slopegraph focused on the overall macro change between two periods points, not changes in each year or intervening period. Slopegraph is a great visualization method for focusing on that aspect of the macro change. From [Table 2](#ijerph-16-01149-t002){ref-type="table"} and [Figure 4](#ijerph-16-01149-f004){ref-type="fig"}, it could be found that PM~2.5~ concentration in subareas except Northwest China and Southwest China presented an obviously increasing trend, and PM~2.5~ concentration in Southwest China increased slowly over the years. However, PM~2.5~ concentration in Northwest China presented a descending trend. Some literatures suggested that sand and dust was the major cause of affecting PM~2.5~ concentration in Northwest China \\[[@B38-ijerph-16-01149]\\]. The possible reason on the minus slope (−0.015) for PM~2.5~ in Northwest China may be an increase in vegetation coverage \\[[@B49-ijerph-16-01149]\\], and the decrease of dust events in Northern China in recent decades. The reduction of the wind speed in the northern hemisphere was the main reason for the decrease of dust event incidence \\[[@B50-ijerph-16-01149]\\]. The socioeconomic factors in the seven geographical subareas all presented an increasing trend, likely leading to the increase of PM~2.5~ concentration between 1998 and 2016. ### 3.2.3. The Spatial Distribution of Temporal Trends for Socioeconomic Factors and PM~2.5~ in Different Provinces {#sec3dot2dot3-ijerph-16-01149} The slope values of different provinces were mapped in [Figure 5](#ijerph-16-01149-f005){ref-type="fig"}. From [Figure 5](#ijerph-16-01149-f005){ref-type="fig"}a, it could be found that PM~2.5~ in most provinces of China increased rapidly. The provinces with a slower growth in PM~2.5~ were mainly distributed in Inner Mongolia, Sichuan, Chongqing, Guizhou and Yunnan. On the contrary, PM~2.5~ of Gansu, Ningxia, and Shaanxi presented showed a downward trend. From [Figure 5](#ijerph-16-01149-f005){ref-type="fig"}b--e, we can see that the fitted slopes of GDPP, IVA and PCO in different provinces were all more than 0.155, indicating that the increased trends of GDPP, IVA and PCO were rapid in provinces in 1998--2016. UPD increased rapidly in most provinces except Beijing, Ningxia, Jiangsu and Hainan, and the fitted slope of UPD only in Beijing was negative, this may be because of Beijing's population control policies. 3.3. The Traditional Statistical Relationship between Socioeconomic Factors and PM~2.5~ {#sec3dot3-ijerph-16-01149} --------------------------------------------------------------------------------------- ### 3.3.1. The Correlation between Socioeconomic Factors and PM~2.5~ in Mainland China {#sec3dot3dot1-ijerph-16-01149} The Spearman's rank correlation coefficients (r-GDPP, r-IVA, r-UPD and r-PCO) between PM~2.5~ concentration and GDPP, IVA, UPD, and PCO in Mainland China in 1998--2016 were shown in [Figure 6](#ijerph-16-01149-f006){ref-type="fig"}. Most of the correlation coefficients in [Figure 6](#ijerph-16-01149-f006){ref-type="fig"} were positive, indicating that PM~2.5~ was positively correlated with socioeconomic factors. From [Figure 6](#ijerph-16-01149-f006){ref-type="fig"}a,b, the values of r-GDPP and r-IVA presented positive increasing trends in 1998--2003 and fluctuated around 0.4 in 2004--2016, with most of the p-values less than 0.05, indicating that PM~2.5~ and GDPP and IVA were significantly positively correlated during the most study years; and the correlations strengthened in 1998--2003, then appeared fluctuations in 2004--2016. From [Figure 6](#ijerph-16-01149-f006){ref-type="fig"}c,d, most of the correlation coefficients were positive except for a few years. All the p-values were higher than 0.05, indicating that PM~2.5~ had a positively correlation with UPD and PCO in most years, but the correlations were not significant during the research period. The weak correlation between PM~2.5~ and PCO increased obviously before 2003. However, the correlation coefficients between PM~2.5~ and UPD presented a downward trend since 2001, indicating that the impact of UPD on PM~2.5~ was getting weaker and weaker. ### 3.3.2. The Relationship between Socioeconomic Factors and PM~2.5~ in Provinces {#sec3dot3dot2-ijerph-16-01149} In the [Figure 7](#ijerph-16-01149-f007){ref-type="fig"}, dark green represents a significant negative correlation, light green is a negative correlation, dark yellow means a significant positive correlation, and pale yellow represents a positive correlation. From [Figure 7](#ijerph-16-01149-f007){ref-type="fig"}, PM~2.5~ in most provinces of Northeast China, North China, Central China, East China and South China showed a significantly positive correlation with GDPP, IVA, and PCO. But PM~2.5~ only in Ningxia was significantly negatively correlated with GDPP, IVA, and PCO. Most provinces of Northeast China, North China, Central China and East China showed significantly positive correlations between PM~2.5~ and UPD. However, PM~2.5~ had a negative correlation with UPD in Beijing, Gansu and Ningxia. Especially in Beijing, PM~2.5~ was significantly negative correlated with UPD. These indicated that socioeconomic factors have contributed to the increased PM~2.5~ in most provinces. But the impacts of GDPP, IVA, and PCO on PM~2.5~ in Shaanxi, Gansu and Ningxia were negative; and PM~2.5~ of Gansu, Ningxia and Beijing were affected negatively by UPD. All of these illustrate the existence of spatial heterogeneity. ### 3.3.3. The Relationship between Socioeconomic Factors and PM~2.5~ in the Geographical Subareas {#sec3dot3dot3-ijerph-16-01149} From [Figure 8](#ijerph-16-01149-f008){ref-type="fig"}, a highly significant (p \\< 0.01) positive correlation between socioeconomic factors and PM~2.5~ was observed in North China, Northeast China and East China, indicating that GDPP, IVA, UPD and PCO played a vital role in North China, Northeast China and East China. In North China, the impact of UPD on PM~2.5~ was relatively low. GDPP and PCO had a stronger effect on PM~2.5~ in Northeast China. Four socioeconomic factors had similar effects on PM~2.5~ in East China. UPD in South China had a slightly greater impact on PM~2.5~. In Central China, UPD was the major effect factor on PM~2.5~. UPD in Southwest China was the most important factor for PM~2.5~. Whether positive correlation or negative correlation, PM~2.5~ in Northwest China had no significant correlations with four influencing factors. This meant that the trend of PM~2.5~ concentration was less affected by those human activities. This was consistent with anthropogenic effects on the dust loading in East China was far higher than near desert source regions in Northwest China \\[[@B50-ijerph-16-01149]\\]. There were other factors which determines the PM~2.5~ trend in Northwest China, PM~2.5~ in Northwest China was mainly affected by sand and dust \\[[@B38-ijerph-16-01149]\\]. Previous studies have shown a positive correlation between air temperature and PM~2.5~ concentration in summer in Northwest China \\[[@B51-ijerph-16-01149]\\]. 3.4. The Spatial Statistical Relationship between Socioeconomic Factors and PM~2.5~ {#sec3dot4-ijerph-16-01149} ----------------------------------------------------------------------------------- ### 3.4.1. Global Spatial Autocorrelation of PM~2.5~ {#sec3dot4dot1-ijerph-16-01149} From [Figure 9](#ijerph-16-01149-f009){ref-type="fig"}, the global Moran's I values of PM~2.5~ were positive at the 95% confidence level and increased over time, but fluctuated around 0.5 since 2003, indicating that PM~2.5~ exibited significantly positive spatial autocorrelation and spatial homogeneous, and spatial autocorrelation of PM~2.5~ in 31 provinces of China strengthened gradually. In other words, PM~2.5~ at one province tended to be similar to those of their neighboring provinces, the spatial spillover effect had been increasing in different provinces. In order to identify the provinces with significant spatial correlation and type of spatial clusters of PM~2.5~, LISA was calculated and mapped in [Figure 10](#ijerph-16-01149-f010){ref-type="fig"}. High--high (HH) clusters means that PM~2.5~ concentration of one province and its neighbors were higher than the annual average PM~2.5~ concentration in Mainland China. While, low--low (LL) clusters refers to the provinces with low PM~2.5~ concentration being surrounded by neighbors with low PM~2.5~ concentration, whose value is lower than the annual average values. High--low (HL) outliers means that high PM~2.5~ concentration had low PM~2.5~ concentration in the neighboring provinces and vice versa for the low--high (LH) outliers. The HH and LL clusters can reflect the similar PM~2.5~ concentration clustering, indicating spatial autocorrelation of PM~2.5~ is positive; spatial dispersion of PM~2.5~ concentration is reflected in the HL and LH outliers, it indicates that PM~2.5~ concentrations have a negative spatial autocorrelation. From [Figure 10](#ijerph-16-01149-f010){ref-type="fig"}, the spatial spillover effect of PM~2.5~ pollution in Southwest China, North China and East China were the most significant from 2003 to 2016. This may be because some geographic and meteorological conditions (wind speed and direction, high temperature) have caused the diffusion of particulate matter. The provinces in Southwest China and Qinghai showed an LL clustering pattern during the study period. This finding may be because of the sparse population, low development intensity, high vegetation coverage and low industrial pollution. Meanwhile, HH clustering were mostly distributed in some provinces of North China, East China, and Central China from 1999 to 2016. This could be largely attributed to intensive industries, car exhaust emissions and a sharp increase in urban population density. HL outliers were mainly distributed in Xinjiang in 2003--2015 except for 2013. ### 3.4.2. Spatial Correlations between PM~2.5~ and Socioeconomic Factors {#sec3dot4dot2-ijerph-16-01149} In this paper, global bivariate Moran's I was used to determine if PM~2.5~ in one province were spatial correlated with socioeconomic factors of its neighbors across the study region. From [Figure 11](#ijerph-16-01149-f011){ref-type="fig"}a,b,d, the global bivariate Moran's I values presented positive growth trends at a 95% confidence level in 1998--2016. These indicated that spatial correlations between PM~2.5~ at a province and GDPP, IVA and PCO of its adjacent provinces were positive and significant, and the positive spatial correlations increased during the study period. From [Figure 11](#ijerph-16-01149-f011){ref-type="fig"}c, the global bivariate Moran's I values presented a positive increasing trend in 1998--2001, a positive decreasing trend in 2001--2005, and a negative decreasing trend in 2006--2016, with the p-values less than 0.05 in 1998--2004, indicating that spatial correlation between PM~2.5~ concentration at a province and UPD of its neighboring provinces was positive and significant in 1998--2004, positive but not significant in 2005, negative but not significant in 2006--2016. The spatial correlation decreased from 2001. As shown in [Figure 12](#ijerph-16-01149-f012){ref-type="fig"}, the bivariate local Moran's I values for PM~2.5~ and socioeconomic factors were calculated. HH clusters means that the provinces with high PM~2.5~ concentration clustered the neighboring provinces with high values of GDPP, IVA, UPD and PCO, and their values were higher than their annual average values. LL clusters means that the provinces with low PM~2.5~ concentration were near predominantly the provinces with low values of GDPP, IVA, UPD and PCO, and their values were lower than their annual average values. HL outliers occur where the neighbors of the provinces with high PM~2.5~ concentration have low GDPP, IVA, UPD and PCO. LH outliers mean that there were low values of PM~2.5~ concentration in one province, and there were high values of GDPP, IVA, UPD and PCO in the adjacent provinces. We used data from 2016 as an example to analyze the local spatial correlations between PM~2.5~ concentration and socioeconomic factors. In 2016, from [Figure 12](#ijerph-16-01149-f012){ref-type="fig"}c, Hubei was the only province where appeared HH clusters of PM~2.5~ concentration and UPD. From [Figure 12](#ijerph-16-01149-f012){ref-type="fig"}a,b,d, the LL clusters of PM~2.5~ concentration and GDPP (IVA or PCO) were mostly covered in some provinces of Southwest China. Shanghai appeared a HH clusters of PM~2.5~ concentration and GDPP. Shandong, Jiangsu, Shanghai and Anhui were the provinces that had a HH clusters of PM~2.5~ concentration and IVA. High PM~2.5~ concentration and high PCO clustered in Henan, Shandong, Jiangsu, Shanghai and Anhui. The place where was the HL outliers of PM~2.5~ concentration and GDPP (IVA or PCO) was Xinjiang. The LH outliers of PM~2.5~ concentration and IVA were covered in Fujian and Jiangxi. Fujian was the province that appeared a LH outliers of PM~2.5~ concentration and PCO. 3.5. Regression Results of the Spatial Regression Model {#sec3dot5-ijerph-16-01149} ------------------------------------------------------- The analysis results of spatial autocorrelation confirmed the existence of spatial dependence of PM~2.5~, so spatial regression models were used to further confirm the spatial dependence of PM~2.5~ concentration. First, the estimated results of OLS were calculated in [Table 3](#ijerph-16-01149-t003){ref-type="table"}. LM test and RLM test were performed for the residuals of OLS regression. The values of SLM-LM and SEM-LM were significant (p \\< 0.05) except for 1999 and 2016. The values of SLM-RLM were significant (p \\< 0.1) in most years, while SEM-RLM was not significant in 1998--2016. Therefore, the SLM model was adopted. The results of spatial lag model regression in 1998--2016 were shown in [Table 4](#ijerph-16-01149-t004){ref-type="table"}. PM~2.5~ increased significantly under GDPP impact in most years (p \\< 0.1). Futhermore, IVA had also a significantly positive impact on PM~2.5~ in 2003--2010, a possible reason for this may be that some provinces (Hebei, Jiangsu and Zhejiang) had significantly increased their industrial energy consumption (\\>50%) in 2000--2010, resulting in the direct impact of industrialization on PM~2.5~, according to China's Energy Statistic Yearbook (2011). But the impact of UPD and PCO on PM~2.5~ was insignificant (p \\> 0.1) in most years. The spatial autoregressive coefficient (W\\PM25) were all significant (p* \\< 0.01) in 1998--2016, indicating there was a significant spatial spillover effect on PM~2.5~ in adjacent provinces. 4. Discussion {#sec4-ijerph-16-01149} ============= 4.1. Spatial Distribution and Temporal Variation of PM~2.5~ and Socioeconomic Factors {#sec4dot1-ijerph-16-01149} ------------------------------------------------------------------------------------- Based on four socioeconomic factors dataset and PM~2.5~ concentration dataset, this study examined the spatial distribution and relationships between socioeconomic factors and PM~2.5~ in 31 provinces of Mainland China during the period of 1998--2016. From [Figure 1](#ijerph-16-01149-f001){ref-type="fig"}, provinces with high PM~2.5~ concentration have shifted from Northwest China to North China and East China since 1998, and most provinces of Northeast China, North China and East China had serious PM~2.5~ pollution in 2016. Previous studies have also shown that high PM~2.5~ concentration were mainly distributed in economically developed areas \\[[@B38-ijerph-16-01149]\\]. From [Figure 2](#ijerph-16-01149-f002){ref-type="fig"}, the temporal variations showed that the overall increase trend of PM~2.5~ is the same as that of GDPP, IVA, UPD and PCO during 1998--2016, but PM~2.5~ exhibited a downward trend from 2006 to 2012. The reason for this phenomenon may be the implementation of sustainable development policies of energy conservation, pollutant reduction and green development proposed in the eleventh five-year plan \\[[@B52-ijerph-16-01149]\\]. The external cause could be meteorological factors. For example, the nitrate and secondary organic aerosols formation was greatly facilitated by high humidity \\[[@B53-ijerph-16-01149]\\]. Wind speed is conducive to the diffusion of PM~2.5~ \\[[@B54-ijerph-16-01149]\\]. The chemical reaction rate of PM~2.5~ precursor pollutants accelerates with the increase of temperature and solar radiation. \\[[@B55-ijerph-16-01149],[@B56-ijerph-16-01149]\\]. From [Table 1](#ijerph-16-01149-t001){ref-type="table"} and [Table 2](#ijerph-16-01149-t002){ref-type="table"} and [Figure 4](#ijerph-16-01149-f004){ref-type="fig"}, in 1998, the two regions with the highest PM~2.5~ concentration were Northwest China and North China, which were replaced by North China and East China respectively in 2016. The growth trend of GDPP, IVA, UPD, PCO and PM~2.5~ in East China, South China, Central China, North China, and Northeast China were fast. Although the growth trend of GDPP, IVA, UPD and PCO in Southwest China and Northwest China were also fast, PM~2.5~ presented a slowly growth trend in Southwest China and a descending trend in Northwest China. Previous studies had come to similar conclusions \\[[@B19-ijerph-16-01149],[@B50-ijerph-16-01149]\\]. From [Figure 5](#ijerph-16-01149-f005){ref-type="fig"}, a downward trend of PM~2.5~ presented in Gansu, Ningxia, and Shaanxi is mainly attributed to implementation of clean air policies in recent years. UPD only in Beijing showed a downward trend, which is in line with the requirements of the Beijing--Tianjin--Hebei coordination to \\"strictly control the increase, dredge the stock, dredge the combination\\" of Beijing's population size. In addition to the policy factor of Beijing--Tianjin--Hebei cooperation, the negative growth of Beijing's permanent population is also related to the overall trend of population returns in labor-exporting provinces. 4.2. The Relationships between PM~2.5~ and Socioeconomic Factors {#sec4dot2-ijerph-16-01149} ---------------------------------------------------------------- From [Figure 7](#ijerph-16-01149-f007){ref-type="fig"}, the Spearman's rank correlation analysis indicated that four socioeconomic factors produced an increase of PM~2.5~ in most provinces of China. However, GDPP, IVA and PCO appeared a negative correlation with PM~2.5~ in Shaanxi, Gansu and Ningxia. Gansu, Ningxia and Beijing were the negative correlation between PM~2.5~ and UPD. From [Figure 8](#ijerph-16-01149-f008){ref-type="fig"}, the socioeconomic factors had strong impact on PM~2.5~ concentration in North China, Northeast China and East China, but in contrast less affected PM~2.5~ concentration in Northwest China. It's worth noting that meteorological factors and urban fugitive dust also contributed to PM~2.5~ concentration \\[[@B57-ijerph-16-01149],[@B58-ijerph-16-01149]\\]. Soil and desert dust was the major cause of high Fe and K contents in urban fugitive dust in Northern China, and PM~2.5~ was more affected by soil dust in northern China than in southern China \\[[@B59-ijerph-16-01149]\\]. Furthermore, coal combustion produced fugitive dust which increased PM~2.5~ concentration. This influence was especially strong in Northern part of China \\[[@B60-ijerph-16-01149]\\]. In addition, it was reported that desert dust and soil dust often affected Northwest China. So, sand and dust played an important role in influencing PM~2.5~ concentration in Northwest China \\[[@B38-ijerph-16-01149],[@B61-ijerph-16-01149],[@B62-ijerph-16-01149]\\]. GDPP and IVA appeared significantly positive correlations with PM~2.5~ in most years in [Figure 6](#ijerph-16-01149-f006){ref-type="fig"}a,b. While the correlation between PM~2.5~ and UPD (or PCO) was all insignificant in [Figure 6](#ijerph-16-01149-f006){ref-type="fig"}c,d. Furthermore, when spatial factors were considered in [Figure 11](#ijerph-16-01149-f011){ref-type="fig"}a,b,d, GDPP (IVA or PCO) imposed a positive externality on PM~2.5~; that is, the increase of GDPP (IVA or PCO) in one province may cause the increase of PM~2.5~ in the neighboring provinces. The reason is that the pollution particles, generated by the activities of residents, emissions from factories and private cars, may be passed from one province to the surrounding provinces through atmospheric movements such as wind speed, wind direction temperature. High temperature and wind speed can promote the convection of air. This can create better conditions for the dilution and dispersion of particulate matter. Notably, the Spearman's rank correlation analysis and bivariate spatial correlation analysis gave a consistent conclusion for the downward trend on the UPD's impact on PM~2.5~ concentration in [Figure 6](#ijerph-16-01149-f006){ref-type="fig"}c and [Figure 11](#ijerph-16-01149-f011){ref-type="fig"}c. It indicated that the impact of UPD on PM~2.5~ was getting smaller and smaller. This may be because of the population control policy. The population size of some provinces has been gradually controlled since the population control policy was implemented. The impact of UPD on PM~2.5~ may be closely related to population size \\[[@B63-ijerph-16-01149]\\]. [Figure 12](#ijerph-16-01149-f012){ref-type="fig"} showed the local bivariate cluster maps for PM~2.5~ and socioeconomic factors in 31 provinces of China, in 2016. For the provinces of the HH clusters, the development of the social economy in their adjacent provinces had positive radiation effect on these provinces. Their economic development in the local provinces have also brought about a number of pollution sources that have indirectly increased PM~2.5~. Some provinces with slow economic growth in Northwestern and Southwestern China had fewer pollution sources, which was easy to form LL clusters. Furthermore, the HL type provinces were mainly distributed in Xinjiang in [Figure 10](#ijerph-16-01149-f010){ref-type="fig"} and [Figure 12](#ijerph-16-01149-f012){ref-type="fig"}. As a region of severe sandstorm and abundant coal resources, the exploitation and utilization of these coal resources have produced many pollutants in Xinjiang and destroyed the ecological balance of atmospheric environment. The complex topography of Xinjiang is also not conducive to the diffusion of atmospheric pollutants. In addition, Qinghai and Tibet with underdeveloped industry have less pollution resources and lower PM~2.5~ concentration. Rich vegetation in Sichuan and Yunnan can effectively reduce PM~2.5~ concentration. The combination of these factors formed the obvious HL outliers around Xinjiang. 4.3. The Spatial Spillover Effect of PM~2.5~ {#sec4dot3-ijerph-16-01149} -------------------------------------------- The spatial spillover effect means that the changes of PM~2.5~ concentration in one province can impact on PM~2.5~ concentration of other provinces. In this paper, spatial spillover effect of PM~2.5~ concentration in adjacent provinces can be reflected by the global Moran's I. From [Figure 9](#ijerph-16-01149-f009){ref-type="fig"}, there was a positive increasing trend of the global Moran's I values of PM~2.5~ concentration during the study period. It indicated that the spatial correlation of PM~2.5~ gradually became stronger over time. The spatial autoregressive coefficient (W\\PM25) were all significant (p* \\< 0.01) in 1998--2016 (column 2 of [Table 4](#ijerph-16-01149-t004){ref-type="table"}). These meant that the spatial spillover effect is becoming more and more significant. From [Figure 10](#ijerph-16-01149-f010){ref-type="fig"} and [Figure 12](#ijerph-16-01149-f012){ref-type="fig"}, the HH clusters of PM~2.5~ concentration (HH clusters of PM~2.5~ and socioeconomic factors) were mainly distributed in some provinces of economically developed area (i.e., North China, East China). At the same time, provinces of economically backward areas (i.e., Southwest China) appeared to have LL clusters. These indicated that the spatial spillover effect of North China, East China and Southwest China were higher than other regions. All the three regions have strong PM~2.5~ pollution homogeneity. In other words, there were spatial spillover effects in different provinces, but were particularly severe in North China, East China and Southwest China. However, we note that the spatial spillover effects on PM~2.5~ pollution for all regions are non-negligible. So local governments should consider the policies of adjacent provinces and coordination with adjacent provinces is indispensable. 4.4. Comparative Analysis of the Effects of GDPP, GDP per Area, IVA and IVA per Area on PM~2.5~ {#sec4dot4-ijerph-16-01149} ----------------------------------------------------------------------------------------------- To further analyze the correlation between PM~2.5~ and aerosol emission density, we used dataset of GDP per area and IVA per area to calculate the Spearman's rank correlation coefficients. Due to the absence of data in 2016 and Tibet, the time sequence of the experiment was from 1998 to 2015, and Tibet was excluded. We have tested the correlations from a spatial perspective. The experiment was designed for the effects of GDPP, GDP per area, IVA and IVA per area on PM~2.5~ from two different scale, including regional scale and provincial scale. On regional scale, the correlation between PM~2.5~ and GDP per area (IVA per area, GDPP, or IVA) were significant in North China, Northeast China, East China, Central China and South China in [Figure 13](#ijerph-16-01149-f013){ref-type="fig"}. On provincial scale, [Table 5](#ijerph-16-01149-t005){ref-type="table"} showed that most provinces of the other five geographical regions except Southwest China and Northwest China presented a significant correlation between PM~2.5~ and GDP per area (IVA per area, GDPP, or IVA). Although there were some slight differences in the correlations values and p values under two different scales, the overall trend was consistent. These indicated that the increase of GDP and industry has a strong positive impact on PM~2.5~, especially in North China, Northeast China, East China, Central China and South China. However, the influence was not strong in Northwest China. The reason may be that PM~2.5~ concentration in Northwest China is more affected by sandstorms. These further validated the idea in this article. That is, human activities contribute to PM~2.5~ concentration, but are not the only factor. 5. Conclusions {#sec5-ijerph-16-01149} ============== This paper estimated spatial distribution, temporal variations and relationships of socioeconomic factors and PM~2.5~ in 31 provinces of China using a unary linear regression model, Spearman's rank correlation analysis method, univariate spatial autocorrelation analysis method, bivariate spatial correlation analysis method and the spatial regression analysis during the period of 1998--2016. Results demonstrated that PM~2.5~ generally increased with the increase of socioeconomic factors from 1998 to 2016, but there were different temporal variations trend and relationships in different provinces and regions. Socioeconomic factors and PM~2.5~ concentration in most provinces in East China, South China, Central China, North China, and Northeast China had rapid growth trend, and socioeconomic factors were significantly correlated with PM~2.5~ concentration. Although the growth trend of socioeconomic factors in Southwest China and Northwest China were also fast, PM~2.5~ presented a slowly growth trend in Southwest China and a descending trend in Northwest China, and socioeconomic factors were weakly correlated with PM~2.5~ concentration. Urban population density was not an important influencing factor in affecting PM~2.5~ concentration. GDP per capita and industrial added values in the local and adjacent provinces were the key influencing factors for the increase of PM~2.5~ concentration. Private car ownership also contributed to PM~2.5~ concentration. PM~2.5~ in neighboring provinces were also an important factor to increase the local PM~2.5~ concentration. The results of the research can provide effective guidelines for urban sustainable development and further protect the environment of cities. This research was funded by the National Natural Science Foundation of China under Grant 41701400. J.L. conceived and designed the study; Y.Y. analyzed the data and wrote the paper. J.L., Y.Y., G.Z and Q.Y. contribute to the editing and reviewing of the paper. The authors declare no conflict of interest. ###### Spatial distribution of socioeconomic factors and PM~2.5~ in 31 provinces of China in 1998 and 2016. (a) 1998 PM~2.5~, (b) 2016 PM~2.5~, (c) 1998 GDP per capita, (d) 2016 GDP per capita, (e) 1998 industrial added values, (f) 2016 industrial added values, (g) 1998 urban population density, (h) 2016 urban population density, (i) 1998 private car ownership, (j) 2016 private car ownership. ![](ijerph-16-01149-g001a) ![](ijerph-16-01149-g001b) ![Temporal variations of standardized PM~2.5~, GDP per capita (GDPP), industrial added values (IVA), urban population density (UPD) and private car ownership (PCO) in Mainland China Figure 1998 to 2016.](ijerph-16-01149-g002){#ijerph-16-01149-f002} ![Seven regions of China.](ijerph-16-01149-g003){#ijerph-16-01149-f003} ###### The slopegraph for explaining standardized annual mean PM~2.5~ concentration, standardized socioeconomic factors changes 1998 vs. 2016, (a) the slopegraph of PM~2.5~ in the seven geographical subareas, (b) the slopegraph of PM~2.5~ and socioeconomic factors in East China, (c) South China, (d) Central China, (e) Northwest China, (f) Southwest China, (g) North China, and (h) Northeast China. ![](ijerph-16-01149-g004a) ![](ijerph-16-01149-g004b) ![The slope of (a) PM~2.5~, (b) GDPP, (c) IVA, (d) UPD and (e) PCO from 1998 to 2016.](ijerph-16-01149-g005){#ijerph-16-01149-f005} ![The correlation coefficients between PM~2.5~ and socioeconomic factors in Mainland China, 1998--2016. (a) Correlation coefficients between PM~2.5~ and GDPP. (b) Correlation coefficients between PM~2.5~ and IVA. (c) Correlation coefficients between PM~2.5~ and UPD. (d) Correlation coefficients between PM~2.5~ and PCO. Notes: the letters a and b above the curve point represent coefficients significant at the 1%, 5% levels, respectively. No letters above the curve point indicate insignificance.](ijerph-16-01149-g006){#ijerph-16-01149-f006} ![The correlation coefficient (r) values in 31 provinces. (a) Correlation between PM~2.5~ and GDPP. (b) Correlation between PM~2.5~ and IVA. (c) Correlation between PM~2.5~ and UPD. (d) Correlation between PM~2.5~ and PCO.](ijerph-16-01149-g007){#ijerph-16-01149-f007} ![The correlation coefficient (r) values between PM~2.5~ and GDPP (IVA, UPD or PCO) in the geographical subareas. Notes: a, b represent coefficients significant at the 1%, 5% levels, respectively. No letters above the bar chart indicate insignificance.](ijerph-16-01149-g008){#ijerph-16-01149-f008} ![Global Moran's I of PM~2.5~ concentration for 31 provinces, 1998--2016. Notes: a, b represent coefficients significant at the 1%, 5% levels, respectively.](ijerph-16-01149-g009){#ijerph-16-01149-f009} ###### LISA cluster map of PM~2.5~ concentration for 31 provinces, 1998--2016. ![](ijerph-16-01149-g010a) ![](ijerph-16-01149-g010b) ![Global Bivariate Moran's I for province-level between PM~2.5~ and socioeconomic factors in Mainland China, 1998--2016. (a) Global Bivariate Moran's I between PM~2.5~ and GDPP. (b) Global Bivariate Moran's I between PM~2.5~ and IVA. (c) Global Bivariate Moran's I between PM~2.5~ and UPD. (d) Global Bivariate Moran's I between PM~2.5~ and PCO. Notes: the letters a and b above the curve point represent coefficients significant at the 1%, 5% levels, respectively. No letters above the curve point indicate insignificance.](ijerph-16-01149-g011){#ijerph-16-01149-f011} ###### Bivariate cluster maps in Mainland China, in 2016. (a) Bivariate cluster map of PM~2.5~ concentration and GDPP. (b) Bivariate cluster map of PM~2.5~ and IVA. (c) Bivariate cluster map of PM~2.5~ and UPD. (d) Bivariate cluster map of PM~2.5~ and PCO. ![](ijerph-16-01149-g012a) ![](ijerph-16-01149-g012b) ![The correlation coefficient (r) values between PM~2.5~ and GDPP (IVA, GDPP per area or IVA per area) in the geographical subareas, 1998-2015. Notes: a, b represent coefficients significant at the 1%, 5% levels, respectively. No letters above the bar chart indicate insignificance.](ijerph-16-01149-g013){#ijerph-16-01149-f013} ijerph-16-01149-t001_Table 1 ###### The values of GDP per capita (GDPP) (yuan/person), industrial added values (IVA) (billion yuan), urban population density (UPD) (person/per square kilometer), private car ownership (PCO) (10^4^ cars) and PM~2.5~ (μg/m^3^) in 1998 and 2016. Region 1998 2016 ----------------- ------- ----------- --------- --------- -------- ------- ----------- ----------- --------- ----------- East China 27.38 10,269.47 1269.72 1501.86 58.90 43.91 74,496.00 11,324.87 2756.00 5439.19 South China 16.32 7025.50 418.47 999.00 34.23 23.86 52,130.00 3995.00 2378.00 1943.85 Central China 30.62 4865.51 369.43 867.67 90.69 38.57 48,207.33 4091.64 3684.67 2056.22 Northwest China 35.26 4563.55 125.08 890.80 29.69 33.84 41,989.40 1398.92 2965.00 1090.65 Southwest China 16.19 3957.29 253.26 443.40 43.24 17.04 39,605.60 2493.59 2531.00 1904.52 North China 31.22 10,074.37 415.56 1338.40 125.75 45.28 76,781.80 3560.12 2634.60 2683.10 Northeast China 20.87 7591.06 350.02 722.00 41.11 32.38 48,363.67 1653.55 2986.67 1212.68 Mainland China 23.97 6860.00 3413.49 459.00 423.65 29.68 53,935.00 24,787.78 2408.00 16,330.22 ijerph-16-01149-t002_Table 2 ###### The variation trend of PM~2.5~, GDPP, IVA, UPD and PCO in the seven geographical subareas and Mainland China, 1998--2016. Region z-slope ----------------- ----------- ------- ------- ------- ------- East China 0.129 0.174 0.175 0.162 0.165 South China 0.110 0.173 0.175 0.148 0.168 Central China 0.108 0.172 0.172 0.158 0.159 Northwest China −0.015 0.172 0.171 0.136 0.160 Southwest China 0.066 0.170 0.170 0.156 0.163 North China 0.128 0.175 0.172 0.166 0.169 Northeast China 0.145 0.172 0.165 0.165 0.165 Mainland China 0.138 0.173 0.174 0.164 0.165 ijerph-16-01149-t003_Table 3 ###### Results of ordinary least squares regressions between PM~2.5~ and socioeconomic factors in Mainland China, 1998--2016. Year Variables ------ -------------- ------------ -------- -------- ------- --------- --------------- ------------ --------------- ------- 1998 0.165 −0.0180 0.026 0.116 0.048 −42.717 5.571 \\\\ 1.583 4.826 \\\\ 0.838 1999 0.202 0.216 −0.012 −0.199 0.092 −41.981 2.778 \\* 0.115 2.667 0.005 2000 0.166 0.216 0.027 −0.076 0.085 −42.103 7.717 \\\\\\* 0.587 7.222 \\\\\\* 0.093 2001 0.361 0.168 0.068 −0.119 0.192 −40.179 7.661 \\\\\\* 2.569 6.106 \\\\ 1.014 2002 0.438 \\\\ 0.422 \\* −0.063 −0.292 0.302 −37.908 7.884 \\\\\\* 0.850 7.036 \\\\\\* 0.003 2003 0.449 \\\\ 0.460 \\* 0.195 −0.280 0.406 −35.417 8.874 \\\\\\* 3.486 \\* 5.816 \\\\ 0.429 2004 0.466 \\\\ 0.470 \\* 0.144 −0.317 0.358 −36.611 6.037 \\\\ 2.729 \\* 3.933 \\\\ 0.625 2005 0.406 \\\\ 0.613 \\\\ 0.113 −0.414 0.363 −36.485 7.922 \\\\\\* 1.938 6.067 \\\\ 0.082 2006 0.504 \\\\\\* 0.384 0.265 −0.199 0.374 −36.216 13.218 \\\\\\* 3.156 \\* 10.158 \\\\\\* 0.096 2007 0.442 \\\\ 0.596 \\* 0.224 −0.354 0.390 −35.819 13.435 \\\\\\* 3.741 \\* 9.842 \\\\\\* 0.148 2008 0.546 \\\\\\* 0.620 \\* 0.120 −0.429 0.429 −34.796 8.044 \\\\\\* 2.218 5.844 \\\\ 0.018 2009 0.564 \\\\\\* 0.494 0.139 −0.310 0.416 −35.141 7.249 \\\\\\* 2.393 4.954 \\\\ 0.098 2010 0.439 \\\\ 0.515 0.515 −0.249 0.356 −36.665 6.853 \\\\\\* 1.221 5.647 \\\\ 0.014 2011 0.501 \\\\\\* 0.264 0.175 −0.012 0.379 −36.096 9.957 \\\\\\* 2.826 \\* 7.183 \\\\\\* 0.052 2012 0.424 \\\\ 0.236 0.144 0.082 0.336 −37.138 7.965 \\\\\\* 3.252 \\* 5.070 \\\\ 0.356 2013 0.515 \\\\\\* 0.013 0.201 0.229 0.371 −36.297 8.174 \\\\\\* 4.133 \\\\ 4.726 \\\\ 0.685 2014 0.462 \\\\ 0.128 0.159 0.169 0.366 −36.422 6.566 \\\\ 4.074 \\\\ 3.335 \\* 0.842 2015 0.575 \\\\\\* −0.019 0.226 0.221 0.419 −35.051 6.294 \\\\ 3.891 \\\\ 3.196 \\* 0.793 2016 0.578 \\\\\\* −0.286 0.122 0.494 0.385 −35.939 5.762 \\\\ 5.050 \\\\ 2.465 1.752 Notes: Log-L denotes Log likelihood; \\, \\\\, \\\\\\represent coefficients are significant at the 10%, 5%, 1% levels, respectively. ijerph-16-01149-t004_Table 4 ###### The results of spatial lag model regression in 1998--2016. Year Variables ------ -------------- ------------ ------------ -------------- ------------- ------- --------- -------- --------- 1998 0.646 \\\\\\* 0.151 0.005 −0.114 0.064 0.328 −39.165 90.330 98.934 1999 0.488 \\\\\\* 0.196 0.149 −0.110 −0.156 0.237 −40.237 92.474 101.078 2000 0.677 \\\\\\* 0.087 0.170 −0.121 −0.057 0.401 −37.598 87.197 95.800 2001 0.694 \\\\\\* 0.245 0.095 −0.128 −0.098 0.483 −35.457 82.914 91.518 2002 0.674 \\\\\\* 0.279 \\\\ 0.258 −0.191 −0.233 0.549 −33.196 78.391 86.995 2003 0.647 \\\\\\* 0.225 \\* 0.345 \\* 0.082 −0.262 0.618 −30.406 72.812 81.416 2004 0.595 \\\\\\* 0.274 \\* 0.345 \\* 0.046 −0.315 0.536 −33.075 78.150 86.754 2005 0.623 \\\\\\* 0.206 0.476 \\\\ 0.028 −0.422 \\* 0.570 −32.075 76.151 84.755 2006 0.766 \\\\\\* 0.227 \\\\ 0.378 \\* 0.274 \\\\\\* −0.311 0.690 −28.214 68.428 77.032 2007 0.754 \\\\\\* 0.207 \\* 0.471 \\\\ 0.217 \\\\ −0.407 \\* 0.695 −27.832 67.664 76.268 2008 0.646 \\\\\\* 0.311 \\\\ 0.535 \\\\ 0.121 −0.483 \\\\ 0.630 −29.898 71.796 80.400 2009 0.645 \\\\\\* 0.321 \\\\ 0.502 \\\\ 0.144 −0.447 \\* 0.614 −30.556 73.112 81.716 2010 0.626 \\\\\\* 0.242 \\* 0.515 \\* 0.153 0.383 0.561 −32.421 76.842 85.446 2011 0.729 \\\\\\* 0.238 \\\\ 0.369 0.186 \\* −0.268 0.653 −29.580 71.160 79.764 2012 0.674 \\\\\\* 0.206 0.290 0.176 −0.128 0.580 −32.073 76.146 84.750 2013 0.679 \\\\\\* 0.244 \\* 0.223 0.204 \\* −0.098 0.607 −31.099 74.198 82.802 2014 0.637 \\\\\\* 0.203 0.302 0.166 −0.137 0.571 −32.146 76.292 84.896 2015 0.639 \\\\\\* 0.266 \\\\ 0.249 0.175 −0.148 0.606 −30.845 73.689 82.293 2016 0.628 \\\\\\* 0.247 \\* 0.081 0.107 0.06 0.570 −32.100 76.201 84.805 Notes: Log-L denotes log likelihood; \\, \\\\, \\\\\\represent coefficients significant at the 10%, 5%, 1% levels, respectively. ijerph-16-01149-t005_Table 5 ###### The correlation coefficients of provinces in seven geographical subareas, 1998--2015. Region Province Correlation Coefficient (r) --------------------- ------------ ----------------------------- ------------ ------------ ------------ North China Beijing 0.785 \\\\ 0.777 \\\\ 0.779 \\\\ 0.779 \\\\ Tianjin 0.701 \\\\ 0.701 \\\\ 0.695 \\\\ 0.695 \\\\ Hebei 0.756 \\\\ 0.756 \\\\ 0.759 \\\\ 0.759 \\\\ Shanxi 0.525 \\* 0.525 \\* 0.548 \\* 0.453 Inner Mongolia 0.323 0.342 0.311 0.443 Northeast China Liaoning 0.822 \\\\ 0.812 \\\\ 0.783 \\\\ 0.783 \\\\ Jilin 0.829 \\\\ 0.829 \\\\ 0.822 \\\\ 0.822 \\\\ Heilongjiang 0.742 \\\\ 0.740 \\\\ 0.600 \\\\ 0.600 \\\\ East China Shanghai 0.604 \\\\ 0.604 \\\\ 0.556 \\* 0.556 \\* Jiangsu 0.754 \\\\ 0.754 \\\\ 0.754 \\\\ 0.754 \\\\ Zhejiang 0.560 \\* 0.558 \\* 0.560 \\* 0.548 \\* Anhui 0.798 \\\\ 0.804 \\\\ 0.798 \\\\ 0.798 \\\\ Fujian 0.474 \\* 0.474 \\* 0.474 \\* 0.474 \\* Jiangxi 0.552 \\* 0.548 \\* 0.554 \\* 0.439 Shandong 0.752 \\\\ 0.752 \\\\ 0.752 \\\\ 0.750 \\\\ Central China Henan 0.756 \\\\ 0.756 \\\\ 0.773 \\\\ 0.763 \\\\ Hubei 0.641 \\\\ 0.641 \\\\ 0.628 \\\\ 0.628 \\\\ Hunan 0.585 \\* 0.585 \\* 0.585 \\* 0.585 \\* South China Guangdong 0.552 \\* 0.552 \\* 0.552 \\* 0.552 \\* Guangxi 0.649 \\\\ 0.626 \\\\ 0.649 \\\\ 0.484 \\* Hainan 0.498 \\* 0.643 \\\\ 0.513 \\* 0.628 \\\\ Southwest China Chongqing 0.331 0.331 0.340 0.340 Sichuan 0.418 0.418 0.449 0.480 \\* Guizhou 0.467 0.467 0.467 0.488 \\* Yunnan 0.457 0.515 \\* 0.449 0.368 Northwest China Shaanxi −0.030 −0.028 −0.003 −0.096 Gansu --0.152 0.038 −0.160 0.189 Qinghai 0.567 \\* 0.451 0.579 \\* 0.480 \\* Ningxia −0.562 \\* −0.562 \\* −0.562 \\* −0.470 \\* Xinjiang 0.240 0.240 0.230 0.232 Notes: \\, \\\\* represent coefficients are significant at the 5%, 1% levels, respectively.
Q: How much can a landlord charge for overnight guests? Here's the part of the contract: The Premises are for the sole use as a residence by the above-mentioned Tenant(s)(Item 1) only, not as physical exercising place or other business or political activity. For occasional guest & visitor who stays overnight less than two days, it is limited according to RSB's rule. Without Landlord's prior written consent, Tenant has no excuse to accommodate any consecutive staying and/or overnight for any guest & visitor. With temporary commendation, day-based, and additional 10% of rent each person is applied. I had 2 guests over just to sleep 2 nights in a row. My rent is $1370. My landlord is charging me $180.65 for this. His math makes no sense since it doesn't even use the factor 10% anywhere and he's including utilities as part of my rent. What he has is ($1400/31) x 2 persons x 2 days = $180.65. Does the contract say that I can have guests over 1 night without charge? If so does it only start charging on nights after the first? Is it supposed to be 10% of monthly rent $137 per guest per night? How is overnight defined? What if they came over at 9AM and slept in the day? What about 2AM? I searched the RSB (rent stabilization board) and couldn't find any information on overnight guests. A: Has this contract been translated (badly) from another language because the construction of the clause is cumbersome and confusing? Does the contract say that I can have guests over 1 night without charge? Without charge, yes. However "Without Landlord's prior written consent, Tenant has no excuse to accommodate ..." so you need the landlord's permission for overnight guests. If so does it only start charging on nights after the first? No, if a person stays more than 1 night (with the landlords permission) then this triggers the landlord's right to charge. See below for how much they can charge. Is it supposed to be 10% of monthly rent $137 per guest per night? "With temporary commendation, day-based, and additional 10% of rent each person is applied." The term is ambiguous, I can see three ways that this would be interpreted: If you have a guest who stays more than 1 night in a month they can charge 10% for that guest for that month (i.e. 2 to 31 days all for the same price). For 2 people for 2 days this would be $1,400 x 10% x 2 = $280. They can charge 10% of the monthly rent per night that the guest stays. $1,400 x 10% x 2 x 2 = $560 As, 1 except the rent would be pro-rata. $1,400 x 10% x 2 x 2/31 = $18.06 Assuming that the landlord put forward this contract the interpretation adopted in the absence of other evidence would be the one least advantageous to the landlord i.e. 3. However, there is other evidence - the landlord accepts that the rate is pro-rata - he has just failed to account for the 10%, so 3. again. How is overnight defined? Well, is it defined in the contract or by the law where you are? If not, it would take its normal English usage - "for the duration of the night". If they arrive before sunset and leave after sunrise the next day then they have stayed overnight. What if they came over at 9am and slept in the day? It says nothing about requiring your guests to sleep. If they party overnight then they are overnight guests. If they sleep all day but don't stay overnight they are not overnight guests. What about 2 am? If sunrise is after 2am then this is not overnight.
Bo Edward Lawrence What I Want You To Be By Bo-Edward Lawrence - Poem by Bo Edward Lawrence I want you to be my seconds you to be my hours you to be my days and you to be my nights you to be everything beautiful in my life I want you to be my wrongs you to be my rights you to keep me grounded when im taking flightbe my queen while we take over everythingwe can do it togethereven with or without a wedding ringyou see, even though we might not be married by words and fancy dressesin my heart.. Our hearts are married for eternitymy blood rushing into a hot scorching joy when we are togetheryour lips, your breath, and the gentle touch of love.There is nothing in my life that shall take this away from me.I want you to accept my love, I want you to love me dearlyI want you to bless me with a woman’s grace...While I thank you everydayFor being what I always wanted.
Connection between masticatory efficiency and pathomorphologic changes in gastric mucosa. The purpose of this investigation was to establish a connection between masticatory deficiency and pathomorphologic alterations of gastric mucosa in patients with dyspepsia. In 40 dyspeptic, edentulous and partially dentate patients and in 40 dyspeptic control patients with good dental status, the Optosil masticatory function test was performed. Histopathologic changes of gastric mucosa and the severity of Helicobacter pylori infection were scored according to the updated Sydney Classification of Chronic Gastritis. The comminution of Optosil particles after increasing the number of chewing strokes was significantly impaired in edentulous and partially dentate patients, indicating masticatory deficiency in this group. This masticatory deficiency group was subdivided into groups with a lower (subgroup 1) and higher (subgroup 2) degree of masticatory deficiency according to median X50 in the Optosil test. The endoscopic appearance of gastric mucosa in masticatory deficiency patients and in the control group suggested chronic gastritis. Higher inflammatory and infection scores were noted in subgroup 2 than in the control group and subgroup 1, especially in the antral part of the stomach. The differences between the antral part and the body of the stomach were significant only in subgroup 2. Masticatory deficiency in patients with dyspepsia was connected with more severe chronic inflammatory changes and H. pylonri infection of gastric mucosa, especially in the antrum of the stomach. Higher values of inflammatory and infection scores in the subgroup with a higher degree of masticatory deficiency suggest its causal role in the promotion of gastritis and H. pylori infection.
The ultimately popular game franchise Plants vs. Zombies now has an online store packed full of merchandise for all of your Plants vs Zombies needs. Got any Plants vs Zombies merch that you’ve got a real hankering for? Well, chances are you’ll find it on the Plants vs Zombies online store HERE. PopCap partnered up with Treehouse Brand Store to create the site, which stocks exclusive and high-quality (none of that rip-off, slightly wonky and out of proportion junk here!) from the UK and United States. With a wide range chances are they’ll have that thing that you really, really want. There are such products as t-shirts, one-sies, hoodies, soft toys and figurines, hats, lunchboes, mugs, art, calenders and Pop! Figures. So seriously, everything. Brennan Townley, the director of brand licensing at PopCap Games had this to say about the opening of the new store: “We’re excited to give our fans access to exclusive Plants vs. Zombies merchandise that they can only find at PvZStore.com. We’ve worked closely with Treehouse, known for its innovative product design, global distribution and excellent customer service, to create a best-in-class online retail experience that will carry everything from plush toys and apparel to limited edition art, with new offerings being added on an ongoing basis.” So what are you waiting for? Head on over to the Plants vs Zombies store NOW and grab your funny PvZ reference t-shirt!
Search Tag Archive for 'genetic genealogy' Over at Your Genetic Genealogist, CeCe Moore talks about investigating evidence of low-level Ashkenazi Jewish descent in her 23andMe data. What I like about this story is how much digging CeCe did; after one tool threw up a “14% Ashkenazi” result, she looked for similar evidence in 23andMe’s tool. She then did the same analysis on her mother’s DNA, finding no apparant Ashkenazi heritage, and to top it all off got her paternal uncle genotyped, which showed even greater Ashkenazi similarity. [LJ] A paper out in PLoS Medicine looks at the interaction between genetics and physical activity in obesity. The take-home message is pretty well summarized in the figure to the left; genetic predispositions are less important in determining BMI for those who do frequency physical excercise than for those who remain inactive. This illustrates the importance of including non-genetic risk factors in disease prediction; not only because they are very important in their own right (the paper demonstrates that physical activity is about as predictive of BMI as known genetic factors), but also because information on environmental influences allows better calibration of genetic risk. [LJ] Trends in Genetics have published an opinion piece in their most recent issue outlining the types of genetic variants we might expect to see for common human diseases (defined by allele frequency and risk), and how exome and whole-genome sequencing could be used to find them. They give a brief, relatively jargon-free, overview of gene-mapping techniques that have been previously used, and discuss how sequencing can take this research further, particularly for the previously less tractable category of low-frequency variants that confer a moderate level of disease risk. [KIM] More Sanger shout outs this week; Sanger Institute postdoc Liz Murchison, along with the rest of the Cancer Genome Project, have announced the sequencing of the Tasmanian Devil genome. The CGP is interested in the Tasmanian Devil due to a rare, odd and nasty facial cancer, which is passed from Devil to Devil by biting. In fact, all the tumours are descended from the tumour of one individual; 20 years or so on, and 80% of the Devil population has been wiped out by the disease. As well as a healthy genome, the team also sequenced two tumour genomes, in the hope of learning more about what mutations made the cells go tumours, and what makes the cancer so unique. I have to say, this isn’t going to be an easy job; assembling a high-quality reference genome of an under-studied organism is a lot of work, especially using Illumina’s short read technology, and identifying and making sense of tumour mutations is equally difficult. Add to this the fact that the tumour genome is from a different individual to the healthy individual, this all adds up to a project of unprecedented scope. On the other hand, the key to saving a species from extinction could rest on this sticky bioinformatics problem, and if anyone is in the position to deal with it, it’s the Cancer Genome Project. [LJ]
Serum IgE in newborns undergoing exchange transfusion. Serum IgE was studied in a group of 20 newborns, ten males and ten females, with neonatal non-immunologic jaundice before and after exchange transfusion and in a control group without jaundice or other immunologic problems. Serum IgE was significantly higher in the study group than in the control group (P less than .005). After exchange transfusion there was a further increase (P less than .005). These changes do not seem to be due to the IgE content of the transfused blood. It is suggested that neonatal jaundice and/or exchange transfusion may stimulate the IgE synthesis in the newborn.
Q: How to get a default html page on MVC3 site I have added an MVC3 web application to an existing website that consists of plain old html files. This works great when you request a specific file but what didn't occur to me was that by changing the site to use .Net 4 it no longer took any notice of the default documents setting in IIS (IIS 6 in this case). So for example I can request www.something.com/index.html but if I request www.something.com I get a resource not found error page. Is there a MapRoute in Global.asax I can specify to map the site route url to index.html? A: Looks like something has changed, I had to do routes.IgnoreRoute(""); ASP.NET complained about the route starting with "/" A: routes.IgnoreRoute(""); Allows the request to fall through to the default documents defined in the site configuration. I only have a single controller and route in this project that I use for ajax requests from the client. I want the rest of the site to continue to behave as it did when it was just plain html. With routes.IgnoreRoute("") the MVC3 app ignores the request which allows IIS to return the default document. Thanks all for your suggestions.
1. Field of the Invention The invention is generally related to nuclear fuel assemblies and more particularly to a reusable locking arrangement for guide tubes and upper end fittings. 2. General Background In a nuclear reactor core, each fuel assembly is fitted with a number of guide tubes that are used to receive control rods. In the nuclear industry, the tubes that are used to receive control rods are referred to as guide tubes or thimble tubes and the upper internal structure that these tubes are attached to are referred to as an upper end fitting or a top nozzle, depending on the manufacturer. Therefore, it should be understood that references herein to a guide tube and upper end fitting should be considered as also referring to a thimble tube and top nozzle. The guide tubes have a relative thin wall thickness and thus require a sleeve at the upper end to provide the necessary support for attachment points and shoulder stops. During assembly, the guide tubes are inserted into the spacer grids. The upper end fitting is then aligned with, received on, and attached to the upper end sleeves of the guide tubes. Typically, upper end fittings and sleeves are attached to one another by the use of threaded joints and locking cups. When it becomes necessary to remove an irradiated fuel assembly upper end fitting or nozzle at the reactor site, the work must be done with remotely controlled tooling under water. This results in the handling of a number of parts and provides the potential for cross threading the fasteners during installation. The remote handling of a number of parts under water increases the potential for loose parts in the system that can damage the reactor and increases working time. Patents directed to nuclear fuel assembly end fitting retainers that applicant is aware of include the following. U.S. Pat. No. 3,769,158 discloses the use of an end fitting over fuel rods where a reduced neck extending through the opening in the end fitting has resilient split rings in grooves and engage the end fitting. U.S. Pat. No. 3,828,868 discloses guide tubes that are threadably attached to the end fitting. U.S. Pat. No. 4,699,761 discloses the use of a threaded sleeve on the upper end of the guide tube.
While at Web Camps London, Jon grabs a quick 15 minute interview with Clint Nelsen to talk about Startup Weekend . Clint gives the elevator pitch and a brief history of Startup Weekend. Jon talks about ... This week on Herding Code, the guys talk with Ayende Rahien (a.k.a. Oren Eini) about RavenDB, a new Open Source (with a commercial option) document database for the .NET/Windows platform. The shows starts ... This week on Herding Code, Cory Foy and Will Green join the guys to discuss general differences between .NET and Ruby development approaches. Is the grass always greener on the other side? Listen in ... This week on Herding Code, the guys discuss compare notes on how to teach software development topics. Is hands-on instruction key? How much should you simplify to focus on mechanics? How do you teach, ... This week on Herding Code, the guys speak with Chris Williams, Rey Bango and Matt Podwysocki about this year’s JSConf. Chris begins the show with a conference overview which will leave you chomping ... This week on Herding Code, John Sheehan joins the cast for a conversation about his open source project, RestSharp. The gang dives into REST and .NET open source. Makes sense, right? And the show wraps ... This week on Herding Code, K Scott leads a conversation with ASP.NET Insider and MVP, Javier Lozano, about his open source project, MVC Turbine, and extensibility and composition with ASP.NET MVC. Javier ... This week on Herding Code, Jon leads a discussion with Daniel Plaisted about Model-Based Testing and the progressive practices of the MEF team. Daniel speaks of the primary development roles at Microsoft ... This week on Herding Code, James Avery and Rob Conery join the cast in a lively discussion about NoSQL, TekPub, the new DotNetKicks and the technical debate du jour, ASP.NET Web Forms vs ASP.NET MVC. ... This week on Herding Code, we talk to Sean Chambers about migrations in .NET with Fluent Migrator. Sean talks about how Fluent Migrator originated from Migrator.NET Sean discusses how the benefits of ...
The taxonomic status of beaked whales of the family Ziphiidae has been previously established; however, their habitat has not yet been precisely elucidated \\[[@r3], [@r15], [@r24]\\]. The existence of beaked whales near Korean territory is particularly uncertain, due to the lack of records in Korea \\[[@r11]\\]. According to reports from Korea from 1970 to 2009, the Ziphiidae species Baird's beaked whales (Berardius bairdii), Blainville's beaked whales (Mesoplodon densirostris), Stejneger's beaked whale (M. stejnegeri), and Cuvier's beaked whales (Ziphius cavirostris) were observed to have been stranded in Korea \\[[@r19]\\]. No beaked whale species were observed during the cetacean sighting surveys conducted within the Korean exclusive economic zone, which were undertaken 53 times between 2000 and 2010 \\[[@r22]\\]. There have been no cases of stranded, bycaught, or observed ginkgo-toothed beaked whales (M. ginkgodens) in Korea \\[[@r10], [@r11], [@r19], [@r22]\\]. Ziphiidae is the most cryptic whale family, and these whales are difficult to observe due to their long diving capacity and because their habitats remain poorly understood \\[[@r3], [@r17]\\]. Two stranded dead whales were found together on the coast (33°31′22.7″N, 126°56′58.80″E) of Jeju Island, South Korea on May 5, 2013. The bigger whale died 14 hr after being found alive. This indicated that the body had not drifted from the remote sea toward the Korean shore as a carcass. To enable individual identification, the whales were given the specimen numbers KJ1181 for the bigger whale and KJ1182 for the smaller whale. The carcasses were dissected and examined to obtain basic biological information on the distribution of Mesoplodon in Korea. The bodies were genetically and morphologically analyzed to identify their species. For genetic identification, genomic DNA was extracted from the muscles of the whales using a G-spin^TM^ Total DNA Extraction Kit (iNtRON Biotechnology, Sungnam, Korea). The mitochondrial (mt) DNA markers, control region (CR), and cytochrome (cyt) b sequences that are commonly used to identify cetaceans were used. Two types of specific primers, M13-Dlp1.5-L (5′-TGTAAAACGACGGCCAGTTCACCCAAAGCTGRARTTCTA-3′) and Dlp5-H (5′-CCATCGWGATGTCTTATTTAAGRGGAA-3′), were used for amplification of the 448 base pairs (bp) mtDNA CR \\[[@r6]\\]. Two other specific primers, GLUDG-L (5′-TGACTTGAARAACCAYCGTTG-3′) and CB2-H (5′-CCCTCAGAATGATATTTGTCCTCA-3′), were used for amplification of the 413 bp mtDNA cyt b gene \\[[@r18]\\]. The polymerase chain reaction (PCR) was performed using an ABI 2720 Thermal Cycler. The amplified products were identified with ultraviolet (UV) ray (260 nm) after electrophoresis (2% agarose gel, 30 min) and dyed with EtBr. Two types of primers, Dlp4-H (5′-GCGGGWTRYTGRTTTCACG-3′) \\[[@r4]\\] and Dlp10-L (5′-CCACAGTACTATGTCCGTATT-3′), were made for base sequence analysis of the mtDNA CR \\[[@r1]\\]. Three types of primers, CB1-L (5′-CCATCCAACATCTCAGCATGATGAAA-3′) \\[[@r18]\\], CYBMF-L (5′-GAACTATAAGAACACTAATGACCAA-3′), and CYBMR-H (5′-TGATTCAGCCATAGTTAACGTCTCGAC-3′), were also made for base sequence analysis of the mtDNA cyt b gene \\[[@r5]\\]. Nucleotide sequence analysis was then performed. PCR products for nucleotide sequence analysis were dried after removal of remaining BigDye using a QIAGEN DyeEx 2.0 spin kit (Qiagen, Redwood City, CA, U.S.A.), and 20 µl of HiDi Foramide was added and the reaction proceeded at 95°C for 2 min. After these processes were complete, the base sequences were assayed using an ABI PRISM 310 Genetic Analyzer. The nucleotide sequences were combined using CLC Main Workbench 5.0 (CLC Bio), and were then compared and analyzed using NCBI Nucleotide BLAST (<http://blast.ncbi.nlm.nih.gov/Blast.cgi>) \\[[@r2]\\]. We obtained partial sequences (448 bp) of mtDNA CR and partial sequences (413 bp) of mtDNA cyt b gene from the two specimens. There was no variable site between the two sequences in both CR and cyt b. From the BLAST search, the two sequences were related to M. ginkgodens with 99% match to accession no. KR534596 in both CR and cyt b. These mtDNA CR and cyt b haplotypes was new in the INSD (the International Nucleotide Sequence Databases). Two novel sequences, MgCR1 and MgCytb1, were deposited in INSD with accession nos. MH019963 and MH019964, respectively. Between the two haplotypes, MgCR1 and KR534596 had four variable sites in 448 bp and MgCytb1 and KR534596 had five variable sites in 413 bp, and these were all transitions. For the molecular phylogenetic analysis, one to four sequences of five Mesoplodon species (M. ginkgodens, M. hotaula, M. stejnegeri, M. carlhubbsi, and M. densirostris, with Ziphius cavirostris as an outgroup; see Appendix for accession nos. for each species sequences) were used to test the position of MgCR1 and MgCytb1 in the trees. Alignment of the CR and cyt b sequences was performed using the CLUSTAL X program \\[[@r23]\\], with visual inspection of the output based on the multiple alignment parameters in the program. A molecular phylogenetic tree was constructed using the Neighbor Joining algorithm \\[[@r20]\\] in MEGA version 7 \\[[@r13]\\], based on the Kimura 2-parameter model \\[[@r12]\\] for the CR (consensus length 434 bp) and cyt b (consensus length 384 bp) separately. Bootstrap values for both data sets were computed using 1,000 replicates \\[[@r9]\\]. All the Mesoplodon species included in the study were monophyletic in both trees ([Fig. 1a and 1b)](#fig_001){ref-type="fig"}Fig. 1.Neighbor joining phylogenetic tree of 15 taxa from six species in the Ziphiidae family based on (a) mtDNA CR sequences (434 bp) and (b) cytochrome b sequences (384 bp). Bootstrap values (1,000 replicates) greater than 60% are shown on the nodes of branches. All taxa are included with accession numbers and scientiﬁc names. Abbreviations for genera: M, Mesoplodon; Z, Ziphius.. M. ginkgodens formed a sister clade to M. hotaula in both trees, with \\>60% statistical bootstrap support ([Fig. 1a and 1b](#fig_001){ref-type="fig"}). MgCR1 and MgCytb1 clustered with other M. ginkgodens reference sequences in both trees ([Fig. 1a and 1b](#fig_001){ref-type="fig"}). Thus, the stranded two whales were strongly identified as M. ginkgodens based on molecular genetic analyses. The total body length of the adult specimen was 456.5 cm ([Fig. 2](#fig_002){ref-type="fig"}Fig. 2.Stranded dead whales suspected to be of the genus Mesoplodon. (a) An adult whale (KJ1181). (b) A juvenile (KJ1182) whale.). Numerous scars were observed on the body surface, particularly round scars that were likely caused by cookie-cutter shark attacks. The total body length of the female calf was 199.0 cm ([Fig. 2](#fig_002){ref-type="fig"}). Both whales were suspected to be of the genus Mesoplodon (family Ziphiidae) because of their outer appearance. Their appearance included a pronounced rostrum that blends into a high forehead without a break, a v-shaped throat groove, a crescent-shaped blowhole, flippers that are relatively small in comparison to entire body size, a small triangular dorsal fin that is placed far back on the body, and the absence of notch at the middle of caudal fin. The whales were identified as being a sexually and physically matured female adult and a female calf based on observation of their external genital organs, mammary slits, and the absence of tusks. Beaked whales have reduced teeth: males have one pair of teeth and females have only one pair of vestigial teeth \\[[@r15]\\]. These individuals are thought to be a dam and her calf, based on evidence including the stranding situation, their body sizes, the highly developed mammary glands of the adult whale ([Fig. 3a and 3b)](#fig_003){ref-type="fig"}Fig. 3.Highly developed mammary gland of adult specimen (a, b). Presence of milk inside the right mammary gland of adult specimen (c). Stomach contents of calf specimen, which only included milk (d). that had plenty of milk in the right gland ([Fig. 3c](#fig_003){ref-type="fig"}), the stomach contents of the smaller whale, which consisted only of milk ([Fig. 3d](#fig_003){ref-type="fig"}), and the results of the genetic analysis did not contradict this hypothesis because the maternal mtDNA haplotype was identical for both individuals. The adult skull specimen was prepared and subsequently compared with the holotype specimen of M. ginkgodens stored in the National Museum of Nature and Science, Japan (NSMT-M8744, Male). There are several variations in skull structure among species of the genus Mesoplodon \\[[@r16]\\]. Among those variations, five distinguishing characteristics of the skull of the holotype specimen of M. ginkgodens were compared with the skull of KJ1181. Firstly, the angle between the frontopremaxillary suture and the frontonasal suture was compared. In the dorsal view of the vertex of the skull where the right frontal bone meets the right nasal bone, the suture between the frontal bone and premaxillary bone formed a sharp angle with the frontonasal suture in the holotype of M. ginkgodens ([Fig. 4a](#fig_004){ref-type="fig"}Fig. 4.Dorsal views of skulls of the holotype of Mesoplodon ginkgodens(NSMT-M8744) (a, c) and KJ1181 (b, d). Figures a and b are magnified from c and d, respectively. 1: Left premaxillary bone; 2: left nasal bone; 3: right frontal bone; 4: right premaxillary bone; 5: right maxilla bone. c, d: Arrows indicate antiorbital notch.). In the same manner, the two sutures also made an acute angle in the skull of KJ1181 ([Fig. 4b](#fig_004){ref-type="fig"}). Secondly, in the dorsal view of the vertex of the skull, the right nasal bone and the right premaxilla ended similarly in the holotype of M. ginkgodens ([Fig. 4a](#fig_004){ref-type="fig"}). This was also observed in the skull of KJ1181 ([Fig. 4b](#fig_004){ref-type="fig"}). Thirdly, the right antorbital notch made an acute angle of less than 90 degrees in the holotype of M. ginkgodens ([Fig. 4c](#fig_004){ref-type="fig"}). Similarly, the angle of the right antorbital notch was sharp in KJ1181 ([Fig. 4d](#fig_004){ref-type="fig"}). The features of a specimen of M. stejnegeri stored in the American Museum of Natural History (AMNH No. 143829) \\[[@r16]\\] were also used to compare the structural differences between M. ginkgodens and M. stejnegeri skulls. In the holotype of M. ginkgodens, the proximal butt-end of the two premaxillae were ascended and truncated dorsally. These dorsally projected ends were relatively flat surfaces on a plane in the lateral view that was approximately parallel to the long axis of the beak ([Fig. 5a](#fig_005){ref-type="fig"}Fig. 5.Morphological comparison of the holotype of Mesoplodon ginkgodens (NSMT-M 8744) (a, c) and KJ1181 (b, d). a, b: Lateral view. Upper arrow: ascended and dorsally truncated proximal butt-end of two premaxillae. Lower arrow: absence of premaxillary brow crease due to dorsally projected ends. c, d: Frontal view. Arrows indicate absence of premaxillary brow crease.). This was also observed in the skull of KJ1181 ([Fig. 5b](#fig_005){ref-type="fig"}). In some species of Mesoplodon, such as M. stejnegeri, there is a crest formed due to the change direction of the butt-end of the premaxillary \\[[@r16]\\]. This crest, called a premaxillary brow crease, was not present in either the holotype of M. ginkgodens or KJ1181 ([Fig. 5a and 5b](#fig_005){ref-type="fig"}). The absence of the premaxillary brow crease was also observed in the front view of the skull of M. ginkgodens and KJ1181 ([Fig. 5c and 5d](#fig_005){ref-type="fig"}). In addition to the genetic analysis, these morphological findings confirmed that the adult specimen belonged to M. ginkgodens. These two bodies were first identified as beaked whales based on their outer appearance and previous references, and the identification was then confirmed by morphological comparison of the adult skull specimen and by genetic analysis. Mesoplodon species are identified based on features of the skull, such length of the rostrum, as well as the placement, shape, and size of the teeth, particularly in adult males. However, specimens have often been misidentified due to anatomical similarities between species, and molecular genetic analyses have become increasingly important for the identification of individual specimens \\[[@r15]\\]. Nowadays, identification by genetic testing is considered to be the most reliable method. Based on the results of genetic and anatomical analyses, the stranded whales were identified as ginkgo-toothed beaked whales (M. ginkgodens). No pathological lesions that could be related to their deaths were observed. This is the first record of a stranded ginkgo-toothed beaked whale in Korea. The ginkgo-toothed beaked whale has not been previously considered to be an inhabitant of the seas near Korea \\[[@r25]\\]. This should be reconsidered based on the results of this study. One previous paper described a stranded ginkgo-toothed beaked whale in China in 1980 \\[[@r21]\\]. The identification was made only on the basis of body length and descriptions of the external features, due to the unavailability of genetic analysis at that time. Variations in each part of the body, including total body length, that can occur within the same species were not considered in that paper. Additionally, an analysis of the skull, which is essential for morphological identification, was not conducted. Thus, the result of the identification cannot be considered to be reliable. Re-identification of this specimen using genetic analysis of bone specimens is required. If this specimen is determined not to be M. ginkgodens on reanalysis, the current specimens from Jeju Island are the first accurate records of M. ginkgodens not only in the Korean Sea, but also in the whole Yellow Sea. Further research will be required to obtain more information about whales of this genus, including their habitat, abundance, and ecological characteristics. This research was supported by the 2017 Scientific Promotion Program funded by Jeju National University and the Research Institute for Veterinary Science, Seoul National University. ###### List of Accession Numbers in GenBank/DDBJ used in the molecular phylogenetic analyses Species name CR cyt b Reference ------------------------- ---------- ------------ ------------ Mesoplodon ginkgodens KR534596 KR534596 \\[[@r26]\\] KF027303 \\[[@r8]\\] AY579544 \\[[@r4]\\] KF027308 \\[[@r8]\\] KF027309 \\[[@r8]\\] M. hotaula KF027298 \\[[@r8]\\] KF027299 \\[[@r8]\\] KF027300 \\[[@r8]\\] KF027301 \\[[@r8]\\] KC951572 \\[[@r14]\\] JX470546 \\[[@r7]\\] JX470547 \\[[@r7]\\] M. carlhubbsi AY579511 \\[[@r4]\\] AY579512 \\[[@r4]\\] AY579538 \\[[@r4]\\] M. densirostris AY579513 \\[[@r4]\\] AY579514 \\[[@r4]\\] AY579540 \\[[@r4]\\] AY579541 \\[[@r4]\\] M. stejnegeri AY579527 \\[[@r4]\\] AY579528 \\[[@r4]\\] AY579553 \\[[@r4]\\] AY579554 \\[[@r4]\\] Z. cavirostris AY579530 \\[[@r4]\\] AY579531 \\[[@r4]\\] AY579561 \\[[@r4]\\] AY579562 \\[[@r4]\\] [^1]: These authors contributed equally to this work.
doug died after he had just put out some fires and was on his way to medbay when he got hit by a missile, this is the aftermathdefeated by a asteroid after just winning a battle with a drone wielding drone ship
Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids. A 4-year prospective study. To determine if deterioration in patients with asthma or chronic obstructive pulmonary disease (COPD) during bronchodilator therapy could be slowed by additional treatment with an inhaled corticosteroid. A 4-year prospective study. Twenty-nine general practices in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands. The study included 56 patients (28 with asthma and 28 with COPD) who showed an annual decrease in the forced expiratory volume in 1 second (FEV1) of at least 80 mL in combination with at least two exacerbations per year during bronchodilator therapy alone. Forty-eight patients completed the study. During the first 2 years of treatment, patients received only bronchodilator therapy (salbutamol, 400 micrograms, or ipratropium bromide, 40 micrograms). During years 3 and 4, they received additional treatment with beclomethasone dipropionate, 400 micrograms two times daily. Prebronchodilator FEV1 increased 458 mL/y (95% CI, 233 to 683 mL/y) during the first 6 months of beclomethasone treatment; FEV1 then decreased 102 mL/y (CI, 57 to 147 mL/y) during months 7 to 24. The annual decline in FEV1 during beclomethasone treatment was less than the decline of 160 mL/y seen before beclomethasone therapy (difference, 58 mL/y; 95% CI, 2 to 87 mL/y). Only in patients with asthma did beclomethasone treatment improve bronchial hyperresponsiveness (assessed by determining the concentration of histamine that provoked a 20% decrease in FEV1 [PC20]) by 3.0 doubling doses per year (95% CI, 0.8 to 5.2 doses per year). Beclomethasone treatment was associated with improvement in peak expiratory flow rate, alleviation of symptoms, and a decrease in the number of exacerbations in both patient groups. Adding beclomethasone, 800 micrograms daily, slowed the unfavorable course of asthma or COPD seen with bronchodilator therapy alone. This effect was most evident in asthmatic patients.
affiliated organizations PVMA works closely with other organizations involved in the veterinary profession in Pennsylvania. Check out some of our partners dedicated to the health and welfare of animals and improving the profession. pennsylvania veterinary foundation The Pennsylvania Veterinary Foundation (PVF) is the charitable arm of PVMA. Through donations, it funds programs which include annual scholarships to veterinary students to lessen the debt burden associated with veterinary school, veterinary reimbursement for animals helped through the Last Chance Fund (TLC), and the Henry's Cupboard Food Bank Pilot Project in Chester County which provides pet food to the elderly and the disabled. pvma assure insurance agency, inc. Unsure about selecting the insurance products you need? pvmaAssure can help! pvmaAssure Insurance Agency, Inc., is the official in-house, full-service agency created and wholly-owned by the Pennsylvania Veterinary Medical Association (PVMA) to serve the veterinary profession. We are able to take advantage of the collective purchasing power of our association and knowledge of the profession to offer you the best insurance products. pennsylvania state animal response team The Pennsylvania State Animal Response Team (PASART) was created through a private-public partnership to serve as a unifying network of organizations, businesses, federal, state, county and local government agencies, and individuals that supports the prevention, preparedness, response and recovery for emergencies affecting animals. Because disaster response needs to happen at a local level, PASART builds County Animal Response Teams (CARTs) across the state. County coordinators are selected to lead the development of county teams consisting of volunteers who will respond to emergencies at the local level. american veterinary medical asssocation The American Veterinary Medical Association (AVMA), established in 1863, is a not-for-profit association representing more than 82,500 veterinarians working in private and corporate practice, government, industry, academia, and uniformed services. Structured to work for its members, the AVMA acts as a collective voice for its membership and for the profession. The AVMA has vast resources for the veterinary professional as well as the pet owning public. partners for healthy pets Partners for Healthy Pets was created by the Partnership for Preventive Pet Healthcare™ to support veterinarians and help pet owners understand the importance of routine care and the critical role of the veterinary professional. Like you, Partners for Healthy Pets strives to improve the overall health of pets. http://www.partnersforhealthypets.org constituent associations WPVMA is a local organization of veterinary professionals. A constituent association of the Pennsylvania Veterinary Medical Association, WPVMA is dedicated to compassionate, quality health care for all animals, protecting the health of the public, strengthening the human-animal bond and providing advanced continuing education for our members. Northeastern Pennsylvania Veterinary Medical Association (NEPVMA)www.nepvma.orgNEPVMA is a local organization of veterinarians and veterinary technicians. A constituent organization of the Pennsylvania Veterinary Medical Association, they provide continuing education via six meetings held throughout the year.They also provide financial support of veterinary education through donations to the University of Pennsylvania, Veterinary Teaching Hospital. In addition, NEPVMA helps support the community on a local and national level to aid both animal and veterinary welfare in times of need as provided in the wake of hurricane Katrina. NWPVMA is a non-profit professional organization that is a constituent association of the Pennsylvania Veterinary Medical Association. It was formed to give local Northwestern Pennsylvania veterinarians opportunities for local CE, networking, discussion about current veterinary legislation, and development of professional relationships with other local veterinarians. The LVVMA is a constituent organization of the Pennsylvania Veterinary Medical Association, comprised of professionals serving the health and welfare of the Lehigh Valley, Pennsylvania community through the practice of Veterinary Medicine.
Elevenses – Working Cocker Spaniel Painting Elevenses – Working Cocker Spaniel Painting After fine morning on the hill and the partridge drive on a Sporting estate Speyside, Scotland. We stopped for elevenses in the barn and now the moment is … Read More Now working on studio projects and commissions – However, some of the exhibitions over the years inc. 2014Field Trip – April 2014 To Perth Western Australia and Victoria, Australia to paint parrots and honeyeaters Australian Galah Cockatoos – Watercolour … Read More Egon Schiele – TATE Liverpool – 24 May – 23 September 2018 See rarely-exhibited drawings by Egon Schiele in an exhibition marking the centenary year of his death Egon Schiele (1890–1918) is internationally known for depicting the human figure in … Read More Bird Artist BlogPondering’s of a bird artist and fellow creatives. Wild moorland and street art roaming’s, studio days and remote corners. Working in a wide range of media from spray paint to traditional oils Tim’s art gives voices to game … Read More We love to get email from friends and clients old and new about bird art ideas and projects. Name(required) Email(required) Website Message Studio based in North east Scotland Artist biography – Tim Niall-Harris and his creative journey began painting in the … Read More Bird Art ProjectsWorking on a wide range of bird art projects commissions for private clients in the studio. Each year work revolves around work in the studio in the UK mixed with art projects for clients in the wild corners … Read More
Q: Regex HTTP Response Body Message I use a jmeter for REST testing. I have made a HTTP Request, and this is the response data: {"id":11,"name":"value","password":null,"status":"ACTIVE","lastIp":"0.0.0.0","lastLogin":null,"addedDate":1429090984000} I need just the ID (which is 11) in {"id":11,.... I use the REGEX below : ([0-9].+?) It works perfectly but it will be a problem if my ID more than 2 digits. I need to change the REGEX to : ([0-9][0-9].+?) Is there any dynamic REGEX for my problem. Thank you for your attention. Regards, Stefio A: If you want any integer between {"id": and , use the following Regular Expression: {"id":(\\d+), However the smarter way of dealing with JSON data could be JSON Path Extractor (available via JMeter Plugins), going forward this option can be much easier to use against complex JSON. See Using the XPath Extractor in JMeter guide (scroll down to "Parsing JSON") to learn more on syntax and use cases.
[Experimental study and clinical application of rapid diagnosis of systemic candida albicans infection in burns by polymerase chain reaction]. For rapid diagnosis of systemic candidiasis, the polymerase chain reaction (PCR) was used to amplify a segment of Candida albican DNA coding for the cytochrome P450 L1 A1 in vitro. The technique provided unambiguous evidence of the presence of Candida albicans in as short as 8 hours with a detection threshold of 20 organisms. 200 blood and 120 urine specimens were collected from thirty rabbits with burn and candidiasis. Specimens of blood (n = 6), urine (n = 6), sputum (n = 7) and wound exudate (n = 7) were also collected from eight serious burn patients. PCR technique was used in all the specimens, and the result was compared with conventional fungus culture. It was shown that: (1) The positive detection rate of Candida by PCR was significantly higher than by culture for blood specimens (P < 0.01) and serial specimens of urine (P < 0.05) in infected burn animals. The clinical specimens showed the same results; (2) In evaluating diagnostic value of PCR for systemic Candida albicans infection, it was found that sensitivity, accuracy and negative prediction rate were superior to the conventional culture method. These results suggest that PCR technic may provide a rapid sensitive and specific means for the diagnosis of systemic Candida albicans infection. In addition, it may be helpful in the evaluation of therapeutic response or recurrence of infection.
The application relates to an apparatus comprising a fuel cell unit and a component, such as for example a heat exchanger or a reformer. The application also relates to a stack component for use for example in such an apparatus or generally for use in combination with devices requiring a fluid flow passing through the device. The application also relates to a component unit comprising two stack components. In order to optimize energy performance of fuel cell stacks, these are combined with heat exchangers, afterburners, reformers or several of these components. Since space is often limited compact systems are preferred. In WO-A-2004/082057 a modularly built fuel cell system is described, wherein further components such as an afterburner, a heat exchanger and a reformer are subsequently arranged to a planar fuel cell stack. The outer geometry of the fuel cell stack and the further components match each other. Through bore holes in the plates and tubes arranged in the components, fluid is guided within the components and from one component to another. Plates are positioned perpendicular to the general flow direction, so that the flow has to be guided by tubes from one component to another. Deflection plates may be required to bridge individual fluid channels in the system. Thus, this system bears high pressure drop and non-uniform temperatures due to fluid flow deflection and requires additional space to accommodate the connecting elements between components. Therefore, there is a need for a compact apparatus comprising a fuel cell unit and a component such as for example a heat exchanger, a reformer, a preheater or an afterburner, which apparatus provides good flow characteristic. There is also a need to provide a component unit comprising two stack components to form for example such an apparatus or a stack component for use for example in such an apparatus, to support the overall performance of such a combined system.
[Surgical and functional anatomy of the base of the skull: middle and posterior sections (author's transl)]. There has recently been renewed interest in the anatomy of the base of the skull. In this anatomical introduction, after an osteological description of views and sections of the base of the skull, exo- and endocranial, the author reviews the environment and relations of the endocranial surface, the exocranial surface as well as those of the structures involved in and passing through the skull base. This precise information concerning certain anatomical details is useful in the interpretation of scanner results and in determining the surgical approach to this region.
# From ftp://gcc.gnu.org/pub/binutils/releases/sha512.sum sha512 dc5b6872ae01c07c12d38f3bb7ead06effc6da3265ac872e2d9c6104304f89f85f2645b029a43f308a7938a7299b1928d385205d0a2245674a621649032a138d binutils-2.28.1.tar.xz sha512 d748d22306477d60d921078804d21943248c23fca0707aac9b016a352c01c75ca69e82624ae37fb0bbd03af3b17088a94f60dfe1a86a7ff82e18ece3c24f0fd0 binutils-2.29.1.tar.xz sha512 e747ea20d8d79fcd21b9d9f6695059caa7189d60f19256da398e34b789fea9a133c32b192e9693b5828d27683739b0198431bf8b3e39fb3b04884cf89d9aa839 binutils-2.30.tar.xz sha512 0fca326feb1d5f5fe505a827b20237fe3ec9c13eaf7ec7e35847fd71184f605ba1cefe1314b1b8f8a29c0aa9d88162849ee1c1a3e70c2f7407d88339b17edb30 binutils-2.31.1.tar.xz # Locally calculated (fetched from Github) sha512 a96dfcea6064fcd1aac1333ac0d631491bed8b0be9bdcf62f1447909c8f30d2cb8d9323ffeb7c9ad6b326ecddb72e3d28281684e73343189d0a4a37a11aef62f binutils-gdb-arc-2018.09-release.tar.gz
1. Field of the Invention The present application relates generally to use of thermal management. Still more particularly, the present application relates to a computer implemented method, data processing system, and processor for tracing thermal data via performance monitoring. 2. Description of the Related Art The first-generation heterogeneous Cell Broadband Engine™ (BE) processor is a multi-core chip comprised of a 64-bit Power PC® processor core and eight single instruction multiple data (SIMD) synergistic processor cores, capable of massive floating point processing, optimized for compute-intensive workloads and broadband rich media applications. A high-speed memory controller and high-bandwidth bus interface are also integrated on-chip. Cell BE's breakthrough multi-core architecture and ultra high-speed communications capabilities deliver vastly improved, real-time response, in many cases ten times the performance of the latest PC processors. Cell BE is operating system neutral and supports multiple operating systems simultaneously. Applications for this type of processor range from a next generation of game systems with dramatically enhanced realism, to systems that form the hub for digital media and streaming content in the home, to systems used to develop and distribute digital content, and to systems to accelerate visualization and supercomputing applications. Today's multi-core processors are frequently limited by thermal considerations. Typical solutions include cooling and power management. Cooling may be expensive and/or difficult to package. Power management is generally a coarse action, “throttling” much if not all of the processor in reaction to a thermal limit being reached. Other techniques such as thermal management help address these coarse actions by only throttling the units exceeding a given temperature. However, most thermal management techniques impact the real-time guarantees of an application. Therefore, it would be beneficial to provide a thermal management solution which provides a processor with a method to guarantee the real-time nature of an application even in the event of a thermal condition which requires throttling of the processor. In the cases where the real-time guarantees can not be met, the application administrator is notified so that a corrective action can be implemented.
[delicious] Tim Wendelboe » Our Coffees?log=out Tim Wendelboe is a micro roastery and we focus on buying unique small lots of coffee that hopefully will challenge your coffee preferences. We strive to only buy coffee according to the harvest season we are currently in. This means we buy small lots of coffee from different countries throughout the year and our offerings are constantly changing. We only do one espressoblend that also changes 4-5 times a year according to the season we are in. This is to highlight the fresh coffees and to also always try to improve ourselves and the espresso blend. We believe that change is good. All our coffees are carefully sourced based on a philosophy where quality, traceability, innovation and social responsibility is the main focus. Sustainability is very important to us and we try to satisfy both our customers as well as our suppliers when we buy our coffee. In the menu to the left ...
# Usage If you want to use default theme, you can skip this step To achieve the level of customizability, React Native Material UI is using a single JS object called uiTheme that is passed in via context. By default, this uiTheme object is based on the lightTheme that you can find [here](https://github.com/xotahal/react-native-material-ui/blob/master/src/styles/themes/light.js). So, you can change almost everything very easily. The uiTheme object contains the following keys (for more of them - check the code): ```js spacing: {} // can be used to change the spacing of components. fontFamily: {} // can be used to change the default font family. palette: { // can be used to change the color of components. primaryColor: blue500, accentColor: red500, ... } typography: {} // can be used to change the typography of components // you can change style of every each component avatar: {} button: {} toolbar: {} ... ``` ```js import React, { Component } from 'react'; import { Navigator, NativeModules } from 'react-native'; import { COLOR, ThemeContext, getTheme } from 'react-native-material-ui'; // you can set your style right here, it'll be propagated to application const uiTheme = { palette: { primaryColor: COLOR.green500, }, toolbar: { container: { height: 50, }, }, }; class Main extends Component { render() { return ( <ThemeContext.Provider value={getTheme(uiTheme)}> <App /> </ThemeContext.Provider> ); } } ``` It means, if you want to change primary color of your application you can just pass to ThemeContext.Provider object with your own settings. The settings will be merged with default theme. ## What else? Another great feature is, you can use the `theme` everywhere. Even in your own components. So if you built your own implementation of `Button` for example, look how you can get the primary color. ```js import { withTheme } from 'react-native-material-ui' class MyButton extends Component { render() { // it's really easy to get primary color everywhere in your app const { primaryColor } = this.props.theme.palette; return ... } } export default withTheme(MyButton) ``` ## Local changes Of course, sometimes we need to change style of only one component. All `buttons` have a red background by default, but only facebook button should have blue background. Every component have a `style` property. So you can very easily override whatever you want. ```js <Button style={{ container: { backgroundColor: 'blue' } }} /> ```
/* * Copyright (C) 2015 Apple Inc. All rights reserved. * * Redistribution and use in source and binary forms, with or without * modification, are permitted provided that the following conditions * are met: * 1. Redistributions of source code must retain the above copyright * notice, this list of conditions and the following disclaimer. * 2. Redistributions in binary form must reproduce the above copyright * notice, this list of conditions and the following disclaimer in the * documentation and/or other materials provided with the distribution. * * THIS SOFTWARE IS PROVIDED BY APPLE INC. ``AS IS'' AND ANY * EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE * IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR * PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL APPLE INC. OR * CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, * EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO, * PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, DATA, OR * PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY THEORY * OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT * (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE * OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. / #include "config.h" #include "WASMFunctionParser.h" #if ENABLE(WEBASSEMBLY) #include "JSCJSValueInlines.h" #include "JSWASMModule.h" #include "WASMFunctionCompiler.h" #include "WASMFunctionB3IRGenerator.h" #include "WASMFunctionSyntaxChecker.h" #define PROPAGATE_ERROR() do { if (!m_errorMessage.isNull()) return 0; } while (0) #define FAIL_WITH_MESSAGE(errorMessage) do { m_errorMessage = errorMessage; return 0; } while (0) #define READ_FLOAT_OR_FAIL(result, errorMessage) do { if (!m_reader.readFloat(result)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_DOUBLE_OR_FAIL(result, errorMessage) do { if (!m_reader.readDouble(result)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_COMPACT_INT32_OR_FAIL(result, errorMessage) do { if (!m_reader.readCompactInt32(result)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_COMPACT_UINT32_OR_FAIL(result, errorMessage) do { if (!m_reader.readCompactUInt32(result)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_EXPRESSION_TYPE_OR_FAIL(result, errorMessage) do { if (!m_reader.readExpressionType(result)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_OP_STATEMENT_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, errorMessage) do { if (!m_reader.readOpStatement(hasImmediate, op, opWithImmediate, immediate)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_OP_EXPRESSION_I32_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, errorMessage) do { if (!m_reader.readOpExpressionI32(hasImmediate, op, opWithImmediate, immediate)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_OP_EXPRESSION_F32_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, errorMessage) do { if (!m_reader.readOpExpressionF32(hasImmediate, op, opWithImmediate, immediate)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_OP_EXPRESSION_F64_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, errorMessage) do { if (!m_reader.readOpExpressionF64(hasImmediate, op, opWithImmediate, immediate)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_OP_EXPRESSION_VOID_OR_FAIL(op, errorMessage) do { if (!m_reader.readOpExpressionVoid(op)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_VARIABLE_TYPES_OR_FAIL(hasImmediate, variableTypes, variableTypesWithImmediate, immediate, errorMessage) do { if (!m_reader.readVariableTypes(hasImmediate, variableTypes, variableTypesWithImmediate, immediate)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define READ_SWITCH_CASE_OR_FAIL(result, errorMessage) do { if (!m_reader.readSwitchCase(result)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define FAIL_IF_FALSE(condition, errorMessage) do { if (!(condition)) FAIL_WITH_MESSAGE(errorMessage); } while (0) #define UNUSED 0 namespace JSC { static String nameOfType(WASMType type) { switch (type) { case WASMType::I32: return "int32"; case WASMType::F32: return "float32"; case WASMType::F64: return "float64"; default: RELEASE_ASSERT_NOT_REACHED(); } } bool WASMFunctionParser::checkSyntax(JSWASMModule module, const SourceCode& source, size_t functionIndex, unsigned startOffsetInSource, unsigned& endOffsetInSource, unsigned& stackHeight, String& errorMessage) { WASMFunctionParser parser(module, source, functionIndex); WASMFunctionSyntaxChecker syntaxChecker; parser.m_reader.setOffset(startOffsetInSource); parser.parseFunction(syntaxChecker); if (!parser.m_errorMessage.isNull()) { errorMessage = parser.m_errorMessage; return false; } endOffsetInSource = parser.m_reader.offset(); stackHeight = syntaxChecker.stackHeight(); return true; } void WASMFunctionParser::compile(VM& vm, CodeBlock* codeBlock, JSWASMModule* module, const SourceCode& source, size_t functionIndex) { WASMFunctionParser parser(module, source, functionIndex); WASMFunctionCompiler compiler(vm, codeBlock, module, module->functionStackHeights()[functionIndex]); parser.m_reader.setOffset(module->functionStartOffsetsInSource()[functionIndex]); parser.parseFunction(compiler); ASSERT(parser.m_errorMessage.isNull()); } template <class Context> bool WASMFunctionParser::parseFunction(Context& context) { const WASMSignature& signature = m_module->signatures()[m_module->functionDeclarations()[m_functionIndex].signatureIndex]; m_returnType = signature.returnType; parseLocalVariables(); PROPAGATE_ERROR(); const Vector<WASMType>& arguments = signature.arguments; for (size_t i = 0; i < arguments.size(); ++i) m_localTypes.append(arguments[i]); for (uint32_t i = 0; i < m_numberOfI32LocalVariables; ++i) m_localTypes.append(WASMType::I32); for (uint32_t i = 0; i < m_numberOfF32LocalVariables; ++i) m_localTypes.append(WASMType::F32); for (uint32_t i = 0; i < m_numberOfF64LocalVariables; ++i) m_localTypes.append(WASMType::F64); context.startFunction(arguments, m_numberOfI32LocalVariables, m_numberOfF32LocalVariables, m_numberOfF64LocalVariables); parseBlockStatement(context); PROPAGATE_ERROR(); context.endFunction(); return true; } bool WASMFunctionParser::parseLocalVariables() { m_numberOfI32LocalVariables = 0; m_numberOfF32LocalVariables = 0; m_numberOfF64LocalVariables = 0; bool hasImmediate; WASMVariableTypes variableTypes; WASMVariableTypesWithImmediate variableTypesWithImmediate; uint8_t immediate; READ_VARIABLE_TYPES_OR_FAIL(hasImmediate, variableTypes, variableTypesWithImmediate, immediate, "Cannot read the types of local variables."); if (!hasImmediate) { if (static_cast<uint8_t>(variableTypes) & static_cast<uint8_t>(WASMVariableTypes::I32)) READ_COMPACT_UINT32_OR_FAIL(m_numberOfI32LocalVariables, "Cannot read the number of int32 local variables."); if (static_cast<uint8_t>(variableTypes) & static_cast<uint8_t>(WASMVariableTypes::F32)) READ_COMPACT_UINT32_OR_FAIL(m_numberOfF32LocalVariables, "Cannot read the number of float32 local variables."); if (static_cast<uint8_t>(variableTypes) & static_cast<uint8_t>(WASMVariableTypes::F64)) READ_COMPACT_UINT32_OR_FAIL(m_numberOfF64LocalVariables, "Cannot read the number of float64 local variables."); } else m_numberOfI32LocalVariables = immediate; return true; } template <class Context> ContextStatement WASMFunctionParser::parseStatement(Context& context) { bool hasImmediate; WASMOpStatement op; WASMOpStatementWithImmediate opWithImmediate; uint8_t immediate; READ_OP_STATEMENT_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, "Cannot read the statement opcode."); if (!hasImmediate) { switch (op) { case WASMOpStatement::SetLocal: parseSetLocal(context, WASMOpKind::Statement, WASMExpressionType::Void); break; case WASMOpStatement::SetGlobal: parseSetGlobal(context, WASMOpKind::Statement, WASMExpressionType::Void); break; case WASMOpStatement::I32Store8: parseStore(context, WASMOpKind::Statement, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::NoOffset); break; case WASMOpStatement::I32StoreWithOffset8: parseStore(context, WASMOpKind::Statement, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::WithOffset); break; case WASMOpStatement::I32Store16: parseStore(context, WASMOpKind::Statement, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::NoOffset); break; case WASMOpStatement::I32StoreWithOffset16: parseStore(context, WASMOpKind::Statement, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::WithOffset); break; case WASMOpStatement::I32Store32: parseStore(context, WASMOpKind::Statement, WASMExpressionType::I32, WASMMemoryType::I32, MemoryAccessOffsetMode::NoOffset); break; case WASMOpStatement::I32StoreWithOffset32: parseStore(context, WASMOpKind::Statement, WASMExpressionType::I32, WASMMemoryType::I32, MemoryAccessOffsetMode::WithOffset); break; case WASMOpStatement::F32Store: parseStore(context, WASMOpKind::Statement, WASMExpressionType::F32, WASMMemoryType::F32, MemoryAccessOffsetMode::NoOffset); break; case WASMOpStatement::F32StoreWithOffset: parseStore(context, WASMOpKind::Statement, WASMExpressionType::F32, WASMMemoryType::F32, MemoryAccessOffsetMode::WithOffset); break; case WASMOpStatement::F64Store: parseStore(context, WASMOpKind::Statement, WASMExpressionType::F64, WASMMemoryType::F64, MemoryAccessOffsetMode::NoOffset); break; case WASMOpStatement::F64StoreWithOffset: parseStore(context, WASMOpKind::Statement, WASMExpressionType::F64, WASMMemoryType::F64, MemoryAccessOffsetMode::WithOffset); break; case WASMOpStatement::CallInternal: parseCallInternal(context, WASMOpKind::Statement, WASMExpressionType::Void); break; case WASMOpStatement::CallIndirect: parseCallIndirect(context, WASMOpKind::Statement, WASMExpressionType::Void); break; case WASMOpStatement::CallImport: parseCallImport(context, WASMOpKind::Statement, WASMExpressionType::Void); break; case WASMOpStatement::Return: parseReturnStatement(context); break; case WASMOpStatement::Block: parseBlockStatement(context); break; case WASMOpStatement::If: parseIfStatement(context); break; case WASMOpStatement::IfElse: parseIfElseStatement(context); break; case WASMOpStatement::While: parseWhileStatement(context); break; case WASMOpStatement::Do: parseDoStatement(context); break; case WASMOpStatement::Label: parseLabelStatement(context); break; case WASMOpStatement::Break: parseBreakStatement(context); break; case WASMOpStatement::BreakLabel: parseBreakLabelStatement(context); break; case WASMOpStatement::Continue: parseContinueStatement(context); break; case WASMOpStatement::ContinueLabel: parseContinueLabelStatement(context); break; case WASMOpStatement::Switch: parseSwitchStatement(context); break; default: ASSERT_NOT_REACHED(); } } else { switch (opWithImmediate) { case WASMOpStatementWithImmediate::SetLocal: parseSetLocal(context, WASMOpKind::Statement, WASMExpressionType::Void, immediate); break; case WASMOpStatementWithImmediate::SetGlobal: parseSetGlobal(context, WASMOpKind::Statement, WASMExpressionType::Void, immediate); break; default: ASSERT_NOT_REACHED(); } } return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseReturnStatement(Context& context) { ContextExpression expression = 0; if (m_returnType != WASMExpressionType::Void) { expression = parseExpression(context, m_returnType); PROPAGATE_ERROR(); } context.buildReturn(expression, m_returnType); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseBlockStatement(Context& context) { uint32_t numberOfStatements; READ_COMPACT_UINT32_OR_FAIL(numberOfStatements, "Cannot read the number of statements."); for (uint32_t i = 0; i < numberOfStatements; ++i) { parseStatement(context); PROPAGATE_ERROR(); } return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseIfStatement(Context& context) { ContextJumpTarget end; ContextExpression expression = parseExpressionI32(context); PROPAGATE_ERROR(); context.jumpToTargetIf(Context::JumpCondition::Zero, expression, end); parseStatement(context); PROPAGATE_ERROR(); context.linkTarget(end); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseIfElseStatement(Context& context) { ContextJumpTarget elseTarget; ContextJumpTarget end; ContextExpression expression = parseExpressionI32(context); PROPAGATE_ERROR(); context.jumpToTargetIf(Context::JumpCondition::Zero, expression, elseTarget); parseStatement(context); PROPAGATE_ERROR(); context.jumpToTarget(end); context.linkTarget(elseTarget); parseStatement(context); PROPAGATE_ERROR(); context.linkTarget(end); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseWhileStatement(Context& context) { context.startLoop(); context.linkTarget(context.continueTarget()); ContextExpression expression = parseExpressionI32(context); PROPAGATE_ERROR(); context.jumpToTargetIf(Context::JumpCondition::Zero, expression, context.breakTarget()); m_breakScopeDepth++; m_continueScopeDepth++; parseStatement(context); PROPAGATE_ERROR(); m_continueScopeDepth--; m_breakScopeDepth--; context.jumpToTarget(context.continueTarget()); context.linkTarget(context.breakTarget()); context.endLoop(); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseDoStatement(Context& context) { context.startLoop(); ContextJumpTarget topOfLoop; context.linkTarget(topOfLoop); m_breakScopeDepth++; m_continueScopeDepth++; parseStatement(context); PROPAGATE_ERROR(); m_continueScopeDepth--; m_breakScopeDepth--; context.linkTarget(context.continueTarget()); ContextExpression expression = parseExpressionI32(context); PROPAGATE_ERROR(); context.jumpToTargetIf(Context::JumpCondition::NonZero, expression, topOfLoop); context.linkTarget(context.breakTarget()); context.endLoop(); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseLabelStatement(Context& context) { context.startLabel(); m_labelDepth++; parseStatement(context); PROPAGATE_ERROR(); m_labelDepth--; context.endLabel(); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseBreakStatement(Context& context) { FAIL_IF_FALSE(m_breakScopeDepth, "'break' is only valid inside a switch or loop statement."); context.jumpToTarget(context.breakTarget()); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseBreakLabelStatement(Context& context) { uint32_t labelIndex; READ_COMPACT_UINT32_OR_FAIL(labelIndex, "Cannot read the label index."); FAIL_IF_FALSE(labelIndex < m_labelDepth, "The label index is incorrect."); context.jumpToTarget(context.breakLabelTarget(labelIndex)); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseContinueStatement(Context& context) { FAIL_IF_FALSE(m_continueScopeDepth, "'continue' is only valid inside a loop statement."); context.jumpToTarget(context.continueTarget()); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseContinueLabelStatement(Context& context) { uint32_t labelIndex; READ_COMPACT_UINT32_OR_FAIL(labelIndex, "Cannot read the label index."); FAIL_IF_FALSE(labelIndex < m_labelDepth, "The label index is incorrect."); context.jumpToTarget(context.continueLabelTarget(labelIndex)); return UNUSED; } template <class Context> ContextStatement WASMFunctionParser::parseSwitchStatement(Context& context) { context.startSwitch(); uint32_t numberOfCases; READ_COMPACT_UINT32_OR_FAIL(numberOfCases, "Cannot read the number of cases."); ContextExpression expression = parseExpressionI32(context); PROPAGATE_ERROR(); ContextJumpTarget compare; context.jumpToTarget(compare); Vector<int64_t> cases; Vector<ContextJumpTarget> targets; cases.reserveInitialCapacity(numberOfCases); targets.reserveInitialCapacity(numberOfCases); bool hasDefault = false; ContextJumpTarget defaultTarget; m_breakScopeDepth++; for (uint32_t i = 0; i < numberOfCases; ++i) { WASMSwitchCase switchCase; READ_SWITCH_CASE_OR_FAIL(switchCase, "Cannot read the switch case."); switch (switchCase) { case WASMSwitchCase::CaseWithNoStatements: case WASMSwitchCase::CaseWithStatement: case WASMSwitchCase::CaseWithBlockStatement: { uint32_t value; READ_COMPACT_INT32_OR_FAIL(value, "Cannot read the value of the switch case."); cases.uncheckedAppend(value); ContextJumpTarget target; context.linkTarget(target); targets.uncheckedAppend(target); if (switchCase == WASMSwitchCase::CaseWithStatement) { parseStatement(context); PROPAGATE_ERROR(); } else if (switchCase == WASMSwitchCase::CaseWithBlockStatement) { parseBlockStatement(context); PROPAGATE_ERROR(); } break; } case WASMSwitchCase::DefaultWithNoStatements: case WASMSwitchCase::DefaultWithStatement: case WASMSwitchCase::DefaultWithBlockStatement: { FAIL_IF_FALSE(i == numberOfCases - 1, "The default case must be the last case."); hasDefault = true; context.linkTarget(defaultTarget); if (switchCase == WASMSwitchCase::DefaultWithStatement) { parseStatement(context); PROPAGATE_ERROR(); } else if (switchCase == WASMSwitchCase::DefaultWithBlockStatement) { parseBlockStatement(context); PROPAGATE_ERROR(); } break; } default: ASSERT_NOT_REACHED(); } } if (!hasDefault) context.linkTarget(defaultTarget); m_breakScopeDepth--; context.jumpToTarget(context.breakTarget()); context.linkTarget(compare); context.buildSwitch(expression, cases, targets, defaultTarget); context.linkTarget(context.breakTarget()); context.endSwitch(); return UNUSED; } template <class Context> ContextExpression WASMFunctionParser::parseExpression(Context& context, WASMExpressionType expressionType) { switch (expressionType) { case WASMExpressionType::I32: return parseExpressionI32(context); case WASMExpressionType::F32: return parseExpressionF32(context); case WASMExpressionType::F64: return parseExpressionF64(context); case WASMExpressionType::Void: return parseExpressionVoid(context); default: RELEASE_ASSERT_NOT_REACHED(); } } template <class Context> ContextExpression WASMFunctionParser::parseExpressionI32(Context& context) { bool hasImmediate; WASMOpExpressionI32 op; WASMOpExpressionI32WithImmediate opWithImmediate; uint8_t immediate; READ_OP_EXPRESSION_I32_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, "Cannot read the int32 expression opcode."); if (!hasImmediate) { switch (op) { case WASMOpExpressionI32::ConstantPoolIndex: return parseConstantPoolIndexExpressionI32(context); case WASMOpExpressionI32::Immediate: return parseImmediateExpressionI32(context); case WASMOpExpressionI32::GetLocal: return parseGetLocalExpression(context, WASMType::I32); case WASMOpExpressionI32::GetGlobal: return parseGetGlobalExpression(context, WASMType::I32); case WASMOpExpressionI32::SetLocal: return parseSetLocal(context, WASMOpKind::Expression, WASMExpressionType::I32); case WASMOpExpressionI32::SetGlobal: return parseSetGlobal(context, WASMOpKind::Expression, WASMExpressionType::I32); case WASMOpExpressionI32::SLoad8: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::NoOffset, MemoryAccessConversion::SignExtend); case WASMOpExpressionI32::SLoadWithOffset8: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::WithOffset, MemoryAccessConversion::SignExtend); case WASMOpExpressionI32::ULoad8: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::NoOffset, MemoryAccessConversion::ZeroExtend); case WASMOpExpressionI32::ULoadWithOffset8: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::WithOffset, MemoryAccessConversion::ZeroExtend); case WASMOpExpressionI32::SLoad16: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::NoOffset, MemoryAccessConversion::SignExtend); case WASMOpExpressionI32::SLoadWithOffset16: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::WithOffset, MemoryAccessConversion::SignExtend); case WASMOpExpressionI32::ULoad16: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::NoOffset, MemoryAccessConversion::ZeroExtend); case WASMOpExpressionI32::ULoadWithOffset16: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::WithOffset, MemoryAccessConversion::ZeroExtend); case WASMOpExpressionI32::Load32: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I32, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionI32::LoadWithOffset32: return parseLoad(context, WASMExpressionType::I32, WASMMemoryType::I32, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionI32::Store8: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionI32::StoreWithOffset8: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::I32, WASMMemoryType::I8, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionI32::Store16: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionI32::StoreWithOffset16: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::I32, WASMMemoryType::I16, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionI32::Store32: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::I32, WASMMemoryType::I32, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionI32::StoreWithOffset32: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::I32, WASMMemoryType::I32, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionI32::CallInternal: return parseCallInternal(context, WASMOpKind::Expression, WASMExpressionType::I32); case WASMOpExpressionI32::CallIndirect: return parseCallIndirect(context, WASMOpKind::Expression, WASMExpressionType::I32); case WASMOpExpressionI32::CallImport: return parseCallImport(context, WASMOpKind::Expression, WASMExpressionType::I32); case WASMOpExpressionI32::Conditional: return parseConditional(context, WASMExpressionType::I32); case WASMOpExpressionI32::Comma: return parseComma(context, WASMExpressionType::I32); case WASMOpExpressionI32::FromF32: return parseConvertType(context, WASMExpressionType::F32, WASMExpressionType::I32, WASMTypeConversion::ConvertSigned); case WASMOpExpressionI32::FromF64: return parseConvertType(context, WASMExpressionType::F64, WASMExpressionType::I32, WASMTypeConversion::ConvertSigned); case WASMOpExpressionI32::Negate: case WASMOpExpressionI32::BitNot: case WASMOpExpressionI32::CountLeadingZeros: case WASMOpExpressionI32::LogicalNot: case WASMOpExpressionI32::Abs: return parseUnaryExpressionI32(context, op); case WASMOpExpressionI32::Add: case WASMOpExpressionI32::Sub: case WASMOpExpressionI32::Mul: case WASMOpExpressionI32::SDiv: case WASMOpExpressionI32::UDiv: case WASMOpExpressionI32::SMod: case WASMOpExpressionI32::UMod: case WASMOpExpressionI32::BitOr: case WASMOpExpressionI32::BitAnd: case WASMOpExpressionI32::BitXor: case WASMOpExpressionI32::LeftShift: case WASMOpExpressionI32::ArithmeticRightShift: case WASMOpExpressionI32::LogicalRightShift: return parseBinaryExpressionI32(context, op); case WASMOpExpressionI32::EqualI32: case WASMOpExpressionI32::NotEqualI32: case WASMOpExpressionI32::SLessThanI32: case WASMOpExpressionI32::ULessThanI32: case WASMOpExpressionI32::SLessThanOrEqualI32: case WASMOpExpressionI32::ULessThanOrEqualI32: case WASMOpExpressionI32::SGreaterThanI32: case WASMOpExpressionI32::UGreaterThanI32: case WASMOpExpressionI32::SGreaterThanOrEqualI32: case WASMOpExpressionI32::UGreaterThanOrEqualI32: return parseRelationalI32ExpressionI32(context, op); case WASMOpExpressionI32::EqualF32: case WASMOpExpressionI32::NotEqualF32: case WASMOpExpressionI32::LessThanF32: case WASMOpExpressionI32::LessThanOrEqualF32: case WASMOpExpressionI32::GreaterThanF32: case WASMOpExpressionI32::GreaterThanOrEqualF32: return parseRelationalF32ExpressionI32(context, op); case WASMOpExpressionI32::EqualF64: case WASMOpExpressionI32::NotEqualF64: case WASMOpExpressionI32::LessThanF64: case WASMOpExpressionI32::LessThanOrEqualF64: case WASMOpExpressionI32::GreaterThanF64: case WASMOpExpressionI32::GreaterThanOrEqualF64: return parseRelationalF64ExpressionI32(context, op); case WASMOpExpressionI32::SMin: case WASMOpExpressionI32::UMin: case WASMOpExpressionI32::SMax: case WASMOpExpressionI32::UMax: return parseMinOrMaxExpressionI32(context, op); default: ASSERT_NOT_REACHED(); } } else { switch (opWithImmediate) { case WASMOpExpressionI32WithImmediate::ConstantPoolIndex: return parseConstantPoolIndexExpressionI32(context, immediate); case WASMOpExpressionI32WithImmediate::Immediate: return parseImmediateExpressionI32(context, immediate); case WASMOpExpressionI32WithImmediate::GetLocal: return parseGetLocalExpression(context, WASMType::I32, immediate); default: ASSERT_NOT_REACHED(); } } return 0; } template <class Context> ContextExpression WASMFunctionParser::parseConstantPoolIndexExpressionI32(Context& context, uint32_t constantPoolIndex) { FAIL_IF_FALSE(constantPoolIndex < m_module->i32Constants().size(), "The constant pool index is incorrect."); return context.buildImmediateI32(m_module->i32Constants()[constantPoolIndex]); } template <class Context> ContextExpression WASMFunctionParser::parseConstantPoolIndexExpressionI32(Context& context) { uint32_t constantPoolIndex; READ_COMPACT_UINT32_OR_FAIL(constantPoolIndex, "Cannot read the constant pool index."); return parseConstantPoolIndexExpressionI32(context, constantPoolIndex); } template <class Context> ContextExpression WASMFunctionParser::parseImmediateExpressionI32(Context& context, uint32_t immediate) { return context.buildImmediateI32(immediate); } template <class Context> ContextExpression WASMFunctionParser::parseImmediateExpressionI32(Context& context) { uint32_t immediate; READ_COMPACT_UINT32_OR_FAIL(immediate, "Cannot read the immediate."); return parseImmediateExpressionI32(context, immediate); } template <class Context> ContextExpression WASMFunctionParser::parseUnaryExpressionI32(Context& context, WASMOpExpressionI32 op) { ContextExpression expression = parseExpressionI32(context); PROPAGATE_ERROR(); return context.buildUnaryI32(expression, op); } template <class Context> ContextExpression WASMFunctionParser::parseBinaryExpressionI32(Context& context, WASMOpExpressionI32 op) { ContextExpression left = parseExpressionI32(context); PROPAGATE_ERROR(); ContextExpression right = parseExpressionI32(context); PROPAGATE_ERROR(); return context.buildBinaryI32(left, right, op); } template <class Context> ContextExpression WASMFunctionParser::parseRelationalI32ExpressionI32(Context& context, WASMOpExpressionI32 op) { ContextExpression left = parseExpressionI32(context); PROPAGATE_ERROR(); ContextExpression right = parseExpressionI32(context); PROPAGATE_ERROR(); return context.buildRelationalI32(left, right, op); } template <class Context> ContextExpression WASMFunctionParser::parseRelationalF32ExpressionI32(Context& context, WASMOpExpressionI32 op) { ContextExpression left = parseExpressionF32(context); PROPAGATE_ERROR(); ContextExpression right = parseExpressionF32(context); PROPAGATE_ERROR(); return context.buildRelationalF32(left, right, op); } template <class Context> ContextExpression WASMFunctionParser::parseRelationalF64ExpressionI32(Context& context, WASMOpExpressionI32 op) { ContextExpression left = parseExpressionF64(context); PROPAGATE_ERROR(); ContextExpression right = parseExpressionF64(context); PROPAGATE_ERROR(); return context.buildRelationalF64(left, right, op); } template <class Context> ContextExpression WASMFunctionParser::parseMinOrMaxExpressionI32(Context& context, WASMOpExpressionI32 op) { uint32_t numberOfArguments; READ_COMPACT_UINT32_OR_FAIL(numberOfArguments, "Cannot read the number of arguments to min/max."); FAIL_IF_FALSE(numberOfArguments >= 2, "Min/max must be passed at least 2 arguments."); ContextExpression current = parseExpressionI32(context); PROPAGATE_ERROR(); for (uint32_t i = 1; i < numberOfArguments; ++i) { ContextExpression expression = parseExpressionI32(context); PROPAGATE_ERROR(); current = context.buildMinOrMaxI32(current, expression, op); } return current; } template <class Context> ContextExpression WASMFunctionParser::parseExpressionF32(Context& context) { bool hasImmediate; WASMOpExpressionF32 op; WASMOpExpressionF32WithImmediate opWithImmediate; uint8_t immediate; READ_OP_EXPRESSION_F32_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, "Cannot read the float32 expression opcode."); if (!hasImmediate) { switch (op) { case WASMOpExpressionF32::ConstantPoolIndex: return parseConstantPoolIndexExpressionF32(context); case WASMOpExpressionF32::Immediate: return parseImmediateExpressionF32(context); case WASMOpExpressionF32::GetLocal: return parseGetLocalExpression(context, WASMType::F32); case WASMOpExpressionF32::GetGlobal: return parseGetGlobalExpression(context, WASMType::F32); case WASMOpExpressionF32::SetLocal: return parseSetLocal(context, WASMOpKind::Expression, WASMExpressionType::F32); case WASMOpExpressionF32::SetGlobal: return parseSetGlobal(context, WASMOpKind::Expression, WASMExpressionType::F32); case WASMOpExpressionF32::Load: return parseLoad(context, WASMExpressionType::F32, WASMMemoryType::F32, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionF32::LoadWithOffset: return parseLoad(context, WASMExpressionType::F32, WASMMemoryType::F32, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionF32::Store: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::F32, WASMMemoryType::F32, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionF32::StoreWithOffset: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::F32, WASMMemoryType::F32, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionF32::CallInternal: return parseCallInternal(context, WASMOpKind::Expression, WASMExpressionType::F32); case WASMOpExpressionF32::CallIndirect: return parseCallIndirect(context, WASMOpKind::Expression, WASMExpressionType::F32); case WASMOpExpressionF32::Conditional: return parseConditional(context, WASMExpressionType::F32); case WASMOpExpressionF32::Comma: return parseComma(context, WASMExpressionType::F32); case WASMOpExpressionF32::FromS32: return parseConvertType(context, WASMExpressionType::I32, WASMExpressionType::F32, WASMTypeConversion::ConvertSigned); case WASMOpExpressionF32::FromU32: return parseConvertType(context, WASMExpressionType::I32, WASMExpressionType::F32, WASMTypeConversion::ConvertUnsigned); case WASMOpExpressionF32::FromF64: return parseConvertType(context, WASMExpressionType::F64, WASMExpressionType::F32, WASMTypeConversion::Demote); case WASMOpExpressionF32::Negate: case WASMOpExpressionF32::Abs: case WASMOpExpressionF32::Ceil: case WASMOpExpressionF32::Floor: case WASMOpExpressionF32::Sqrt: return parseUnaryExpressionF32(context, op); case WASMOpExpressionF32::Add: case WASMOpExpressionF32::Sub: case WASMOpExpressionF32::Mul: case WASMOpExpressionF32::Div: return parseBinaryExpressionF32(context, op); default: ASSERT_NOT_REACHED(); } } else { switch (opWithImmediate) { case WASMOpExpressionF32WithImmediate::ConstantPoolIndex: return parseConstantPoolIndexExpressionF32(context, immediate); case WASMOpExpressionF32WithImmediate::GetLocal: return parseGetLocalExpression(context, WASMType::F32, immediate); default: ASSERT_NOT_REACHED(); } } return 0; } template <class Context> ContextExpression WASMFunctionParser::parseConstantPoolIndexExpressionF32(Context& context, uint32_t constantIndex) { FAIL_IF_FALSE(constantIndex < m_module->f32Constants().size(), "The constant pool index is incorrect."); return context.buildImmediateF32(m_module->f32Constants()[constantIndex]); } template <class Context> ContextExpression WASMFunctionParser::parseConstantPoolIndexExpressionF32(Context& context) { uint32_t constantIndex; READ_COMPACT_UINT32_OR_FAIL(constantIndex, "Cannot read the constant pool index."); return parseConstantPoolIndexExpressionF32(context, constantIndex); } template <class Context> ContextExpression WASMFunctionParser::parseImmediateExpressionF32(Context& context) { float immediate; READ_FLOAT_OR_FAIL(immediate, "Cannot read the immediate."); return context.buildImmediateF32(immediate); } template <class Context> ContextExpression WASMFunctionParser::parseUnaryExpressionF32(Context& context, WASMOpExpressionF32 op) { ContextExpression expression = parseExpressionF32(context); PROPAGATE_ERROR(); return context.buildUnaryF32(expression, op); } template <class Context> ContextExpression WASMFunctionParser::parseBinaryExpressionF32(Context& context, WASMOpExpressionF32 op) { ContextExpression left = parseExpressionF32(context); PROPAGATE_ERROR(); ContextExpression right = parseExpressionF32(context); PROPAGATE_ERROR(); return context.buildBinaryF32(left, right, op); } template <class Context> ContextExpression WASMFunctionParser::parseExpressionF64(Context& context) { bool hasImmediate; WASMOpExpressionF64 op; WASMOpExpressionF64WithImmediate opWithImmediate; uint8_t immediate; READ_OP_EXPRESSION_F64_OR_FAIL(hasImmediate, op, opWithImmediate, immediate, "Cannot read the float64 expression opcode."); if (!hasImmediate) { switch (op) { case WASMOpExpressionF64::ConstantPoolIndex: return parseConstantPoolIndexExpressionF64(context); case WASMOpExpressionF64::Immediate: return parseImmediateExpressionF64(context); case WASMOpExpressionF64::GetLocal: return parseGetLocalExpression(context, WASMType::F64); case WASMOpExpressionF64::GetGlobal: return parseGetGlobalExpression(context, WASMType::F64); case WASMOpExpressionF64::SetLocal: return parseSetLocal(context, WASMOpKind::Expression, WASMExpressionType::F64); case WASMOpExpressionF64::SetGlobal: return parseSetGlobal(context, WASMOpKind::Expression, WASMExpressionType::F64); case WASMOpExpressionF64::Load: return parseLoad(context, WASMExpressionType::F64, WASMMemoryType::F64, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionF64::LoadWithOffset: return parseLoad(context, WASMExpressionType::F64, WASMMemoryType::F64, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionF64::Store: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::F64, WASMMemoryType::F64, MemoryAccessOffsetMode::NoOffset); case WASMOpExpressionF64::StoreWithOffset: return parseStore(context, WASMOpKind::Expression, WASMExpressionType::F64, WASMMemoryType::F64, MemoryAccessOffsetMode::WithOffset); case WASMOpExpressionF64::CallInternal: return parseCallInternal(context, WASMOpKind::Expression, WASMExpressionType::F64); case WASMOpExpressionF64::CallImport: return parseCallImport(context, WASMOpKind::Expression, WASMExpressionType::F64); case WASMOpExpressionF64::CallIndirect: return parseCallIndirect(context, WASMOpKind::Expression, WASMExpressionType::F64); case WASMOpExpressionF64::Conditional: return parseConditional(context, WASMExpressionType::F64); case WASMOpExpressionF64::Comma: return parseComma(context, WASMExpressionType::F64); case WASMOpExpressionF64::FromS32: return parseConvertType(context, WASMExpressionType::I32, WASMExpressionType::F64, WASMTypeConversion::ConvertSigned); case WASMOpExpressionF64::FromU32: return parseConvertType(context, WASMExpressionType::I32, WASMExpressionType::F64, WASMTypeConversion::ConvertUnsigned); case WASMOpExpressionF64::FromF32: return parseConvertType(context, WASMExpressionType::F32, WASMExpressionType::F64, WASMTypeConversion::Promote); case WASMOpExpressionF64::Negate: case WASMOpExpressionF64::Abs: case WASMOpExpressionF64::Ceil: case WASMOpExpressionF64::Floor: case WASMOpExpressionF64::Sqrt: case WASMOpExpressionF64::Cos: case WASMOpExpressionF64::Sin: case WASMOpExpressionF64::Tan: case WASMOpExpressionF64::ACos: case WASMOpExpressionF64::ASin: case WASMOpExpressionF64::ATan: case WASMOpExpressionF64::Exp: case WASMOpExpressionF64::Ln: return parseUnaryExpressionF64(context, op); case WASMOpExpressionF64::Add: case WASMOpExpressionF64::Sub: case WASMOpExpressionF64::Mul: case WASMOpExpressionF64::Div: case WASMOpExpressionF64::Mod: case WASMOpExpressionF64::ATan2: case WASMOpExpressionF64::Pow: return parseBinaryExpressionF64(context, op); case WASMOpExpressionF64::Min: case WASMOpExpressionF64::Max: return parseMinOrMaxExpressionF64(context, op); default: ASSERT_NOT_REACHED(); } } else { switch (opWithImmediate) { case WASMOpExpressionF64WithImmediate::ConstantPoolIndex: return parseConstantPoolIndexExpressionF64(context, immediate); case WASMOpExpressionF64WithImmediate::GetLocal: return parseGetLocalExpression(context, WASMType::F64, immediate); default: ASSERT_NOT_REACHED(); } } return 0; } template <class Context> ContextExpression WASMFunctionParser::parseConstantPoolIndexExpressionF64(Context& context, uint32_t constantIndex) { FAIL_IF_FALSE(constantIndex < m_module->f64Constants().size(), "The constant index is incorrect."); return context.buildImmediateF64(m_module->f64Constants()[constantIndex]); } template <class Context> ContextExpression WASMFunctionParser::parseConstantPoolIndexExpressionF64(Context& context) { uint32_t constantIndex; READ_COMPACT_UINT32_OR_FAIL(constantIndex, "Cannot read the constant index."); return parseConstantPoolIndexExpressionF64(context, constantIndex); } template <class Context> ContextExpression WASMFunctionParser::parseImmediateExpressionF64(Context& context) { double immediate; READ_DOUBLE_OR_FAIL(immediate, "Cannot read the immediate."); return context.buildImmediateF64(immediate); } template <class Context> ContextExpression WASMFunctionParser::parseUnaryExpressionF64(Context& context, WASMOpExpressionF64 op) { ContextExpression expression = parseExpressionF64(context); PROPAGATE_ERROR(); return context.buildUnaryF64(expression, op); } template <class Context> ContextExpression WASMFunctionParser::parseBinaryExpressionF64(Context& context, WASMOpExpressionF64 op) { ContextExpression left = parseExpressionF64(context); PROPAGATE_ERROR(); ContextExpression right = parseExpressionF64(context); PROPAGATE_ERROR(); return context.buildBinaryF64(left, right, op); } template <class Context> ContextExpression WASMFunctionParser::parseMinOrMaxExpressionF64(Context& context, WASMOpExpressionF64 op) { uint32_t numberOfArguments; READ_COMPACT_UINT32_OR_FAIL(numberOfArguments, "Cannot read the number of arguments to min/max."); FAIL_IF_FALSE(numberOfArguments >= 2, "Min/max must be passed at least 2 arguments."); ContextExpression current = parseExpressionF64(context); PROPAGATE_ERROR(); for (uint32_t i = 1; i < numberOfArguments; ++i) { ContextExpression expression = parseExpressionF64(context); PROPAGATE_ERROR(); current = context.buildMinOrMaxF64(current, expression, op); } return current; } template <class Context> ContextExpression WASMFunctionParser::parseExpressionVoid(Context& context) { WASMOpExpressionVoid op; READ_OP_EXPRESSION_VOID_OR_FAIL(op, "Cannot read the void expression opcode."); switch (op) { case WASMOpExpressionVoid::CallInternal: return parseCallInternal(context, WASMOpKind::Expression, WASMExpressionType::Void); case WASMOpExpressionVoid::CallIndirect: return parseCallIndirect(context, WASMOpKind::Expression, WASMExpressionType::Void); case WASMOpExpressionVoid::CallImport: return parseCallImport(context, WASMOpKind::Expression, WASMExpressionType::Void); default: RELEASE_ASSERT_NOT_REACHED(); } } template <class Context> ContextExpression WASMFunctionParser::parseGetLocalExpression(Context& context, WASMType type, uint32_t localIndex) { FAIL_IF_FALSE(localIndex < m_localTypes.size(), "The local index is incorrect."); FAIL_IF_FALSE(m_localTypes[localIndex] == type, "Expected a local of type " + nameOfType(type) + '.'); return context.buildGetLocal(localIndex, type); } template <class Context> ContextExpression WASMFunctionParser::parseGetLocalExpression(Context& context, WASMType type) { uint32_t localIndex; READ_COMPACT_UINT32_OR_FAIL(localIndex, "Cannot read the local index."); return parseGetLocalExpression(context, type, localIndex); } template <class Context> ContextExpression WASMFunctionParser::parseGetGlobalExpression(Context& context, WASMType type) { uint32_t globalIndex; READ_COMPACT_UINT32_OR_FAIL(globalIndex, "Cannot read the global index."); FAIL_IF_FALSE(globalIndex < m_module->globalVariableTypes().size(), "The global index is incorrect."); FAIL_IF_FALSE(m_module->globalVariableTypes()[globalIndex] == type, "Expected a global of type " + nameOfType(type) + '.'); return context.buildGetGlobal(globalIndex, type); } template <class Context> ContextExpression WASMFunctionParser::parseSetLocal(Context& context, WASMOpKind opKind, WASMExpressionType expressionType, uint32_t localIndex) { FAIL_IF_FALSE(localIndex < m_localTypes.size(), "The local variable index is incorrect."); WASMType type = m_localTypes[localIndex]; if (opKind == WASMOpKind::Expression) FAIL_IF_FALSE(expressionType == WASMExpressionType(type), "The type doesn't match."); ContextExpression expression = parseExpression(context, WASMExpressionType(type)); PROPAGATE_ERROR(); return context.buildSetLocal(opKind, localIndex, expression, type); } template <class Context> ContextExpression WASMFunctionParser::parseSetLocal(Context& context, WASMOpKind opKind, WASMExpressionType expressionType) { uint32_t localIndex; READ_COMPACT_UINT32_OR_FAIL(localIndex, "Cannot read the local index."); return parseSetLocal(context, opKind, expressionType, localIndex); } template <class Context> ContextExpression WASMFunctionParser::parseSetGlobal(Context& context, WASMOpKind opKind, WASMExpressionType expressionType, uint32_t globalIndex) { FAIL_IF_FALSE(globalIndex < m_module->globalVariableTypes().size(), "The global index is incorrect."); WASMType type = m_module->globalVariableTypes()[globalIndex]; if (opKind == WASMOpKind::Expression) FAIL_IF_FALSE(expressionType == WASMExpressionType(type), "The type doesn't match."); ContextExpression expression = parseExpression(context, WASMExpressionType(type)); PROPAGATE_ERROR(); return context.buildSetGlobal(opKind, globalIndex, expression, type); } template <class Context> ContextExpression WASMFunctionParser::parseSetGlobal(Context& context, WASMOpKind opKind, WASMExpressionType expressionType) { uint32_t globalIndex; READ_COMPACT_UINT32_OR_FAIL(globalIndex, "Cannot read the global index."); return parseSetGlobal(context, opKind, expressionType, globalIndex); } template <class Context> ContextMemoryAddress WASMFunctionParser::parseMemoryAddress(Context& context, MemoryAccessOffsetMode offsetMode) { uint32_t offset = 0; if (offsetMode == MemoryAccessOffsetMode::WithOffset) READ_COMPACT_UINT32_OR_FAIL(offset, "Cannot read the address offset."); ContextExpression index = parseExpressionI32(context); PROPAGATE_ERROR(); return ContextMemoryAddress(index, offset); } template <class Context> ContextExpression WASMFunctionParser::parseLoad(Context& context, WASMExpressionType expressionType, WASMMemoryType memoryType, MemoryAccessOffsetMode offsetMode, MemoryAccessConversion conversion) { FAIL_IF_FALSE(m_module->arrayBuffer(), "An ArrayBuffer is not provided."); const ContextMemoryAddress& memoryAddress = parseMemoryAddress(context, offsetMode); PROPAGATE_ERROR(); return context.buildLoad(memoryAddress, expressionType, memoryType, conversion); } template <class Context> ContextExpression WASMFunctionParser::parseStore(Context& context, WASMOpKind opKind, WASMExpressionType expressionType, WASMMemoryType memoryType, MemoryAccessOffsetMode offsetMode) { FAIL_IF_FALSE(m_module->arrayBuffer(), "An ArrayBuffer is not provided."); const ContextMemoryAddress& memoryAddress = parseMemoryAddress(context, offsetMode); PROPAGATE_ERROR(); ContextExpression value = parseExpression(context, expressionType); PROPAGATE_ERROR(); return context.buildStore(opKind, memoryAddress, expressionType, memoryType, value); } template <class Context> ContextExpressionList WASMFunctionParser::parseCallArguments(Context& context, const Vector<WASMType>& arguments) { ContextExpressionList argumentList; for (size_t i = 0; i < arguments.size(); ++i) { ContextExpression expression = parseExpression(context, WASMExpressionType(arguments[i])); PROPAGATE_ERROR(); context.appendExpressionList(argumentList, expression); } return argumentList; } template <class Context> ContextExpression WASMFunctionParser::parseCallInternal(Context& context, WASMOpKind opKind, WASMExpressionType returnType) { uint32_t functionIndex; READ_COMPACT_UINT32_OR_FAIL(functionIndex, "Cannot read the function index."); FAIL_IF_FALSE(functionIndex < m_module->functionDeclarations().size(), "The function index is incorrect."); const WASMSignature& signature = m_module->signatures()[m_module->functionDeclarations()[functionIndex].signatureIndex]; if (opKind == WASMOpKind::Expression) FAIL_IF_FALSE(signature.returnType == returnType, "Wrong return type."); ContextExpressionList argumentList = parseCallArguments(context, signature.arguments); PROPAGATE_ERROR(); return context.buildCallInternal(functionIndex, argumentList, signature, returnType); } template <class Context> ContextExpression WASMFunctionParser::parseCallIndirect(Context& context, WASMOpKind opKind, WASMExpressionType returnType) { uint32_t functionPointerTableIndex; READ_COMPACT_UINT32_OR_FAIL(functionPointerTableIndex, "Cannot read the function pointer table index."); FAIL_IF_FALSE(functionPointerTableIndex < m_module->functionPointerTables().size(), "The function pointer table index is incorrect."); const WASMFunctionPointerTable& functionPointerTable = m_module->functionPointerTables()[functionPointerTableIndex]; const WASMSignature& signature = m_module->signatures()[functionPointerTable.signatureIndex]; if (opKind == WASMOpKind::Expression) FAIL_IF_FALSE(signature.returnType == returnType, "Wrong return type."); ContextExpression index = parseExpressionI32(context); PROPAGATE_ERROR(); ContextExpressionList argumentList = parseCallArguments(context, signature.arguments); PROPAGATE_ERROR(); return context.buildCallIndirect(functionPointerTableIndex, index, argumentList, signature, returnType); } template <class Context> ContextExpression WASMFunctionParser::parseCallImport(Context& context, WASMOpKind opKind, WASMExpressionType returnType) { uint32_t functionImportSignatureIndex; READ_COMPACT_UINT32_OR_FAIL(functionImportSignatureIndex, "Cannot read the function import signature index."); FAIL_IF_FALSE(functionImportSignatureIndex < m_module->functionImportSignatures().size(), "The function import signature index is incorrect."); const WASMFunctionImportSignature& functionImportSignature = m_module->functionImportSignatures()[functionImportSignatureIndex]; const WASMSignature& signature = m_module->signatures()[functionImportSignature.signatureIndex]; if (opKind == WASMOpKind::Expression) FAIL_IF_FALSE(signature.returnType == returnType, "Wrong return type."); ContextExpressionList argumentList = parseCallArguments(context, signature.arguments); PROPAGATE_ERROR(); return context.buildCallImport(functionImportSignature.functionImportIndex, argumentList, signature, returnType); } template <class Context> ContextExpression WASMFunctionParser::parseConditional(Context& context, WASMExpressionType expressionType) { ContextJumpTarget elseTarget; ContextJumpTarget end; ContextExpression condition = parseExpressionI32(context); PROPAGATE_ERROR(); context.jumpToTargetIf(Context::JumpCondition::Zero, condition, elseTarget); parseExpression(context, expressionType); PROPAGATE_ERROR(); context.jumpToTarget(end); context.linkTarget(elseTarget); // We use discard() here to decrement the stack top in the baseline JIT. context.discard(UNUSED); parseExpression(context, expressionType); PROPAGATE_ERROR(); context.linkTarget(end); return UNUSED; } template <class Context> ContextExpression WASMFunctionParser::parseComma(Context& context, WASMExpressionType expressionType) { WASMExpressionType leftExpressionType; READ_EXPRESSION_TYPE_OR_FAIL(leftExpressionType, "Cannot read the expression type."); ContextExpression leftExpression = parseExpression(context, leftExpressionType); PROPAGATE_ERROR(); if (leftExpressionType != WASMExpressionType::Void) context.discard(leftExpression); return parseExpression(context, expressionType); } template <class Context> ContextExpression WASMFunctionParser::parseConvertType(Context& context, WASMExpressionType fromType, WASMExpressionType toType, WASMTypeConversion conversion) { ContextExpression expression = parseExpression(context, fromType); PROPAGATE_ERROR(); return context.buildConvertType(expression, fromType, toType, conversion); } } // namespace JSC #endif // ENABLE(WEBASSEMBLY)
A predominant number of color picture tubes in use today have line screens and shadow masks that include slit-shaped apertures. The apertures are aligned in columns, and the adjacent apertures in each column are separated from each other by webs or tie bars in the mask. Such tie bars are essential in the mask to maintain its integrity when it is formed into a dome-shaped contour which somewhat parallels the contour of the interior of a viewing faceplate of a tube. Tie bars in one column are offset in the longitudinal direction of the column (vertical direction)from the tie bars in the immediately adjacent columns. When electron beams strike the shadow mask, the tie bars block portions of the beams, thus causing shadows on the screen immediately behind the tie bars. When the electron beams are repeatedly scanned in a direction perpendicular to the aperture columns (horizontal direction), this scanning results in a series of bright and dark horizontal lines on the screen. These bright and dark horizontal lines interact with the shadows formed by the tie bars, creating lighter and darker areas and producing a wavy pattern on the screen, called a moire pattern. Such moire pattern greatly impairs the visible quality of image displayed on the screen. It is highly desirable to select a moire mode that will minimize the moire pattern for any scan condition used in a television receiver. The two scan conditions presently in use are interlaced scan and noninterlaced scan. A moire mode is the ratio of scan line pitch to tie bar shadow pitch. Because of the practical limitations of light output and mask strength, the moire mode is usually chosen to be between 6/8 and 10/8. The moire mode most frequently selected is 7/8. Such mode can be expressed by the equation: ##EQU1## where T.sub.s is the pitch or period of the scanning lines, which is equal to the vertical height, H, of the viewing screen divided by the number, n.sub.e, of effective scanning lines for a given TV system: and a.sub.v is the vertical repeat distance of the mask apertures on the screen. There is a possibility for use of a third scan condition. This third condition is called progressive scan and may be used on high definition television receivers. A higher scan frequency is necessary for progressive scan. In the special case of progressive scan, only one scan condition is considered to minimize the moire pattern. This scan condition produces less moire and a much smoother picture. For this condition, a moire mode lower than 6/8 or higher than 10/8 would be used. The moire mode most frequently selected for this condition is 5/8. There have been many techniques suggested to reduce the moire problem. Most of these techniques involve rearranging the locations of the tie bars in a mask to reduce the possibility of the electron beam scan lines beating with the tie bar shadows. Although many of these techniques have been used successfully in the past to reduce moire, most of the prior techniques do not correct the moire, problem in all parts of a screen, so that there is still a need for improved moire reduction techniques. Such improved techniques are especially needed for the newer higher quality color picture tubes that are required for higher definition television. For example, as the quality of electron guns improves to meet the needs of higher definition television, such improved guns produce smaller electron beam spots at the screen. This reduction in electron beam spot size produces visually sharper scan lines on the screen which interact with the tie bar shadows and increase the moire pattern problem.
Q: How would I fix this code to allow me to leave one channel when switching to the next This is what I have to switch between channels in the chat, but it does not leave the channel even when calling the .leave() function new Twilio.Chat.Client.create(data.token).then(function(chatClient) { $(".change-channel").on("click", function(){ if ($(this).text() == "General Button"){ if(currentChannel != "general"){ chatClient.getSubscribedChannels().then(joinChannel(chatClient, 'general','General Chat Channel')); currentChannel.leave(); } // if not current channel general then: } if ($(this).text() == "Specific Button"){ if(currentChannel != "generals"){ chatClient.getSubscribedChannels().then(joinChannel(chatClient, 'generals','Generals Chat Channel')); currentChannel.leave(); } // if not currentchannel generals then: } }); }); A: Twilio developer evangelist here. I think the channels may be getting confused as you join and leave them and promises and callbacks are resolved. I would try making sure that you have left the channel first, before joining the next one and disallowing the switching of channels while the process is going on. Something like this: new Twilio.Chat.Client.create(data.token).then(function(chatClient) { let currentChannel, nextChannel, nextChannelName; let changingChannel = false; // fired when a channel has been left completely chatClient.on('channelLeft', channel => { chatClient.getSubscribedChannels() .then(joinChannel(chatClient, nextChannel, nextChannelName)); }) // fired when a channel has been successfully joined chatClient.on('channelJoined', channel => { currentChannel = channel; changingChannel = false; nextChannel = nextChannelName = null; }) $(".change-channel").on("click", function(){ if (changingChannel) { // already switching channels, don't do anything return; } if ($(this).text() == "General Button"){ if(currentChannel.uniqueName != "general"){ changingChannel = true; nextChannel = 'general'; nextChannelName = 'General Chat Channel'; // start the process to leave the channel currentChannel.leave(); currentChannel = null; } // if not current channel general then: } if ($(this).text() == "Specific Button"){ if(currentChannel.uniqueName != "generals"){ changingChannel = true; nextChannel = 'generals'; nextChannelName = 'Generals Chat Channel'; // start the process to leave the channel currentChannel.leave(); currentChannel = null; } // if not currentchannel generals then: } }); }); Let me know if that helps at all.
Q: Video exceeds window's size - JavaFX and FXML i've a trouble with JavaFX and FXML. I've a simple FXML file structured in this way: <?xml version="1.0" encoding="UTF-8"?> <?import javafx.scene.control.Button?> <?import javafx.scene.control.SplitPane?> <?import javafx.scene.control.ToolBar?> <?import javafx.scene.layout.AnchorPane?> <?import javafx.scene.layout.BorderPane?> <?import javafx.scene.media.MediaView?> <BorderPane maxHeight="1.7976931348623157E308" maxWidth="1.7976931348623157E308" minHeight="480.0" minWidth="720.0" xmlns="http://javafx.com/javafx/8.0.111" xmlns:fx="http://javafx.com/fxml/1" fx:controller="mediaplayer.MediaPlayerControllerSplit"> <center> <SplitPane dividerPositions="0.5" maxHeight="1.7976931348623157E308" maxWidth="1.7976931348623157E308" minHeight="-Infinity" minWidth="-Infinity" BorderPane.alignment="CENTER"> <items> <AnchorPane fx:id="mediaPaneL" style="-fx-background-color: green;"> <children> <MediaView fx:id="mediaViewL" /> </children> </AnchorPane> <AnchorPane fx:id="mediaPaneR" style="-fx-background-color: red;"> <children> <MediaView fx:id="mediaViewR" /> </children> </AnchorPane> </items> </SplitPane> </center> <bottom> <ToolBar minHeight="-Infinity" minWidth="-Infinity" style="-fx-background-color: black;" BorderPane.alignment="BOTTOM_CENTER"> <items> <Button mnemonicParsing="false" onAction="#openVideo" text="Openfile" /> <Button mnemonicParsing="false" onAction="#playVideo" text=">" /> <Button mnemonicParsing="false" onAction="#pauseVideo" text="\|\|" /> <Button mnemonicParsing="false" onAction="#stopVideo" text="stop" /> <Button mnemonicParsing="false" text="<<<" /> <Button mnemonicParsing="false" text="<<" /> <Button mnemonicParsing="false" text=">>" /> <Button mnemonicParsing="false" text=">>>" /> <Button mnemonicParsing="false" onAction="#exitVideo" text="EXIT" /> </items> </ToolBar> </bottom> </BorderPane> The controller will load 2 videos and show them in the relative 2 AnchorPanes inside the SplitView, as shown in the following image: ClickMe The video exceeds from width bounds of the Parent AnchorPane, how can i set them properly? Thanks all. A: I've solved this with the following line of codes in the Controller class: mediaViewL.fitWidthProperty().bind(mediaPaneL.widthProperty()); The left (same for the right one) mediaView width has been fitted to his first Parent width (AnchorPaneL / AnchorPaneR).
Dodged Bullets: 14 Actors Who Were Almost Superheroes Dougray Scott as Wolverine Not far behind the Spider-Man franchise is X-Men, which really paved the way for the superhero genre in the 21st century after Batman and Robin ripped it to shreds at the end of the 20th. However, would X-Men have been such a success without Hugh Jackman anchoring the role of Logan, aka Wolverine? Dougray Scott, the Scottish actor, was actually hired to play the Canadian wildman with the super-sideburns when director Bryan Singer was assembling his mutant team for X-Men in 1999. Scott was ultimately forced to pull out just as they began filming, due to scheduling conflicts with Mission: Impossible II. In stepped the multi-talented Jackman, who grabbed the film by the scruff of the neck and got himself a Hollywood career, including his own spin-off film, X-Men Origins: Wolverine. Jackman talked about taking over from Scott during a 2003 interview: “I have spoken to him, I didn’t quite have the guts to say thank you, I kind of apologized more to him … he said ‘Ah, that’s Hollywood, these things happen’.” Legend has it that before Scott and Jackman were cast, Gary Sinise, Russell Crowe, Viggo Mortensen, Aaron Eckhart and even Jean-Claude van Damme were also considered for the role of Wolverine, while Fox Studios reportedly wanted Keanu Reeves (shows what they know). Jim Caviezel as Cyclops While Patrick Stewart was understandably the only actor considered for the part of wheelchair-bound Professor Xavier in Bryan Singer’s X-Men, the early contenders for the role of Scott Summers (aka Cyclops) were said to be Thomas Jane, Johnny Lee Miller, Eric Mabius, Owen Wilson, Edward Burns, Edward Norton and Jude Law, with Jim Caviezel actually winning out. However, much like Dougray Scott, Caviezel was forced to drop out due to a prior engagement – Frequency with Dennis Quaid. The role of Cyclops then went to James Marsden, and with it, platform shoes so Marsden wouldn’t look so short in comparison to the likes of Hugh Jackman (Wolverine) and Tyler Mane (Sabretooth). Caviezel probably didn’t miss much – and may have been the one who dodged the bullet – considering that Scott Summers/Cyclops’ involvement in the X-Men series diminished more and more with each film, though his lack of screen-time in X-Men: The Last Stand was the result of Marsden’s own decision to switch comic book camps – from the Marvel universe to DC – to play Lois Lane’s fiancee in Superman Returns. Ironically Caviezel would eventually play a ‘superhero’ of another kind – Jesus in Mel Gibson’s The Passion of the Christ, which in turn led to director Bryan Singer to disqualify him from the race to play the Man of Steel in Superman Returns. Apparently Singer didn’t want Jesus playing Superman. “I first saw Superman with Christopher Reeve and I just thought that he set the standard there. The first one, the (Richard) Donner film, was amazing. But (Caviezel’s involvement in Singer’s new Superman) just never came to be … I think that by playing Jesus made them stay away from that, as there was too much attention drawn to it.”
Knowledge among important actors in the field of adaptive equipment for young people with disabilities. Access to adaptive equipment is a crucial factor that can determine if a child or youth with disabilities is going to participate in physical activities, sports and play in different local settings. A prerequisite for success is awareness of and specific knowledge concerning the equipment and its use among relevant actors. The aim of this paper is to explore how important groups of actors working with young people with disabilities perceive their level of knowledge concerning adaptive equipment and discuss these actors' role in children and youths' opportunities to obtain relevant equipment to participate in activities. An online, population-based national survey was distributed to: (1) occupational therapists and physiotherapists, (2) teachers, and (3) leaders and coaches in sports clubs in Norway. The findings generally indicate that overall knowledge concerning adaptive equipment among the three groups is limited. However, significant statistical difference is found, indicating that occupational therapists and physiotherapists have higher levels of general knowledge, about the accessibility of equipment, regulations and legislation and that they are more familiar with adaptive equipment than teachers, leaders and coaches. A practical implication of the results is that the actors' varying knowledge and experiences need to be brought together to form a coherent picture of how the equipment will be used and by whom. This can contribute to an increased understanding concerning adaptive equipment and its importance among different actors, which could help more young people with disabilities to participate. Implications for Rehabilitation Important actors must utilize the knowledge and experience possessed by young people with disabilities concerning adaptive equipment. Improved access to knowledge concerning adaptive equipment among important actors is required. Increased collaboration between different actors relating to adaptive equipment and participation is needed.