"Subs created by:" "David Coleman." "You know what I just noticed?" "Connie's knees look more like balls than my balls look like balls." "Oh, my God, they do." "Man, I'm starving." "Being the best Park Ranger on Earth can really work up an appetite." "Oh, no!" "My leftover Chinese food!" "It's gone!" "Steve, if I'd a known, I never would have..." "And look at that!" "Someone drew a mustache on my ranger of the month picture!" "Don't you people understand?" "There's only one explanation!" "It's the ghost!" "Yeah, uh, a ghost ate your Chinese food." "And drew a mustache on your picture." "And, uh, got drunk and took a shit on your toothbrush." "Uh, I mean, uh, what ghost?" "I never told you about the ghost that ruined my childhood?" "It all started 25 years ago." "I got up on Christmas morning, and there were no presents." "My dad said the ghost stole them." "Then the ghost gambled away my college fund, backed over my dog, and gave my mom two black eyes on her birthday." " The ghost did all that, huh?" " Yeah, and now he's back." "But this time, I'm gonna get my revenge and kill that dead son of a bitch!" "All right, all right, I don't want to hear another word about that ghost!" "Woody used to be a '70s porn star named Rex Erection." "Tell me more about that ghost, Steve." "Ah!" "♪Brickleberry!" "♪Brickleberry!" "[Music]" "What?" "I like full bush." "I'm a bear." "Anyway, I found this." "[Doorbell rings]" "Just a minute." "Trick or treat." "And what are you supposed to be?" "I'm supposed to be [Bleep] you." "[Grunts]" "[Moaning]" " That's Woody?" " Can't be!" "If I wasn't gay, I am now." "Ewe!" "There's no way that's him." "Okay, baby, it's time to bust ass!" "Okay, Rangers, it's time to bust ass!" "Well, that dried me up." "Woody, what'd you do for a living before you worked at Brickleberry?" "Oh, I had my fingers in this and that." "By this and that, I'm assuming you meant vagina's and buttholes?" "[Moans softly]" "Well, I knew this day would come." "Back in the '70s, I made a living as a pornographic actor named Rex Erection." "Woody Johnson wasn't a good enough porn name for you?" "Huh?" "I don't get it." "Anyhow, porn was just one of those jobs you stumble into when you're young and new to the big city, and you've got a dishonest Pinocchio nose for a dick!" "[Laughs]" "Yeah, we noticed." "Oh, no!" "It's my husband and his brother!" "They just finished playing 18 holes." "I got two more holes you guys can play." "[Grunts]" "Gay porn too?" "So you're gay?" "Ewe!" "Hell no!" "I didn't enjoy it!" "It's called acting." "But there's one unanswered question." "Why were those two men playing golf at night on Halloween?" "Connie, I ought to whup your ass." "Woody, why'd you quit?" "Quit?" "No." "It wasn't my choice." "I was a pornographic pioneer." "The world was at my feet." "I even invented my own signature move..." "The Rex Rocket!" "[Grunts]" "Oh, my God!" "That was amazing!" "I had legions of fans who adored me." "Could you make it out to Duke?" "You're my hero, Rex." "I want to be just like you when I grow up." " What are you, seven?" " I'm only six." "Six inches?" "Not enough cable, son." "You'll never make it in porn." "Stay in school." "Oh." "Oh, I was on top of the world, but I flew too close to the sun." "[Snorts] I burned out." "Couldn't do what I, uh, needed to do." "Oh, boy." "I'm..." "I'm really embarrassed about this, folks." "Well, one minute." "Oh, brother." "I'm thinking of everything." "Sorry, guys." "I know this seems unprofessional, but maybe you guys can hit craft service." "Oh, oh, starting to get a tingle." "No!" "Shit!" "It's gone!" "Come on, come on!" "My presence in porn films was reduced to non-sexual character roles." "Like the pool boy's boss and one of the students not kept after class." "It flung me into a deep depression." "[Crying]" "[Lid pops]" "[Crying]" "[Snorts]" "Huh?" "What are all you people doing in my bathroom?" "[Thud]" "Fortunately, Uncle Sam straightened me out." "Then I took this job at Brickleberry and found my true calling, you know what I mean?" "Where the hell is everybody?" "You see, Malloy, when a man and a woman really love each other, or they're being paid and there's a camera there, they have what are called... [spits]" "Relations." "Sometimes that woman can be a man or a gang of men or a Shetland pony." "You following me?" "Yeah, yeah, yeah." "You had sex with a horse." "Why didn't you ever tell me you were in porn?" "I have always dreamed of getting into porn." "You want to be a porn actor?" "Hell no, they're disgusting." "I want to direct, like the great storytellers from the golden age of porn." "Back when there was an art to exploiting people and ruining their lives." "Hey, that reminds me." "Porn Con is this week, we have to go." "You are a God to tons of sad, lonely, pathetic people." "Oh, sorry, Fuzzywubs." "I have made my peace with porn, and I'm never going back to that dark place." "What about for 100 bucks an autograph?" "Hello, dark place!" " Hey... hey, guys!" " Break's over." " Wait!" "It's here!" " What's here?" "My ghost-hunting equipment!" " Man, that's just a bat!" " No, it's a ghost bat." "You can't hit a ghost with a regular bat." "It'd go right through them." "Ghost tape recorder, ghost glasses, ghost-a-meter." "That's a rectal thermometer duct-taped to a tennis racquet." "Steve, how much did you spend on all this crap?" " $800." " What?" "Small price to pay for revenge, am I right?" "Yeah, uh..." "Steve, that reminds me." "I have this ghost mop I want to sell you." "No, thanks." "Already have one." "Well, this sucks, Malloy." "I can't believe no one wants to meet me." "There's even a line to see the fatties from Filipino Foot Fetish 5!" "[Camera shutter clicking]" "That was a surprisingly solid film, despite the fact that you didn't realize it was a prequel till the end." "I'm a joke." "I can't believe you talked me into coming here." "My legacy is dead." "Cheer up, Woody." "These porn nerds are just cheap." "Autographs now only $10." "$1.00 autographs." "[Thud]" " Okay, no one loves you." " Jesus does!" "Not after he saw the Rexerection IV Easter [Bleep]day." "Ladies and gentlemen, it is my pleasure to introduce the biggest porn star in the world!" "The God of rod, the master ass blaster, the shoe-in for this year's Boney Award!" "Duke Dick!" "[Cheers and applause]" "Hey, those are my moves!" "That's my Navajo Chap Slap and my Inverted Clam!" "[Gasps] And that's my Mr. Belvedere!" "Yo!" "Duke Dick in the hit zone!" " What time is it?" " It's time to bust ass!" "And that's my catchphrase!" "Now, who wants to see Duke do his famous move?" "The Duke Rocket!" "[Cheers and applause]" "Stop right there!" "Someone get this Queen offstage before the Duke gets filled with rage!" "You stole all of my moves, asshole!" "Asshole?" "My asshole has won five Boney Awards!" "Show some respect, son!" "Oh, I ain't your son, hombre." "I'm Rex [Bleep] Erection!" "Rex Erection was my hero until he told me I'd never make it." "What the..." ""Dear Duke, you got a small tool." "Stay in school." "Rex"." "Well, I showed you." "Now I'm on top, and you're all washed up, old man." "Not for long, because you know what I'm gonna do?" "I don't know." "Skype with your grand kids?" "No, I'm gonna come out of retirement," "I'm gonna make my own movie, I'm gonna win that Boney!" "And then I'm gonna shove it up your award-winning asshole!" "Yeah, right." "What Director would touch your washed-up white ass?" "I will." "Dude, a hairy little woodland creature can't direct a movie." "Uh, what about Peter Jackson?" "Okay, I stand corrected." "[Music]" "Alright Malloy, I snorted four lines of Levitra." "There's soup in the mushroom!" "Let's shoot this thing!" "Put a pin in that boner." "I'm still auditioning actresses." "Connie, bring them in!" "Too fat, trucker arms, flat ass." "That's a Moose." "Christ!" "Connie, bring me some real women with no self-esteem." "Sorry, Malloy, I'm just really tired." "I'm really tired too... of having a wheezing elephant seal for an assistant." "I never actually asked to be your assistant." "Connie, don't ever [Bleep] backtalk me." " I'm so sorry." " Oh, God." "What is this now?" "Do you have any idea how demeaning this is to women?" "Yes." "And, no, you cannot be in it." "I would never be in this movie." "Wait, why can't I be in this movie?" "You don't think I have trucker arms, do you?" "It is my nose?" "[Gasps] Are my boobs too small?" "You know what?" "I'm not gonna fall into your little trap." "You put me in this goddamn movie!" "Put me in!" "Malloy, put me in this movie!" "Fine, but I'm not gonna pay you." "Yes, I'm pretty." "So you're saying the only time the ghost didn't bother you was during the four weeks your daddy was in jail?" "Yeah, I guess he was too busy framing my dad for all those DUI's." "[Pounding on door]" " Ooh, you ordered us a pizza?" " No, it's a medium." " So, you ordered yourself a pizza?" " No, I got us a medium." "Oh, so we only get three slices a piece?" "You at least get some bread sticks or some shit?" "No, Denzel, a medium to help us hunt down this ghost." "How's a pizza gonna hunt down a ghost, Steve?" " Hi, I'm St..." " No, no, no, no, no." "Don't tell me about yourself." "I'll tell you about yourself." " You like to eat candy." " Yes!" " You don't have a girlfriend." " No!" "And you brought me here for some information on..." "Some subject." "Oh, my God, yes!" "I'm looking for an evil ghost." "Where do you think he is?" "Uh... ooh!" "The graveyard." "I knew it!" "Steve, can't you see this woman's playing you?" "This is bullshit!" "Oh, a non-believer." "Let me go check in with the other side." "[Gasps]" "I'm sensing..." "Your Grandmother mispronounces words like libary and bafroom." "Holy shit!" "Can I help you?" "I'm the CEO of this sperm bank, and we are very busy today." "[Stilted] Well, you're going to get even busier because I need a loan." "Ooh, I can give you a loan." "A loan bone." "Cut!" "The line is bone loan." "What the hell is a loan bone?" "I'm having a real problem understanding my character." "He wants to have sex." " Well, what's his motivation?" " To have sex." "Well, did he have a happy childhood?" "Just take off your clothes and [Bleep] her in her [Bleep] [Bleep]." "What?" "I couldn't hear you over all the beeps." "[Microwave beeps]" "Sorry." "I was making Taquitos in the microwave." "Can someone check his green card?" "And where the hell do you think you're going?" "Me?" "Oh, I'm just gonna go grab lunch while my, uh, body double steps in." "Wait, you didn't think I was gonna do a nude scene, did you?" "If I wanted a shitty actress who wouldn't show her tits," "I would have hired Kevin James." "Oh, I don't have to take this from you, Malloy." " I quit!" " Oh, no!" "How will I ever replace you?" "I could just glue two oranges to a mop." "You'll regret this!" "Nobody walks out on me, you [Bleep]!" "I'm sorry." "The shell is warm and crispy, but the Taquito is still cold on the inside." "[Music]" "Steve, you look like a Mexican Astronaut." "Thank you, but this is not about how bad ass I look." " This is about vengeance." " [Snickers] Okay." "Good luck with that vengeance." "If you need me, I'll be home, sleeping." "Boo..." "Aah!" "Aah!" "Ah!" "You ruined my life, you son of a bitch!" "Steve, Steve, hold on!" "I was just messing with you!" "You morphed into Denzel, huh?" " You shape-shifting ghost!" " Whoa, Steve, it's me!" "Ask me something only I would know." " What's my last name?" " I don't [Bleep] know." " Oh, thank God, it's you, Denzel." " Man, this is worse than I thought." "You need some therapy, Steve." "The only therapy I need is to kill this ghost." "Steve, there is no..." "[Rustling]" "Both:" "Ghost!" "Could we soften this light a little bit?" "I don't need or deserve to see every wrinkle on Woody's sac." "If that boom mic gets in the shot one more time, whoa-ho-ho, we're gonna find out what the inside of your ass sounds like." "Probably not good." "He ate a whole plate of Taquitos." "How did you get back into the country?" "Okay, action!" "What the hell is this?" "I did a bunch of coke and rewrote the whole script last night." "Just read the cue cards." "[Stilted] Any last requests, Osama Bin Laden?" "Yes, infidels, I want you to run a train on me with your seal-team dicks or I'll 69/11 you!" "What?" "This is bullshit, Malloy!" "People just want to see The Rex Rocket!" "You're right." "That was garbage." "I'm gonna rewrite the whole script... [snorts]" "Right now." "[Typing furiously]" "[Robotically] Beep-boop, beep-boop, beep." "You ordered a pizza from the future?" "[Grunts]" "Cut!" "Woody, stop breathing!" "Robots don't breathe." "This is the 100th take." "Could we stop for a minute?" " I'm tired." " You're tired?" "You've flubbed your lines so many times that" "Chastity here is starting to question her life choices." "I think I might want to go to nursing school." "I'm pretty sure they drug test." "Oh, well." "Seriously, something's wrong." "I am in real pain here." "Great!" "Use it!" "Action!" " [Thud] - [Groans]" "That was not in the script!" "[Snorts]" "But it is now." "[Typing furiously]" "You're a very lucky man, Woody." "Everything's going to be fine." "Great!" "So I can perform?" "[Laughs] Of course you can perform..." "In stage plays, Lifetime original movies." "Even black face minstrel shows." "Just not pornography." "You see, Woody, you're suffering from a rare ailment..." "Multiple scrot cysts." "I have multiple sclerosis?" "Shit!" "Oh, heavens no." "I wish you did." "I said, multiple scrot cysts, as in multiple cysts in your scrotum." "Each cyst is a little, ticking time bomb." "Every single bounce of your ball bag brings you closer to death." "Level with me, Doc." "How many thrusts do I have left?" "I can't give you an exact number, Woody, but it's somewhere between, say, 70 and 72." "So..." "Seventy one?" "[Laughs]" "If only medicine could be that precise." "[Whimpering] [Door bangs open]" "Aah!" "Aah!" "The ghost!" "He's coming for us." " Grab the ghost bats!" " Take that, you ghost!" "[Overlapping grunts]" "Take that!" "Kill that ghost!" "Kill that ghost!" " Hah!" " Aah!" "I think we got him!" "[Moans]" "Oh, no!" "Connie!" "The ghost must have beat her up!" "We beat her up, you dumb ass!" "It was Connie sleepwalking the whole time!" "I hate to tell you this, Steve, but that ghost was just your alcoholic father beating your mama up on her birthday." "Sorry, I was zoning out." "I didn't hear anything you just said." "Steve, it wasn't a ghost!" "It was your dad the whole time!" "Damn it." "Happened again." "I didn't hear anything after the word Steve." "You just had a shitty dad!" "Sorry, I was holding in a fart." "I give up." "[Squeaky fart]" "Denzel, I just realized something." "It was my dad the whole time." "There is no ghost." " [Munching] - [Shudders]" "[Munching]" "Hey, Steve, long time no see." "Remember when I stole your Christmas presents and made the bank foreclose on your house?" "[Laughs]" "Good times." "Hey, give this to you mom for me." "[Grunts]" "[Music]" "I'm sorry, Snugglewubs, but I just can't do porn anymore." "Doctor's orders." "It kills me more than anyone." "You rest up, Woody." "I completely understand." "Besides, I already found your replacement." "Yo, yo, yo, Duke Dick in the father-suckin' house." "Ooh, hell no!" "I ain't done yet!" "It's time to bust ass!" "Action!" "[Typing furiously]" "[Typing furiously]" "[Typing furiously]" "No!" "No, no, no!" "No, no, no, no, no, no!" "No, no, no, no!" "[Elephant trumpeting]" "All right, Woody, this is your final scene." "Oh, it better be." "This is the 93rd rewrite of this movie... today!" "I know you're tired, but nail this shot, and Rex Erection will never be forgotten again." "Time for The Rex Rocket." "You ready?" "[Grunts]" "It's time to... [takes deep breath]" "Bust ass!" "The Rex Rocket!" "[Thud]" "[Cheers and applause]" "Oh, my God, he's dead and still in me!" "Gross!" "And that's how you direct a snuff film." "Perfect!" "The world mourns today as beloved pornographic film star Rex Erection has died." "A true innovator, he developed specialized coitus procedures." "Like the Clam Slam..." "The Drippy Pickle..." "The Nancy Reagan." "And his signature, Rex Rocket." "One thing is for certain..." "The legacy of Rex Erection will live on forever." "We now join the Boney Awards, already in progress." "Ladies and gentlemen, here are the porn actors and actresses we lost this year." "_." "_." "_." "_." "_." "_." "And now, to present the Boney for best actor!" "Please welcome Flesh Devil, the leather-bound midget freak." "And academy award winner Susan Sarandon." "[Applause]" "Susan, it is said that a good porn actor invites the audience to come." "Yes, Flesh Devil, but a great porn actor also invites the audience to feel." "The Boney Award for best actor goes to..." "Rex Erection!" "[Applause]" "I'd like to accept this on behalf of Rex Erection." "He wasn't sexy or handsome, he was a horrible actor, but you guys will jerk off to anything." "Thank you. [Applause]" "[Grunts] [Audience gasps]" "This is bullshit!" "Everyone knows Duke is the greatest of all time!" "[Thwack] [Groans] [Thud]" "That's not the one I take home, is it?" "I can't believe Woody's gone." "Do you have any idea what he left me in his will?" "His love." "Oh, isn't that sweet?" "Hope you rot in hell, cheap old man." "Connie, what happened to you?" "Steve said a ghost got me, then Denzel said the ghost left, and there's no use investigating the situation any further." "Howdy, Rangers." "It's time to bust ass!" " What the..." " I faked my own death so Rex Erection's legacy could live on forever." "I wasn't about to let Duke Dick steal everything I worked for!" "But there was a body in the casket that we buried." "Huh?" "Oh, yeah." "That was some homeless Navajo I found passed out behind Quiznos." "What?" "I gave him 50 bucks." "Sorry we're late." "Ghost!" "Quick!" "Grab the ghost bats!" "[Groans]"


Q:

Answer to the Hyperledger Components

What is 1. and 8. and why they are using the same Connection name? Why it is required or what does it convey?
What are these two cards i.e. 2,3 and why they are required? Can't we have single of these?
What and why are these two UserId i.e. 4,5? When are are going to use them? Can't we have single of these?
Again Business network i.e. 6,7. What and why first is NONE and Second is tutorial-network?
Why 13. is not enabled and 14. is enabled.
What is the use of redundant network with same application deployed on two Organisation?
Source:
Deploying a Hyperledger Composer blockchain business network to Hyperledger Fabric (multiple organizations)
https://hyperledger.github.io/composer/latest/tutorials/deploy-to-fabric-multi-org

A:

Playground is showing you all the cards in your card store that you used when going through the byfn tutorial. You have acted as 2 different organisations on a single machine (however in the real world you are only likely to have cards for a single organisation). Also Playground can have issues working with a multi-organisation fabric network, such as byfn, around deploying/updating business networks, so it's use with these fabrics is not recommended.
1) Connection Profiles in a network card represent the fabric you want to communicate with. Connection profiles have a name and it is this name that you are seeing. You have 2 sections with the same name because with BYFN you are pretending to be 2 organisations on the same machine and the connection profiles are different between the 2 organisations but have the same name.
2,3) The first card represents a fabric network card and has the name PeerAdmin (used for doing fabric level interaction such as deploying a business network) The second card represents a business network card for interacting with the business network as the userid shown. They are 2 different cards that provide different types of access.
4) A fabric network card doesn't connect to a business network, this is why it shows NONE. The other one is the name of the business network that the card will connect you to.
5) 13 is not enabled because a fabric network card can never connect to a business network, whereas 14, because it is a business network card can connect to a business network.
6) don't understand the question.


Q:

Why does IR spectroscopy specifically require a change in dipole moment, and why doesn't this apply to other types of spectroscopy?

I would really appreciate any amount of detail/depth. I do not have a background in quantum, which is probably why I don't know the answer to this. However, any answer referencing quantum concepts is welcome and appreciated; I will follow up on any resources provided.
My question is basically as follows: Why does IR absorption require a change in dipole moment, and why is it that other types of spectroscopy (UV Vis, microwave) don't have this requirement? What causes this requirement specifically for IR?
Thank you!

A:

All the types of spectroscopy you mention have a similar condition for a spectrum to be observed.  This is that the molecule has to be able to interact with the radiation in the first place and then the radiation has to be of the correct energy to change the energy of the molecule from one level to another.
A plain (classical) explanation is as follows. (We implicitly assume that the radiation has the correct energy). As radiation is electric dipole in nature (it consists of oscillating electric and magnetic fields) if the molecule also generates an oscillating electric field it can interact with the radiation; energy is taken from the radiation field and enters the molecule. Thus a molecule may gain a quantum of vibrational or rotational energy or an excited state may be produced.
In the case of a vibrating diatomic molecule only if it is hetero-nuclear e.g. HCl, will it have a dipole and thus an oscillating dipole and oscillating electric field as it vibrates. Thus hetero-nuclear diatomics show an IR spectrum, homo-nuclear diatomics do not. In a polyatomic molecule vibrations can distort the molecule, e.g. benzene is distorted so that it is no longer 6 fold symmetric, so that a  dipole is produced and an IR spectrum may result. What form this takes depends on the molecule's symmetry and group theory point groups are used to determine this.
In a rotating diatomic molecule we usually use a rigid-rotor model. If the molecule has a dipole then this clearly changes as the molecule rotates, produced an oscillating electric field, and so a microwave (rotational) spectrum is produced. A homo-nuclear diatomic e.g. $\ce{O2}$ has no microwave spectrum.
In a UV/visible transition an excited state may be produced but only if the electron distribution in the excited state is different from that of the ground state, i.e. a dipole is produced that can interact with the radiation. A molecule such a benzene has a forbidden first electronically excited state due to its symmetry (which is however observed weakly due to other effects) and so absorbs very little compared to aniline (amino-benzene) or many dye molecules where symmetry does not limit any electronic dipole formation.
Thus although the details vary, the underlying ideas are the same. You should understand now that the statements about spectra in your question are not all correct. The rules used to determine what transitions are allowed or not allowed (called forbidden) are called 'selection rules'.
You can read about this in more detail, as a quantum version, in most undergraduate phys. chem. textbooks.
You may realise that the vibrational frequencies of homo-nuclear molecules are known even though they have no ir spectrum and this is because they can be measured by Raman spectroscopy. This depends on the change in shape/size of the 'electron cloud' (polarisability) a molecule possesses. Electro-magnetic radiation also possesses an oscillating magnetic field but this interacts far more weakly with molecules than its electric counterpart and can often but not always be ignored, the exception being NMR spectroscopy.

A:

Lets begin with the absorption.
The probability of ANY absorption taking place is given by the the Einstein's B coefficient, which is \begin{equation}
    B_{n^{\prime}n^{\prime\prime}}=\frac{8 \pi^3}{3h^2}[|\int \psi_{n^\prime}\mu_{X} \psi_{n^{\prime\prime}}d \tau|^2 + |\int \psi_{n^\prime}\mu_{Y} \psi_{n^{\prime\prime}}d \tau|^2 + |\int \psi_{n^\prime}\mu_{Z} \psi_{n^{\prime\prime}}d \tau|^2]
\end{equation}
Above equation is in complete generality, and the wave function $\psi$ is the complete wave function. $\mu_{X}$ is the dipole moment component (in X, using Cartesian coordinates). Integration is over all space.
RULE: if the dipole moment components for a given transition are zero, the absorption will not take place. (By components I mean the integral. If the integral goes to zero then no absorption for that component, if all three integrals are zero then no absorption at all) This determines the selection rules for all absorption processes (and also induced emission, but not discussing here !).
Back to absorption, the wave-function for the molecule  can be expressed as
\begin{equation}
    \psi= \psi_{E} \psi_{V} \psi_{R} \psi_{T}
\end{equation}
where $\psi_{E}, \psi_{V}, \psi_{R}$ and $\psi_{T}$ are the electronic, vibrational, rotational and translational wave-functions. For vibrational analysis the electronic wave function does not matter and we can safely exclude it. (This is the wave function needed for the calculation of the integral. For general understanding consider the wave function as a mathematical function whose integral gives you information about the molecule.)
The translational selection rule is that the change in the quantum number should be $\Delta n =0$ that is the quantum number does not change (while translation in space).
[At the stage we have separated the electronic and translational wave functions, and we deal with only vibrations, hence $\psi_{v}$.]
Coming to rotational and vibrational part,
If $X_{\alpha}$, $Y_{\alpha}$ and $Z_{\alpha}$ is the coordinate which moves with the molecule, then a new coordinate can be introduced which moves and also rotates with the molecule. This is say $x_{\alpha}$, $y_{\alpha}$ and $z_{\alpha}$.
 The relation between $X_{\alpha}$ and $x_{\alpha}$ are governed by angles expressed as trigonometric relations, also known as direction cosines.
 Advantage of this transformation is that we can separate vibration from rotation and discuss vibration.
The electric moment of the full system of molecule has three components in Cartesian coordinates, \begin{equation}
    \mu_{x}=\sum_{\alpha}e_{\alpha}x_{\alpha}
\end{equation}
\begin{equation}
    \mu_{y}=\sum_{\alpha}e_{\alpha}y_{\alpha}
\end{equation}
\begin{equation}
    \mu_{z}=\sum_{\alpha}e_{\alpha}z_{\alpha}
\end{equation}
Now, during vibration the charged entities are moving. To be more clear I would say the nuclei are moving. The dipole moment is dynamic and changing with the vibration. The changing dipole moment can be expressed a Taylor expansion so as to include the change from equilibrium position. This expansion is carried out using the normal coordinates( normal coordinates are coordinates of the atoms which change with the vibration, when all atoms move with same frequency but different amplitudes).\begin{equation}
    \mu_{x}=\mu_{x}^{0}+\mu_{x}^{1}Q_{1}+\mu_{x}^{2}Q_{2}+...
\end{equation}
where $\mu_{x}^{n}$ is the nth derivative. Generally, only the first derivative is taken and hence, \begin{equation}
    \mu_{x}=\mu_{x}^{0}+  \frac{d \mu_{x}}{dQ_{1_{0}}}\hspace{1ex}Q_{1}
\end{equation}
Above result is now used with the vibrational wave function.
\begin{equation}
    \int \psi_{n^\prime}\mu_{x} \psi_{n^{\prime\prime}}d\tau= \int \psi_{n^\prime} [ \mu_{x}^{0}+  \frac{d \mu_{x}}{dQ_{1_{0}}}\hspace{1ex}Q_{1} ]\psi_{n^{\prime\prime}}d\tau
\end{equation}
\begin{equation}
    \int \psi_{n^\prime}\mu_{x} \psi_{n^{\prime\prime}}d\tau=\mu_{x}^{0} \int \psi_{n^\prime}  \psi_{n^{\prime\prime}} d \tau + \int \psi_{n^\prime} [ \frac{d \mu_{x}}{dQ_{1_{0}}}\hspace{1ex}Q_{1} ]\psi_{n^{\prime\prime}}d \tau
\end{equation}
The first term would go to zero since the vibrational wave functions are orthogonal. In the second term, the condition of non-zero derivative of dipole moment is required to have this term being non-zero. Hence the change if dipole moment with vibration is utmost necessary.
Other comments: With similar approach one can derive, for UV and visible absorption that the dipole is required; and for microwave absorption we need a permanent dipole moment.
References:
Physical Chemistry by Atkins, Paula.;
Modern Spectroscopy by Hollas ;
(More advanced reference. Molecular vibrations by Wilson, Decius, Cross.)


/*

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/**
 * @private
 * @class Ext.layout.component.field.TextArea
 * @extends Ext.layout.component.field.Field
 * Layout class for {@link Ext.form.field.TextArea} fields. Handles sizing the textarea field.
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Ext.define('Ext.layout.component.field.TextArea', {
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    alias: 'layout.textareafield',

    type: 'textareafield',

    /**
     * Given the target bodyEl dimensions, adjust them if necessary to return the correct final
     * size based on the text field's {@link Ext.form.field.Text#grow grow config}. Overrides the
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     * @param {Number} width The bodyEl width
     * @param {Number} height The bodyEl height
     * @return {Number[]} [inputElWidth, inputElHeight]
     */
    adjustForGrow: function(width, height) {
        var me = this,
            owner = me.owner,
            inputEl, value, max,
            curWidth, curHeight, calcHeight,
            result = [width, height];

        if (owner.grow) {
            inputEl = owner.inputEl;
            curWidth = inputEl.getWidth(true); //subtract border/padding to get the available width for the text
            curHeight = inputEl.getHeight();

            // Get and normalize the field value for measurement
            value = inputEl.dom.value || ' ';
            value += owner.growAppend;

            // Translate newlines to
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            value = value.replace(/\n/g, '
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            // Find the height that contains the whole text value
            calcHeight = Ext.util.TextMetrics.measure(inputEl, value, curWidth).height +
                         inputEl.getBorderWidth("tb") + inputEl.getPadding("tb");

            // Constrain
            max = owner.growMax;
            if (Ext.isNumber(height)) {
                max = Math.min(max, height);
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            result[1] = Ext.Number.constrain(calcHeight, owner.growMin, max);
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        return result;
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Estonia Industrial production May 2016

Estonia: Industrial production falls back into contraction in May

July 1, 2016

According to Statistics Estonia, industrial production decreased a working-day adjusted 1.9% over the same month last year in May, which marked a significant deterioration from the revised 0.7% increase registered in April (previously reported: +0.8% year-on-year). May’s drop marked a further decrease in Estonian industrial production, which, apart from last month, has been falling since April 2015. May’s reading was mainly driven by a drop in energy production.

A seasonally-adjusted month-on-month assessment shows that industrial production decreased 3.3% in May, which contrasted April’s 5.6% expansion. Meanwhile, the annual average variation in industrial production was minus 3.3% in May, the same reading tallied in April.

FocusEconomics Consensus Forecast panelists expect industrial production to grow 2.0% in 2016, which is down 0.9 percentage points from last month’s projection. The panel foresees industrial production increasing 3.8% in 2017.

Author:Andrea Vetrugno, Economist

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List of lakes of Germany

The largest lake on German territory is Lake Constance, while Lake Müritz is the largest lake located entirely within German territory.

List
(incomplete)

The following is a list of some larger lakes in Germany:

See also
 List of dams and reservoirs in Germany
 List of lakes in Bavaria
 List of lakes of Hesse
 List of lakes in Mecklenburg-Vorpommern
 List of lakes of Rhineland-Palatinate
 List of lakes in Schleswig-Holstein

*
Lakes


1. Technical Field of the Invention
The present invention relates generally to a current mirror.
More specifically, the invention relates to a current mirror of the type comprising at least a first and a second mirror transistors inserted between a first and a second voltage reference and connected to an input terminal and to an output terminal of the current mirror, respectively. A base current compensation block is inserted between said input terminal and common control terminals of the first and second mirror transistors and connected to a voltage reference.
2. Description of Related Art
As it is well known, current mirrors are widely used in all kinds of electronic circuits. Basically, a current mirror is a circuit designed to copy a current flowing through one active device by controlling a current in another active device, keeping an output current of an output terminal of the current mirror constant regardless of loading values applied to the output terminal itself.
A current mirror realized by using bipolar transistors is schematically shown in FIG. 1.
In particular, the current mirror 1 comprises a first or input leg comprising a current generator G1 issuing a reference current Iref, a first mirror transistor Q1 and a first emitter resistor R1, inserted, in series with each other, between a first and a second voltage reference, in particular a supply voltage reference Vcc and ground GND.
Furthermore, the current mirror 1 comprises a second or output leg comprising a second mirror transistor Q2 and a second emitter resistor R2, inserted, in series with each other, between an output terminal OUT of the current mirror 1 and ground GND.
The first and second mirror transistors, Q1 and Q2, are bipolar transistors and have their base terminals connected to each other.
To increase current mirror accuracy, a classic solution is to use emitter resistors and a base current compensation block, as shown in FIG. 1 and globally indicated at 2.
In particular, the base current compensation block 2 is connected to the common base terminals of the mirror transistors, Q1 and Q2, and to the collector terminal of the first mirror transistor Q1. The collector terminal of the first mirror transistor Q1 is also the input terminal IN of the current mirror 1.
The base current compensation block 2 is used to compensate the base currents of the first and second mirror transistors, Q1 and Q2. A well known realization of this block is described in Analysis and Design of Analog Integrated Circuits, Paul R. Gray, Robert G. Meyer, Third edition, page 276, and schematically shown in FIG. 2.
In particular, the base current compensation block 2 comprises a compensation transistor Q3, inserted between the supply voltage reference Vcc and the common control or base terminals of the mirror transistors, Q1 and Q2, and having a base terminal connected to the collector terminal of the first bipolar mirror transistor Q1. The compensation transistor Q3 is a bipolar transistor.
It can be verified that the compensation transistor Q3 reduces the error of an output current of the output terminal OUT according to the following equation:
                    Iout        =                  Iref                      1            +                          2                                                β                  F                                                                  (                                                            β                      F                                        +                    1                                    )                                                                                (        1        )            where Iout is the output current, Iref is the reference current and βF is the bipolar current gain of Q1, Q2 and Q3 (supposed to be equal at a first order approximation).
Moreover, the first and second emitter resistors, R1 and R2, increase the matching of the current mirror 1, as explained in the above cited handbook, pages 317 to 320.
Also known is an alternative realization of the base current compensation block 2 using a MOS transistor M3, as shown in FIG. 3.
In this case, as the gate current of a MOS transistor is zero, the output current Iout is equal to the reference current Iref and the base currents of the first and second bipolar mirror transistors, Q1 and Q2, are supplied by the MOS transistor M3.
While advantageous from many points of view, the known solution has shown several drawbacks, among which is the fact that an input voltage applied to the collector terminal of the first mirror transistor Q1 should be higher than a threshold value, which turns out to be too high in many applications. In particular, such a threshold voltage is:                2×Vbe+R1×Iref, for the base current compensation block 2 realized by a bipolar transistor and shown in FIG. 2, or        Vgs+Vbe+R1×Iref, for the base current compensation block 2 realized by a MOS transistor and shown in FIG. 3,where:        Vbe is the base-emitter voltage of the first mirror transistor Q1; and        Vgs is the gate source voltage of the MOS transistor M3.
As an example, if Vbe=0.8V, Vgs=1V and R1×Iref=0.2V (which are common amounts for these values) the minimum input voltage is about 1.8V or 2V, increasing to 2V or 2.3V with temperature and process variations.


German Chancellor Angela Merkel’s invitation to migrants to come to her country has been described as “insane” by U.S. Presidential candidate Donald Trump, who has predicted more violence will follow in the country as a result.

Donald Trump, the Republican Party presidential front-runner, was talking about Mrs. Merkel’s invitation to migrants on the American political interview show, ‘Face The Nation’.

Mr Trump said: “I do not like the migration. I do not like the people coming”. Instead he favours “a safe zone for people”, an idea on which he expanded.

He said: “Frankly, look, Europe is going to have to handle — but they’re going to have riots in Germany. What’s happening in Germany, I always thought Merkel was like this great leader. What she’s done in Germany is insane. It is insane. They’re having all sorts of attacks.”

Mr Trump was talking about the decision to throw open Germany’s doors to Syrian migrants taken by Frau Merkel in August, which Breitbart London previously reported. The ‘open doors’ policy is an idea for which she has come under attack, even from those within her own political ranks.

“What they should do is get all the countries together, including the Gulf States, which have nothing but money. They should all get together and they should take a big swath of land in Syria.

“They should do a safe zone for people where they could live. And then ultimately go back to their country, go back to where they came from.”

Mr Trump was asked how many migrants he would take into the U.S. were he in charge. He replied: “10,000, I’m not thrilled, but maybe. 200,000 people? This could be the greatest Trojan Horse. This could make the Trojan horse look like peanuts if these people turned out to be a lot of ISIS.”

He commented on the fact that most of the migrants are young men:

“…I have been watching this migration. And I see the people. I mean, they’re men. They’re mostly men, and they’re strong men. These are physically young, strong men. They look like prime-time soldiers.

“Now, it’s probably not true, but where are the women? You see some women. You see some children. But for the most part, I’m looking at these strong men. So, you ask two things. Number one, why aren’t they fighting for their country? And, number two, I don’t want these people coming over here.

“And even on a humanitarian — when I was first asked this question — you asked it to me a long time ago — when they were talking about 3,000 people, I begrudgingly would say, oh, maybe, I don’t know. Maybe.”


Blackpool 3 - Southampton 0

Blackpool cruise past league leaders

Blackpool improved on their recent performances to cruise past the league leaders at Bloomfield Road in the weekend`s evening kick off. Southampton missed a golden chance to go in front when Matt Gilks saved a Billy Sharp penalty in the first half, and Blackpool never looked back. Stephen Dobbie marked his second home debut for the club with a brace, before Ian Evatt nodded in from a corner to seal all three points.

yebrows were raised when the teamsheet was unveiled, with Barr Ferguson, Stephen Crainey, Craig Cathcart and Kevin Phillips all missing from the matchday squad, with Bob Harris starting at left back, Angel Martinez restored to the midfield, while Dobbie played in the hole behind Taylor-Fletcher up front. Tom Ince and Matt Phillips were both brought back in after missing the defeat at Reading. Southampton were without the division`s leading scorer Rickie Lambert, the 24 goal man succumbing to a groin injury, while Jason Puncheon also missed out on a return to Bloomfield Road.

outhampton dominated the opening exchanges of the game, with Guly Do Prado missing an excellent chance when clean through, only to dink it wide of the goal, while Neal Eardley and Bob Harris were kept busy by Adam Lallana as he covered important ground on both wings. The visitors were well on top, and were given a great chance to lead when Bob Harris was caught out, and Do Prado was about to pull the trigger, Harris dragged him down, leaving the assistant referee no choice but to flag for the penalty.

regular scorer at Bloomfield Road whenever he visits, the world expected Billy Sharp to put the Saints in front, but his weak effort from 12 yards was well saved by Gilks. Moments later Gary Taylor-Fletcher showed great footwork on the left side before bursting into the area, only to be upended by Morgan Schneiderlin. The referee pointed to the spot once again, and Stephen Dobbie gleefully accepted the opportunity to open his account in his second loan spell.

obie didn`t have to wait long for his second, when a long ball from Eardley was flicked on by Taylor-Fletcher, and the Scot showed great pace to get beyond Jos Hooiveld, then strength to hold off the big centre back before guiding a wonderful right footed effort into the far corner with his first touch.

he remainder of the first half was dominated by the Seasiders, with Tom Ince and Matt Phillips causing the visiting back four all sorts of problems with their pace, regularly catching the full back pairing of Butterfield and Fox out of position, and Blackpool could have been out of sight at half time.

he second half saw Southampton make a change, with Steve De Ridder replacing Richard Chaplow, but the Blackpool carried on where they left off, forcing the league leaders onto the back foot with their movement and pace up front. After a succession of corners, Phillips delivered a wonderful cross to the back post which picked out the run of Ian Evatt, who powered a header into the top corner to effectively kill off any hopes of a Southampton come back.

s Blackpool looked to see the game out, the division`s top side started to cause problems, but the new back four looked solid under pressure, with Bob Harris particularly impressing with one goal line clearance from a Sharp flick, before denying the former Scunthorpe and Doncaster man again with a last ditch tackle when Evatt and Baptiste were caught flat footed by a ball into Sharp`s feet 10 yards out.

he substitutions had the desired effects, as LuaLua, Ormerod and Fleck all came on to run the clock down, with Gilks only having to save once from a Danny Fox free kick, and Blackpool held on to a first clean sheet in 14 games, and an impressive win to get their playoff push back on track.

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Q:

Html & Css Table Cell Width Issue how to show Icon always on the right side?

I have a Table with 3 Table-Cells.
The first one should represent a Profile Picture, the second one should represent a title (text) and the third one should represent a button with a flag icon in it.
How it should be:

How it is at the moment:

As you can see the middle cell resizes its width automatically.
Thats the Problem because no matter how long the text in the middle is it should always fit/fill the screen. The Left and Right ones should always have the same fixed width.
What I have tried already:

  ........here is the img

  ..... here is the text

 ...... button with icon

css:
.table{
 display: table;
}
.tablecellleft{
 display: table-cell;
 min-width: 17vw;
 max-width: 17vw;
}
.tablecellmiddle{
 display: table-cell;
 vertical-align: top;
 //No width because it should fill
}
.tablecellright{
 display: table-cell;
 min-width: 17vw;
 max-width: 17vw;
}

A:

Use calc and subtract what width you have given to left and right section by 100%;
width: calc(100% - 34vw);

var fees = ['$0.9 + $.1', '$20 + $2', '$5 + $0.5', '$0 + $0.01', '$100 + $9', '$1 + $1', '$2 + $0.5'];
.table{
 display: table;
width: 100%;
}
.tablecellleft{
 display: table-cell;
 width: 17vw;
}
.tablecellmiddle{
 display: table-cell;
 vertical-align: top;
 width: calc(100% - 34vw);
 //No width because it should fill
}
.tablecellright{
 display: table-cell;
 width: 17vw;
text-align: right;
}

  ........here is the img

  ..... here is the text

 ...... button with icon


Some of the experts are saying that Megan Fox is already done and as proof they point out that ‘Jennifers Body’ didn’t make any money. Keep in mind however that the experts never have any idea WTF they’re talking about.

‘Jennifers Body’ didn’t make any money because it sucked, and it sucked because it was written by Diablo Cody. Even with that anchor around it’s neck, ‘Body‘ made 6.9 million on it’s opening weekend. Compare that to ‘Whiteout’, starring Kate Beckinsale. That made 4.9 million. ‘Love Happens’, starring Jennifer Aniston, opened with 8 million. Before that, Aniston starred in ‘Management’. It opened on May 15th, and as of yesterday, it’s made a total of 934,658 dollars. You could have been collecting cans since May 15th and made more than that.

Point being: Look. At. Her. Just look at Megan in this bootleg version of her girl kissing scene from ‘Jennifers Body’. You can find better dialogue in a mentos commercial, and your local weatherman has better special effects, but Megan overcomes it all, she rises up like a Phoenix from the ashes, and takes us on a journey of erotic delights.


New developments in meat starter cultures.
Meat starter cultures containing one or more strains of lactic acid bacteria,Actinobacteria, staphylococci,Halomonas elongata, Aeromonas spec., and moulds or yeasts are widely in practical use. The progress in microbial systematic has led to changes in the taxonomy of familiar bacterial species which are described. Studies of flavour genesis led to the identification of the contribution of the enzyme activities endogenously present in the meat matrix as well as of those exerted by the starter cultures. Characteristic compounds of the aroma of fermented meat products originating from the starter organisms were also described. New knowledge was accumulated on the physiology and genetics of starter bacteria and some insight has been gained in the regulation of the expression of genes encoding important properties such as bacteriocin production or catalase activity. The applicability of gene technology to starter strains has been shown and strains have been constructed that have the potential to further improve the technological and hygienic suitability of starter cultures. New applications of the micro-organisms as protective or probiotic cultures have been developed for application in meat science.


Stroop performance and difficulties of older adults using automatic teller machines.
This study examined the relationship between inhibition of older dults and difficulties using automatic teller machines. 22 older adults performed three transactions on an ATM simulator, and errors were recorded. Participants also performed the Stroop interference task to assess inhibition. Both interference effect in response latencies and rate of intrusion errors in the Stroop task were moderately correlated with number of errors on the task. Older adults with low Stroop performance made more errors in the categories of Forgetting an operation, Screen mix-up, and Overlooking an input error than those with high performance. These results suggest that low inhibition may be associated with difficulties in automatic teller machine use, and the importance of designing a user interface which lessens the likelihood of errors for older adults or others.


Introduction {#s1}
============

Coronary heart disease (CHD) remains the major cause of morbidity and mortality worldwide, responsible for about one in every seven deaths ([@B13]). It is predicted to continue until 2030, accounting for 14% of all deaths ([@B15]). Currently, the incidence of CHD is still on the rise and is associated with a high mortality rate, despite the use of effective Western medicine treatments. Therefore, effective complementary and alternative therapy is necessary to improve functional status and quality of life in CHD patients. Traditional Chinese medicine (TCM) integrated with Western medicine in the treatment of CHD has made great progress. As an effective complementary and alternative therapy, TCM has improved the prognosis of CHD patients. According to the TCM theory, Qi is the commander of blood. Qi stagnation causes blood stasis, which leads to heart vessel blockage stasis. CHD with Qi stagnation and blood stasis is a common syndrome of CHD. Therefore, one of the critical treatments of CHD in TCM is to regulate Qi and promote blood circulation ([@B26]). Xuefu Zhuyu (XFZY) decoction, which originated from the ancient Chinese document "Yilin Gaicuo" in the late Qing Dynasty, has effects on regulating Qi and promoting blood circulation, which is the basic prescription for the treatment of CHD ([@B14]). Previous studies confirmed that XFZY decoction reduced the incidence of cardiovascular events and improved the prognosis of patients with CHD; however, the underlying mechanism is still unclear.

CHD is characterized by an atherosclerotic plaque-induced narrowing of the coronary arteries, which results in myocardial ischemia, infarction, and postinfarction heart failure. The abnormal substrate and energy metabolism induced by myocardial ischemia is fundamental in the development of CHD ([@B7]). Because complete metabolism of glucose is more oxygen efficient than that of fatty acids (FA; [@B16]), myocardial ischemia causes the limitation of FA oxidation and the effective utilization of glucose catabolism, which may lead to the decrease of adenosine triphosphate (ATP) production. In addition, several additional pathways that do not lead to ATP generation, such as the pentose phosphate pathway and the hexosamine biosynthetic pathway, are activated. Therefore, metabolic abnormality plays a key role in affecting the development and prognosis of CHD ([@B18]; [@B10]). Recently, it was found that metabolites involved in amino acid metabolism and tricarboxylic acid (TCA) cycle might partially constitute the material foundation of Qi, according to the Qi and blood theory of TCM ([@B28]). Therefore, we studied differential metabolites in the serum of CHD patients to explore the effects of TCM on regulating Qi and promoting blood circulation. It is of great significance to elucidate the mechanism of improving the prognosis of CHD patients through Qi-regulating and blood-promoting herbs and to study Qi and blood in TCM theory.

Metabolomics is one of the youngest branches of "-omics" (such as genomics, transcriptomics, proteomics) techniques to offer the most up-to-date insight into the state of the system in the field of systems biology. It contains approaches to detect low-molecular-weight metabolites (molecular mass \<1,500 Da), which reflects changes in the final representations of an organism's phenotype. In our study, we used nontargeted metabolomics analysis to focus on the differential metabolites in the serum from CHD patients treated with placebo and XFZY decoction. We aimed to provide references for the pathogenesis of CHD and the treatment of Qi-regulating and blood-promoting drugs, which refined the understanding of Qi and blood in TCM theory.

Materials and Methods {#s2}
=====================

Participants {#s2_1}
------------

In this study, a total of 10 CHD patients were recruited from the Chinese PLA General Hospital from April to July 2017. On the basis of routine Western medicine treatment according to the guidelines, participants were treated with placebo granules and XFZY decoction granules randomly and double blindly (twice a day for 12 weeks). The study was approved by the Ethics Review Committee of Chinese PLA General Hospital (No. S2015-048-01) and registered at [www.chictr.org.cn](www.chictr.org.cn) (registration number ChiCTR-IOR-15006989).

Inclusion criteria included age \<75 years and compliance with the diagnostic criteria for stable CHD according to the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines in 2014 ([@B8]). All participation was voluntary, and patients signed an informed agreement. We excluded patients with severe renal dysfunction (serum creatinine \>220 μmol/l in males or \>175 μmol/l in females), liver dysfunction (aspartate aminotransferase or alanine aminotransferase level three times higher than normal), uncontrolled blood pressure, diabetes mellitus, hemorrhagic diseases, malignant tumors, autoimmune diseases, or hematological or psychiatric diseases; pregnant women; and those who were allergic to components of the research drugs. We also excluded patients with a history of myocardial infarction, severe chronic heart failure, severe arrhythmia, or a cardiac pacemaker. Patients were treated with routine Western medicine according to the guidelines, including anti-ischemia drugs (β receptor blocker or calcium antagonist), antiplatelet drugs (aspirin or clopidogrel), anticoagulant drugs (heparin or low-weight-molecular heparin), and lipid-lowering drugs (statins). Complications, such as hypertension and dyslipidemia, were treated according to relevant guidelines. During the study, nitroglycerin was used to relieve acute angina pectoris. The specifications of nitroglycerin are 0.5 mg/tablet. The original treatment was maintained during the trial.

TCM Treatment {#s2_2}
-------------

Both XFZY decoction granules and placebo granules were prepared and standardized from China Resources Sanjiu Medical & Pharmaceutical Company (Shenzhen, China). XFZY decoction granules refer to the proportion of components of XFZY decoction, and the botanical compositions are shown in Table 1. The voucher specimens of total compositions were stored by China Resources Sanjiu Medical & Pharmaceutical Company (Shenzhen, China). The chemical compositions of XFZY decoction mainly consisted of ferulic acid, paeoniflorin, amygdalin, hydroxysafflor yellow A, catalpol, platycodin D, liquiritin, and ammonium glycyrrhizinate, as indicated by the high-performance liquid chromatography (HPLC) profile of the extract performed by the manufacturer ([**Supplementary Figure 1**](#SM1){ref-type="supplementary-material"}). The chemical structures of those major compounds are depicted in [**Supplementary Figure 2**](#SM1){ref-type="supplementary-material"}. The main components of placebo granules were caramel pigments (4 g), and maltodextrin (1,000 g). Using the technical requirements of the quality standards of TCM formula granules, a mixing solution was dried, and granules were then formed. Quality control (QC) of the pharmaceutical process was carried out in accordance with Pharmaceutical Production Quality Management Standards (2015).

######

Botanical compositions of Xuefu Zhuyu decoction.

  Herb (local name)                                         Medicinal parts   Amount in application (g)
  --------------------------------------------------------- ----------------- ---------------------------
  *Prunus persica* (L.) Batsch (Tao Ren)                    Seed              12
  *Angelica sinensis* (Oliv.) Diels (Dang Gui)              Root              15
  *Conioselinum anthriscoides* "Chuanxiong" (Chuan Xiong)   Root              10
  *Carthamus tinctorius* L. (Hong Hua)                      Flower            10
  *Paeonia lactiflora* Pall. (Chi Shao)                     Root              10
  *Rehmannia glutinosa* (Gaertn.) DC. (Di Huang)            Root              15
  *Citrus × aurantium* L. (Zhi Qiao)                        Fruit             6
  *Bupleurum chinense* DC. (Chai Hu)                        Root              3
  *Platycodon grandiflorus* (Jacq.) A.DC. (Jie Geng)        Root              4.5
  *Achyranthes bidentata* Blume (Niu Xi)                    Root              9
  *Glycyrrhiza uralensis* Fisch. ex DC. (Gan Cao)           Root              6

All components in Xuefu Zhuyu decoction granules were fully validated using <http://mpns.kew.org/mpns-portal/?_ga=1.111763972.1427522246.1459077346>.

Randomization, Control, and Double Blinding {#s2_3}
-------------------------------------------

Subjects were randomly grouped by researchers using a random-number table by SAS statistical software. The allocation ratio between the XFZY decoction group and placebo group was 1:1. Drugs were coded and packaged according to random numbers. The blind bottom could not be disassembled during the trial. A placebo group was established as the control of XFZY decoction to exclude the effect of the placebo on CHD treatment. The participants, staff, and researchers were blinded to the treatment group allocation.

Sample Collection and Preparation {#s2_4}
---------------------------------

All subjects fasted overnight, and 4 ml of peripheral venous blood was drawn in the morning of the day of the consultation. The blood was then coagulated for 30 min at 4°C and centrifuged at 3,000 × *g* for 15 min. The serum supernatant was collected. We then added 400 μl of prechilled methanol to 100 μl serum samples to precipitate the proteins. The mixture was shaken for 15 s, incubated at --80°C for 1 h, and then centrifuged at 13,400 × *g* for 20 min at 4°C. The supernatant was transferred to a new Eppendorf tube and dried before storage in the --80°C freezer. A pooled QC sample solution was prepared by combining equal volumes of serum from each sample and treated using the same procedure. This sample was used to monitor the reliability of the entire experiment. One QC sample was inserted in front of the batch of experimental samples, and each QC sample was inserted in an interval of 10 to 15 samples. Once a QC sample ended, the instrumental stability was monitored throughout the batch process ([@B12]).

Untargeted LC-MS/MS Analysis and Metabolite Identification {#s2_5}
----------------------------------------------------------

Samples were analyzed by untargeted liquid chromatography with tandem mass spectrometry (LC-MS/MS) using an Ultimate 3000 UHPLC (Dionex) system combined with a Thermo Q-Exactive (Orbitrap) mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA). Data identifications were performed by Trace Finder (Thermo Fisher Scientific, San Jose, CA, USA). First, metabolites were potentially identified by accurate masses according to the endogenous MS database. Meanwhile, metabolites that matched with the spectra in the fragment database were confirmed at the MS/MS level. The mass tolerances of primary and secondary identifications were 10 and 15 ppm, respectively. Moreover, a 0.25-min retention time shift was applied ([@B19]).

Data Processing and Statistical Analysis {#s2_6}
----------------------------------------

SIMCA 14.0 software (Umetrics AB, Umea, Sweden) was used for multivariate statistical analysis. Unsupervised principal component analysis (PCA) was employed to assess the quality, homogeneity, outlier identification, and dominating trends of the group separation inherent in the data set. A supervised orthogonal partial least squares discriminant analysis (OPLS-DA) was applied to distinguish between the classes and to identify the differential metabolites. Variable importance in the projection (VIP) value was generated in PLS-DA model. The quality of the multivariate statistical analysis model was evaluated by R^2^X and Q^2^. Student's *t* test was used to determine the difference in metabolites between the two groups. Metabolites with VIP \> 1 and *P* \< 0.05 were considered to be the most probable metabolites, which could be used to analyze the difference between the two groups and to assess the severity of CHD. Subsequently, the internal metabolite MS/MS database was used to identify metabolites by matching accurate quality and MS/MS spectra. MetaboAnalyst 4.0 (<http://www.metaboanalyst.ca/>; Wishart Research Group, McGill University, Canada) was used to show differential metabolites with a heat map and to predict the metabolic pathways ([@B4]). SPSS v13.0 (Chicago, IL, USA) was used for statistical analysis. Student's *t* test was performed for two-group comparisons on baseline characteristics. One-way analysis of variance was used to detect the homogeneity of variance. Values are presented as mean ± SD. *P* \< 0.05 was considered statistically significant.

Results {#s3}
=======

Baseline Characteristics {#s3_1}
------------------------

Ten CHD patients were randomly and double blindly divided into two groups: five patients were treated with placebo granules for 12 weeks, and five patients were treated with XFZY decoction granules for 12 weeks. Serum samples from 10 CHD patients were detected by nontargeted metabolomics analysis. The baseline characteristics of the subjects are shown in Table 2 and include age, body mass index (BMI), blood pressure (systolic pressure, diastolic pressure), heart rate, five kinds of blood routine indices \[including red blood cell (RBC), hemoglobin (HGB), white blood cell (WBC), neutrophil (NE), and platelet (PLT)\], 10 kinds of biochemical indices \[including alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (SCr), blood urea nitrogen (BUN), uric acid (UA), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and fasting glucose (Glu)\], and four kinds of coagulation parameters \[including prothrombin time (PT), activated partial thrombin time (APTT), fibrinogen (FIB), and thrombin time (TT)\]. The average ages of the CHD patients in the two groups were 54.4 ± 5.73 years and 57.0 ± 15.84 years, respectively. The mean BMIs of the two groups were 28.26 ± 6.62 kg/m^2^ and 28.49 ± 3.71 kg/m^2^, respectively. With the statistical analysis by Student's *t* test, the levels of HGB and Glu were increased, whereas APTT was decreased in the XFZY decoction group as compared with those in the placebo group (*P* \< 0.05). However, all values were within the normal range. There was no significant difference in other characteristics between the two groups (*P* \> 0.05).

######

Baseline characteristics of patients.

                          Placebo (n = 5)   XFZY (n = 5)     *P* Value
  ----------------------- ----------------- ---------------- -----------
  Gender (F/M)            2/3               1/4              0.690
  Age, years              54.4 ± 5.73       57 ± 15.84       0.739
  BMI, kg/m^2^            28.26 ± 6.62      28.49 ± 3.71     0.946
  Blood pressure, mmHg
  SBP                     126.80 ± 15.40    133.60 ± 11.61   0.453
  DBP                     86.80 ± 6.42      82 ± 8.37        0.339
  Heart rate, beats/min   67.20 ± 5.22      71.40 ± 15.19    0.575
  Library data
  RBC, ×10^12^/L          4.78 ± 0.08       5.12 ± 0.42      0.153
  HGB, g/L                140.4 ± 7.57      159 ± 16.02      0.047\*
  WBC, ×10^9^/L           6.03 ± 1.98       7.08 ± 2.34      0.465
  NE, %                   64.94 ± 9.80      63.99 ± 4.54     0.849
  PLT, ×10^9^/L           231 ± 47.43       231.6 ± 92.69    0.990
  AST, U/L                20.18 ± 4.98      20.86 ± 7.06     0.865
  ALT, U/L                22.80 ± 10.51     27.40 ± 8.86     0.476
  SCr, μmoI/L             68.34 ± 23.38     82.08 ± 15.89    0.309
  UA, μmoI/L              319.74 ± 90.24    319.84 ± 24.85   0.998
  BUN, mmoI/L             4.63 ± 1.20       5.31 ± 1.23      0.399
  TG, mmol/L              2.22 ± 1.15       1.32 ± 0.38      0.135
  CHOL, mmol/L            3.07 ± 1.59       4.48 ± 0.68      0.106
  HDL, mmol/L             1.29 ± 0.48       1.18 ± 0.12      0.630
  LDL, mmol/L             1.94 ± 0.47       2.70 ± 0.74      0.088
  Glu, mmol/L             4.83 ± 0.37       5.64 ± 0.59      0.031\*
  PT, s                   13.18 ± 0.63      12.52 ± 0.98     0.242
  APTT, s                 37.84 ± 1.63      32.94 ± 3.14     0.015\*
  FIB, g/L                2.84 ± 0.35       3.19 ± 0.44      0.201
  TT, s                   16.68 ± 0.66      16.72 ± 1.58     0.960

Values are mean ± SD. \*P \< 0.05 versus placebo group.

Analysis of QC Samples {#s3_2}
----------------------

We randomly selected 10 serum samples from CHD patients for metabolomics testing (five in the placebo group and five in the XFZY decoction group). In our research, we used a customized database and nontargeted metabolomics methods to analyze the data. From data collection to data analysis of clear compounds, we quantitatively identified hundreds of compounds according to the established Orbitrap workflow. A total of 513 metabolites were detected in the samples after treatment, which were identified with known MS/MS information. Samples were then subjected to PCA and OPLS-DA analysis.

Serum Metabolomics and Pathway Analysis {#s3_3}
---------------------------------------

To evaluate the identification ability of 513 metabolites, we analyzed the metabolic differences between the two groups, merged all identified compounds (513 in total), and imported them into SIMCA-P software for PCA. The results showed that there was no significant difference between the two groups (*P* \> 0.05). Further analysis with two- or three-dimensional orthogonal partial least -squares discriminant method obtained an OPLS-DA score chart ([**Figure 1**](#f1){ref-type="fig"}), which confirmed that there was significant difference between the XFZY decoction group and the placebo group. The OPLS-DA model established a good model and made an accurate prediction (R^2^X = 76.2% and Q^2^ = 39.1%).

![The orthogonal projection to latent structure-discriminant analysis (OPLS-DA) score plots compared the Xuefu Zhuyu decoction group to the placebo group. The left image is the two-dimensional graph of the OPLS-DA score plots, and the right image is the three-dimensional graph of the OPLS-DA score plots. The placebo group is shown in green, and the Xuefu Zhuyu decoction group is shown in red.](fphar-10-00985-g001){#f1}

After filtering 513 different metabolites in each group with the requirements of VIP \> 1 and *P* \< 0.05, six differential metabolites in the XFZY decoction group were changed as compared with the placebo group, namely, tetracosanoic acid (24:0), N-acetylglycine, FA (20:2)-H, 2-deoxy-D-glucose (2-DG), cis-aconitic acid, and spermine. Compared with the placebo group, tetracosanoic acid (24:0), N-acetylglycine, FA (20:2)-H, 2-DG, and cis-aconitic acid were downregulated, whereas spermine was upregulated in the XFZY decoction group.

As shown in [**Table 3**](#T3){ref-type="table"}, the differential metabolites related to FA metabolism were tetracosanoic acid (24:0) and FA (20:2)-H, which were obtained by election spray ionization negative (ESI--) mode with a mass of 367.358 and 307.264, respectively. Compared with the placebo group, tetracosanoic acid (24:0) and FA (20:2)-H in the XFZY decoction group were decreased, exhibiting that the ratio (XFZY/placebo) of tetracosanoic acid (24:0) or FA (20:2) was 0.46 (VIP = 2.40596, *P* = 0.008) or 0.78 (VIP = 2.21854, *P* = 0.020). 2-DG and cis-aconitic acid, which are related to glucose metabolism and obtained by ESI-- mode, were downregulated with XFZY decoction treatment. The mass, VIP value, *P* value, and FC (XFZY/placebo) of 2-DG were 163.061, 2.03138, 0.039, and 0.50, respectively. The mass, VIP value, *P* value, and FC (XFZY/placebo) of cis-aconitic acid were 173.009, 1.9734, 0.048, and 0.81, respectively. The differential metabolites associated with amino acid metabolism were N-acetylglycine and spermine obtained by ESI+ mode. The concentration of N-acetylglycine in the XFZY decoction group was decreased as compared with the placebo group, which showed that the ratio (XFZY/placebo) of N-acetylglycine was 44% (VIP = 2.28626, *P* = 0.015). However, the concentration of spermine was increased by 208% compared with that in the placebo group (VIP = 1.99192, *P* = 0.045). As shown in [**Figure 2**](#f2){ref-type="fig"}, the heat map illustrated total differential metabolites between the XFZY decoction group and placebo group: tetracosanoic acid, N-acetylglycine, FA, 2-DG, and cis-aconitic acid were downregulated, whereas spermine was upregulated.

######

Differential metabolites between the XFZY group and placebo group patients from LC-MS/MS analysis.

  Differential metabolite     Related metabolism      ESI mode   Mass (m/z)   RT (min)   FC (XFZY/placebo)   VIP       *P* value
  --------------------------- ----------------------- ---------- ------------ ---------- ------------------- --------- -----------
  Tetracosanoic acid (24:0)   Fatty acid metabolism   Neg        367.358      14.85      0.46                2.40596   0.008
  N-acetylglycine             Amino acid metabolism   Pos        118.050      8.29       0.44                2.28626   0.015
  FA(20:2)-H                  Fatty acid metabolism   Neg        307.264      13.25      0.78                2.21854   0.020
  2-deoxy-D-glucose           Glucose metabolism      Neg        163.061      1.04       0.50                2.03138   0.039
  Spermine                    Amino acid metabolism   Pos        203.223      8.76       3.08                1.99192   0.045
  cis-aconitic acid           Glucose metabolism      Neg        173.009      0.87       0.81                1.9734    0.048

XFZY, Xuefu Zhuyu decoction; ESI, election spray ionization; RT, retention time; VIP, variable importance in the projection; P, probability; FC, fold change; Pos, positive; Neg, negative; FA, fatty acid.

![The six differential metabolites in the two groups are shown in the heat map using MetaboAnalyst 4.0 (A: placebo group; B: Xuefu Zhuyu decoction group). The row represents the metabolites, and the column represents the individual samples. Red bands indicate upregulated metabolites, and blue bands indicate downregulated metabolites in the two groups. The deeper the color, the greater the difference in metabolites.](fphar-10-00985-g002){#f2}

MetaboAnalyst 4.0 software was used to analyze and predict the potential metabolic pathways involved in differential metabolites with XFZY decoction treatment. As shown in [**Figure 3**](#f3){ref-type="fig"}, six differential metabolites were involved in seven metabolic pathways: citrate cycle (TCA cycle), β-alanine metabolism, glycerolipid metabolism, glutathione metabolism, glyoxylate and dicarboxylate metabolism, FA metabolism, and arginine and proline metabolism.

![The disturbed metabolic pathways showed differential metabolites changed in the Xuefu Zhuyu decoction group as compared with the placebo group by MetaboAnalyst 4.0 software. Node radius was based on pathway impact values. Node color was based on *P* value.](fphar-10-00985-g003){#f3}

Further studies showed that cis-aconitic acid was involved in the TCA cycle as well as in glyoxylate and dicarboxylate metabolism. Spermine was predicted to participate in glutathione metabolism, arginine and proline metabolism, and β-alanine metabolism, respectively. FA (20:2) were predicted to be involved in FA metabolism and glycerolipid metabolism ([**Table 4**](#T4){ref-type="table"}).

######

Differential metabolic pathway between the XFZY group and placebo group.

  Pathway name                              Match status   Match metabolites
  ----------------------------------------- -------------- -------------------
  Citrate cycle (TCA cycle)                 1/20           cis-aconitic acid
  β-alanine metabolism                      1/28           Spermine
  Glycerolipid metabolism                   1/32           Fatty acid
  Glutathione metabolism                    1/38           Spermine
  Glyoxylate and dicarboxylate metabolism   1/50           cis-aconitic acid
  Fatty acid metabolism                     1/50           Fatty acid
  Arginine and proline metabolism           1/77           Spermine

XFZY, Xuefu Zhuyu decoction; TCA cycle, tricarboxylic acid cycle; match status, the number of accumulated metabolites/the number of all metabolites in metabolic pathways.

Discussion {#s4}
==========

CHD is the leading cause of morbidity and mortality throughout the world ([@B13]). The high mortality rate of CHD asks for effective complementary and alternative therapy to improve the prognosis of CHD patients. TCM based on syndrome differentiation is one of the effective complementary and alternative therapies. XFZY decoction, a classical traditional Chinese medication that regulates Qi and promotes blood circulation, is confirmed to be of clinical benefit for CHD treatment; however, the underlying mechanism is still unknown. The key pathogenesis of CHD is based on the abnormal metabolism of myocardial substrates and the disturbance of energy metabolism induced by myocardial ischemia or hypoxia ([@B7]). A recent study found that metabolites involved in the TCA cycle and amino acid metabolism (tryptophan, arginine, and proline metabolism) were significantly decreased in fasting morning urine of CHD patients with Qi and Yin deficiency syndrome, suggesting that the metabolites in amino acid metabolism and TCA cycle were partially the material foundation of Qi ([@B28]). In TCM theory, Qi is the commander of blood. Qi replenishment causes the promotion of blood circulation, whereas Qi stagnation leads to blood stasis, which suggests that Qi plays a leading role in CHD with Qi stagnation and blood stasis. In our study, the effect of XFZY decoction on low-molecular-weight metabolites was investigated by nontargeted metabolomics analysis. Compared with the placebo group, 513 kinds of metabolites were detected, and six metabolites were significantly differential in the serum from CHD patients after treatment with XFZY decoction. Among the six differential metabolites, FA (20:2)-H and tetracarboxylic acid (24:0), which are involved in FA metabolism; cis-aconitic acid, which participates in the TCA cycle; 2-DG, which is involved in glucose metabolism; and N-acetylglycine, which is involved in amino acid metabolism, were decreased, whereas spermine, which is involved in amino acid metabolism (such as arginine and proline, glutathione, and β-alanine metabolism), was increased as compared with the placebo group. This suggests that those low-molecular-weight metabolites might be the material foundation of XFZY decoction for regulating Qi and promoting blood circulation in CHD treatment.

FA Metabolism {#s4_1}
-------------

Because of continuous mechanical work, the heart has a high rate of ATP utilization. Because the high-energy phosphate pool in the heart is significantly small and could be exhausted within a few seconds, cardiomyocytes are very sensitive to changes in energy metabolism, and cardiac work strongly depends on ATP generation. Nearly 70% to 90% of ATP is produced by the oxidation of FA in cardiomyocytes ([@B7]). Free FA are esterified to fatty acylCoA in the cytosol and are transported into the mitochondria matrix by carnitine. There, they form Acyl-CoA to enter β-oxidation ([@B1]). Xu et al. found that FA and carnitine in the plasma of CHD patients were decreased compared with controls ([@B27]). However, others detected the lipid profile of H9c2 cells and then found that different types of FA were increased or decreased in hypoxic cardiomyocytes, which demonstrates that FA (18:1) was decreased, whereas FA (16:0) and FA (18:0) were increased as compared with controls. This indicates that different FA might change differently in special periods of hypoxia or ischemia in cardiomyocytes ([@B22]). FA (20:2)-H and tetracarboxylic acid (24:0) are very-long-chain FA and should be oxidized by peroxisome to form medium- or short-chain FA. They are then transported to the mitochondria matrix by carnitine for β-oxidation. This means that FA (20:2)-H and tetradecanoic acid (24:0) provide substrates for β-oxidation, and the decrease in carnitine indicates the limitation of FA β-oxidation. In this study, we found that FA (20:2)-H and tetradecanoic acid (24:0) were downregulated, whereas carnitine did not decrease after XFZY decoction treatment as compared with the placebo group, suggesting that XFZY decoction might promote FA β-oxidation, which led to the decrease of FA in the serum.

Glucose Metabolism {#s4_2}
------------------

In myocardial metabolism, FA and glucose utilization is tightly linked and co-regulated. Utilization of one substrate may directly inhibit the utilization of the other, which is referred to as the "Randle cycle" ([@B21]). In ischemic myocardium, FA oxidation is limited, and the utilization of glucose is increased. As a glucose analogue, 2-DG inhibited the critical enzymes of glycolysis (hexokinase and phosphoglucose isomerase), which inhibited glycolysis with the downregulation of glucose-6-phosphate and fructose-6-phosphate. In addition, 2-DG possessed a mannose-like property, which competed with mannose during the initial steps of N-linked glycosylation, resulting in protein misfolding and endoplasmic reticulum stress ([@B25]). In rat models, 2-DG was encountered as cardiac toxicity, with microscopic findings of vacuolar degeneration and hypertrophy of the endothelial cells of the endocardium ([@B24]). Studies in tumors have found that at low doses, 2-DG mainly interfered with N-linked glycosylation, resulting in endoplasmic reticulum stress, apoptosis, and autophagy. At medium doses, 2-DG also blocked glycolysis, leading to ATP reduction, and the subsequent growth inhibition. At high doses, 2-DG started to disrupt the pentose phosphate pathway, which caused growth arrest and oxidative stress ([@B25]). It was found for the first time that 2-DG in the serum of CHD patients was decreased after treatment with XFZY decoction, which suggested that XFZY decoction could attenuate the inhibition of N-glycosylation and glycolysis; alleviate endoplasmic reticulum stress, apoptosis, and autophagy; promote ATP production; and protect cardiomyocytes by downregulating 2-DG.

Acetyl-CoA, a common end product of glucose and FA oxidation, enters the TCA cycle and provides energy for cardiomyocytes ([@B20]). Cis-aconitic acid is an important intermediate that participates in the TCA cycle. It combines with aconitase, which converts citric acid to isocitric acid, and maintains the progress of the TCA cycle. The decrease in cis-aconitic acid suggests the limitation of TCA cycle metabolism. Our study first found that cis-aconitic acid, one intermediate of the TCA cycle, had the same change as 2-DG. Compared with the placebo group, cis-aconitic acid was decreased after XFZY decoction treatment. Combined with the previous changes in FA metabolism, it suggested that the upregulation of FA metabolism might inhibit glucose metabolism, as shown in the decrease of the intermediate in the TCA cycle.

Amino Acid Metabolism {#s4_3}
---------------------

Amino acids can also be used as energy metabolites. They form precursors of glucose and FA metabolism through deamination or transamination and participate in metabolic pathways, such as the TCA cycle. In addition, amino acid-derived bioactive substances play an important role in the cardiovascular system. Spermine is a kind of polyamine that is further produced by putrescine converted from arginine and has many physiological functions. It was reported that spermine was significantly decreased after myocardial ischemia/reperfusion injury in rats, suggesting that spermine may play a key role in myocardial ischemia/reperfusion injury ([@B9]). Animal experiments showed that spermine enhanced the antioxidant status: spermine supplementation and extended spermine administration could promote the expression of antioxidant enzymes, such as glutathione reductase by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) expression ([@B2]). Arginine plays a critical antiatherogenic role in the development of cardiovascular disease by regulating endothelial cell homeostasis. Nitric oxide (NO), produced by the oxidation of arginine in endothelial cells, promotes beneficial effects in the vasculature, including vasodilation, enhanced fibrinolysis, and inhibition of multiple atherothrombotic biological processes, such as platelet aggregation, leukocyte adhesion, endothelin generation, and smooth muscle cell proliferation ([@B17]; [@B23]). β-alanine can be transaminated to pyruvate, providing a substrate for cardiac glucose oxidation. In our study, we found for the first time that the serum spermine concentration in CHD patients was increased after treatment with XFZY decoction. Bioinformatics analysis further indicated that spermine was involved in glutathione metabolism, arginine and proline metabolism, and β-alanine metabolism. It was suggested that XFZY decoction could alleviate oxidative stress in cardiomyocytes by promoting glutathione metabolism, maintain endothelial function by upregulating arginine metabolism, and increase the production of aerobic oxidative substrates in cardiomyocytes by promoting β-alanine metabolism.

In our study, we further investigated the mechanism of XFZY decoction for regulating Qi and promoting blood circulation from the perspective of biological functions of low-molecular-weight metabolites. Some studies have shown that XFZY decoction alleviated cardiomyocyte apoptosis and oxidative stress ([@B14]) as well as the inhibition of platelet aggregation ([@B11]). For the first time, we found that 2-DG was decreased whereas spermine was increased in the serum of CHD patients after treatment with XFZY decoction. Through exploration of the effects of those two differential metabolites on ischemic myocardium, we confirmed the potential mechanism of XFZY decoction in CHD treatment: the decrease of 2-DG alleviated apoptosis and autophagy and promoted glycolysis to generate ATP after treatment with XFZY decoction, and the increase in spermine alleviated apoptosis and oxidative stress and inhibited platelet aggregation in the XFZY decoction group, which explained the similar functions of XFZY decoction in previous animal experiments. The elevation of spermine also illustrated the increase of arginine metabolism, which might generate more NO to alleviate coronary atherosclerosis. In addition, the decrease in 2-DG promoted ATP synthesis. Because NO and ATP are regarded as a part of the involvement of Qi in TCM theory ([@B5]; [@B3]), it is suggested that the metabolites of Qi might be associated with 2-DG and spermine.

Limitation {#s4_4}
----------

Although we believe that our study investigated the effects of XFZY decoction on metabolic profiles in CHD patients and the results could partly explain the mechanism of XFZY decoction for regulating Qi and promoting blood circulation, some limitations should still be considered. One limitation is that the sample size in this study is small. Another limitation is that the follow-up time is not long enough, so we did not focus on the study of the primary or second end points. Because there was statistical difference between the placebo group and the XFZY decoction group before treatment, we excluded the metabolites that have similar trends in our analysis. In addition, metabolomics itself has some limitations. Because of the wide concentration range and chemical diversity of metabolites, there is no instrument to detect all metabolites in a single analysis. In this study on metabolomics of CHD, we detected the metabolites in the serum. However, the metabolites in the circulatory system may originate from nonmyocardial tissues. The use of metabolic drugs and the excretion function of the liver and kidney may also affect the level of metabolites. Those two reasons increased the uncertainty of applying metabolomics to clinical detection of CHD ([@B6]). Moreover, some energy metabolites, such as ATP, adenosine diphosphate (ADP), and phosphocreatine were not detected in this study. Considering the limitation of nontargeted metabolomics, we should optimize the methods, such as choosing targeted metabolomics in the future.

Conclusion {#s5}
==========

In conclusion, we found that XFZY decoction caused the changes in six metabolites in FA, glucose, and amino acid metabolism with the detection of the serum in CHD patients by nontargeted LC-MS/MS analysis. We further predicted seven metabolic pathways according to those differential metabolites. Among them, 2-DG and spermine might partially be the material foundation of Qi in TCM theory, which suggests potential targets of XFZY decoction for regulating Qi and promoting blood circulation in CHD treatment.

Data Availability {#s6}
=================

The datasets generated for this study are available on request to the corresponding author.

Ethics Statement {#s7}
================

The studies involving human participants were reviewed and approved by the Ethics Review Committee of Chinese PLA General Hospital (No. S2015-048-01). The patients/participants provided their written informed consent to participate in this study.

Author Contributions {#s8}
====================

XL conceived, designed, and supervised the clinical trial and experiments and contributed to manuscript revision. TT performed the trials and statistical analysis and drafted the manuscript. TH coperformed the trials. XW coperformed the statistical analysis. All authors read and approved the submitted version.

Funding {#s9}
=======

This work was supported by the National Basic Research Program of China (XL: No. 2015CB554402 and 2015CB554405) and the National Natural Science Foundation of China (XL: No. 31771287).

Conflict of Interest Statement {#s10}
==============================

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary Material {#s11}
======================

The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fphar.2019.00985/full#supplementary-material>

######

Click here for additional data file.

[^1]: Edited by: Jianxun Liu, China Academy of Chinese Medical Sciences, China

[^2]: Reviewed by: Dazhuo Shi, China Academy of Chinese Medical Sciences, China; Jinggang Xia, Capital Medical University, China

[^3]: This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology


Antique Folding Butter Mould

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$500.00

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Probably a love token for an industrious housewife is this elaborately carved folding butter mould. Worked in with the rich swirling floral motifs is the letter "G," undoubtedly the lady's initial Would form a good kilo of butter into an elegant block. Scandinavian, 19th Century, approximately 19-3/4 inches long by 4-1/2 inches high.


The conventional balloon-occluded retrograde transvenous obliteration procedure: indications, contraindications, and technical applications.
Transvenous obliteration of gastric varices can be performed from the systemic venous side (draining veins or shunts) or from the portal venous side (portal afferent feeders). Balloon-occluded transvenous obliteration from the systemic veins is referred to as balloon-occluded retrograde transvenous obliteration (BRTO) and balloon-occluded transvenous obliteration from the portal veins is referred to as balloon-occluded antegrade (anterograde) transvenous obliteration (BATO). BRTO is the conventional balloon-occluded transvenous obliteration procedure and BATO is considered an alternative or adjunctive approach. This is because, from a technical standpoint, the least invasive choice of access or approach for balloon-occluded transvenous obliteration of gastric varices is the traditional or conventional transrenal route. The objective of BRTO or BATO or both is complete obliteration of the gastric varices with preservation of the anatomical hepatopetal flow of the splenoportal circulation. This article reviews the indications, contraindications, and technical considerations of the conventional BRTO procedure. The indications of concomitant portal venous modulators such as splenic embolization or the creation of a transjugular intrahepatic portosystemic shunt or both are also discussed.


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Alex Tomko pitches 3rd complete game in shutout of Rocky River Pirates

By SCOTT SOMMERSsports@MorningJournal.com

AVON — Avon junior Alex Tomko certainly has developed a knack of finishing what he starts.

Using precise location on his pitches, the right-hander scattered six hits and threw his third complete game of the season in blanking visiting Rocky River 5-0 in West Shore Conference play Wednesday at All Pro Freight Stadium.

“I just keep working on hitting my spots,” Tomko said. “(It’s) the same stuff I have been doing all year. I try to get it over the plate and let my defense make the plays. They did well.”

While Tomko isn’t the fastest pitcher in terms of velocity, his ability to locate his pitches frustrated Pirates (2-4, 1-2) batters early and often. When Tomko did get into trouble in the third inning with two outs; he was able to force a fielder’s choice to end the threat.

Tomko’s counterpart Mitch Williams equaled Tomko’s effort. Though Avon (4-7, 2-1) was able to squeeze in a run in the first inning on Kevin Maloney’s RBI single, Williams kept them in check until the fifth inning.

With two outs and Bradford Dill on second, Andrew Lee was able to beat out a slow grounder to short. While Lee did his job, Dill raced around third, never stopping to score an insurance run.

Rocky River appeared to have figured out Tomko in the sixth inning, putting runners at first and third with no outs.

Tomko proved to be a magician, starting a 1-6-3 double play and keeping the runner at third. He got out of the inning with a ground-out to first.

“That was huge,” Tomko said. “First and third with no one out, you expect at least they will get one of them in. That double play — he (runner on third) didn’t go home, so that was huge. I was able to get the next guy, so no one ended up scoring that inning.”

The defensive effort ended up giving a spark to the offense.

In the bottom half of the inning, the Eagles put the ball in play and forced Rocky River to make plays. It ended up working to Avon’s advantage with the Pirates allowing a pair of runs to score on miscues. Jonny Morales had an RBI on a fielder’s choice to score Austin Bevins.

Ian Long, who started at second base for the first time this season and played well defensively, scored on an errant throw. Morales scored on a second throwing error by the Pirates.

Seeing his team put the ball in play pleased Avon coach Frank DeSmit.

“We tried to work on the fact we have been terrible this year in getting two-out RBIs,” DeSmit said. “We’ve taken a lot of called third strikes. We needed to work on situational hitting. That was the focus in practice.

“I asked them that every guy have a plan stepping into the box and executing it. For the most part, they did a good job.”

With the additional run support, Tomko (3-0) closed out the complete game effort with his fifth strikeout of the game.

“We were taking a few too many pitches early,” Rocky River coach Darryl Sanders said. “We started swinging late. Now we are hitting it to people, then we get a hit with two outs. When you get runners in scoring position with two outs; it’s tough to get that next hit.”

Avon travels to Bay on Thursday, while Rocky River hosts North Ridgeville.


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/*!
//! [scxml state machines]

    \section1 Using SCXML State Machines

    To use QML together with an SCXML state machine, add states and
    bind them to the state machine in the \uicontrol Backends tab
    of the \uicontrol Connections view, as
    described in \l {Managing C++ Backend Objects}.

    In the \uicontrol States view, you can select \uicontrol Actions >
    \uicontrol {Set when Condition} to edit the \c when condition of states
    to map QML states to the states of the SCXML state machine. For an example,
    see \l {Qt SCXML Traffic Light QML Example (Dynamic)}.

    \image qmldesigner-states-when-condition.png

    If you add animation to the states, you can \l{Previewing}{preview}
    or \l{Running on Multiple Platforms}{run} the application to test
    the animation.

//! [scxml state machines]
*/