#( ooc. ) AMELIORATION.

[tonydaddingham]

how in the world do you do it? i sent that ask yesterday and i'm still making my way through your masterpost kind of reeling- almost every moment i paused the show (s2 especially) and thought, that's weird, but couldn't put my finger on why, you've talked about, and expanded on, and it's all so well put. you're slowly curing the countless little ⁉️⁉️⁉️⁉️⁉️ bouncing around in my head. it's so satisfying, too, to see all those asks with LWA disagreeing with popular fanon. i'd been thinking it was only me.

i'm curious about your interpretation of the bullet catch, specifically aziraphale's motives. i scrolled through a few of your tags and didn't find much about it, but i might have missed something.

i've seen people say it was retaliation for the holy water request (ooc?), or some deliberate test of crowley's willingness to go through with it (and so go through with their relationship, in spite of the danger, or something). then, of course, there's the generally accepted afaik "elaborate trust fall, general aziraphalean ridiculousness" version, but convincing somebody to nearly shoot you seems like a lot (understatement), even then.

it comes across to me as a bit cruel, if that makes sense. this isn't reliant on crowley not wanting to shoot him, or just doing well under pressure. if he's never even shot a gun before, this is almost entirely luck, and i don't buy that the only thing at stake is paperwork, however much they repeat it to themselves. crowley's hands wouldn't have been shaking so badly. if he messes up, he's gonna hurt aziraphale, or have to watch his human body die. it's so fucked.

maybe it could be said that, without their miracles working, they knew they were being watched, and had to continue, but i don't buy that either. aziraphale didn't act like he felt threatened afterwards until furfur showed up- was doing the complete opposite.

that's all i've got for now, but yeah. this blog is awesome and i'm so here for your sideburn theories. have a nice day pls

oh anon✨ you're so sweet!!! i really dk about all that, i just like chatting shit and trying to spot patterns/contradictory stuff/things that don't make sense beyond the script (if that makes sense), so whilst you all might not get Smart out of me you will at least get Passionate🤌

(also YES for LWA appreciation, they deserve it 💕 - still dont know why they do it but im just happy to be involved)

ooooh okay bullet catch. couple of thoughts from me:

aziraphale was happy to go on stage and try to ameliorate the situation between crowley and mrs h (my beloved), but reticent to scope out any Showy-Offy tricks from goldstones shop

crowley hyped aziraphale up enough to go into the shop and find a new trick to perform; hes the angel who fooled nefertiti and is performing on the West End Stage, after all!!!

aziraphale is taken in by the bullet catch trick upon seeing it, but was previously happy to consider another trick. he also, presumably, wasnt aware of the element of trusting a stooge until it was told to him

aziraphale persuades crowley to perform it, even when crowley is obviously uncomfortable, and crowley isn't truthful with him re: firearms experience

crowley agreed, providing that they make use of their miracles if it goes tits up

aziraphale doesnt inform crowley on any of the plan; crowley is notably caught unawares when called out in the audience

miracles don't work, neither of them stop the performance. crowley once again still very uncomfortable, literally shaking on stage, and yet seems to calm at aziraphale ploughing on ahead.

so okay, yeah, ive basically just recited the scene - but a few conclusions:

aziraphale doesn't want to let crowley down or embarrass him by backing out of the act, or indeed by messing it up

i think there's probably some element of aziraphale doing it for himself (self-esteem), but in a way that, post-Realisation, he is showing off a bit... it strikes me that crowley wasn't fully cognizant of this little hobby of his, and aziraphale is taking a moment to do something that (bless him, he thinks) he's good at, and wow crowley as a result

i don't think the holy water request came into his motivations at all, for the same reasons you said. however, it is an appropriate mirror to the holy water request narratively; i think it will come back up in s3, and i think the bullet catch will at least emotionally inform aziraphale on whether to give crowley the water or not

as for crowley's motivations in going along with it; i think to some extent he's paying back the favour, but mainly that it's truly just to make aziraphale happy. a step beyond that; to him, aziraphale is in need of something, and that is something aziraphale is only trusting crowley to deliver. crowley of course assumes miracles will be their safety net, so agrees to be aziraphale's knight in shining armour (*cough* playing hero)

when the miracles fail, aziraphale still has trust in crowley to do it properly. crowley however is left to trust in aziraphale's trust in kind. he still wants to do this for him, but the stakes are a bit higher in that he could shoot his best friend (?) in the face and not see him again on earth for any number of years (imo, it's never, ever been about the paperwork). but aziraphale isn't backing down; is crowley about to disappoint him? of course not.

tl;dr: they're both arseholes for their respective lacks of transparency with each other, deliberately put themselves in harm's way, and it was by sheer luck that they pulled it off. but it is a huge seismic shift in how they see each other, and i don't think we've been shown/suggested the full implications of the whole thing just yet.

thank you so much for your kind words, they honestly make my day!!! hope you have a lovely day too!!!✨💕

[somehowmags]

NAND THANK YOU 😭😭😭😭 VIL, IN FACT, WOULDN'T FORCE THE BODILY STANDARDS HE HOLDS HIMSELF TO ONTO YOU!!!! i once saw someone write a fic entailing epel's development of an ED as a result of vil and it genuinely did make me sad. epel and vil's bond is so beautiful. epel, despite his lower rank and duties to vil as his protégé, still has that strong spirit. he probably would just have another outburst at vil, attempt to challenge him, and/or run away. not to mention, vil genuinely cares about epel and loves him. he learns to embrace epel literally and figuratively, especially in chapter 6. sure vil would maintain a diet for epel and is extremely adamant on it, but vil isn't stupid. he wouldn't deprive epel of his right to eat sufficiently, or hold him to the strict diet vil maintains. vil would personally curate a diet suited to epel's needs and tastes. vil's watchful eye would probably sense if epel was struggling with his diet and would ameliorate that by either making changes to it, or talking to epel himself. rook is also there to gently chide vil if he ever did come to this (NO HE WOULD NEVER...) it's just. rggrgrhrghr. vil just wants you to make the best of yourself. follow basic hygiene. plus size? doesn't matter to him, as long as your body serves you healthily. skin full of scars? if you want a serum that helps clear marks, he'd readily provide you some. if you don't want it, atleast hydrate and keep your skin clean. crooked teeth? just remember to brush and flush regularly; if it impedes your health or self image, braces would help. point is, he wouldn't care in "fixing" these bodily "flaws" or other traits that do not personally align with what he holds himself to, but rather a general state of wellness and the effort in taking care of yourself so you are both satisfied with yourself and make the progress you are capable of. sure, he'd recommend it, but if you don't want to, he likely wouldn't bother to press you. because he just. wouldn't!!! do that to you!!!!!! if it's not in your interest to change that part of YOU, its not in HIS!!! and if you have any sort of mental illness that impedes your ability to take care of your hygiene, he would NEVER think of you as lazy! he'd very likely want to help you out of your rut! he does not like people who have every right and ability to make a change, but do not. or people who intentionally wallow in their own shortcomings. he does not have anything against people who are struggling mentally and emotionally! you are facing obstacles out of your control and as long as you make the effort to overcome them, even if it's the smallest step, even if you stumble and fail, even if you need time first, that's all he needs. that you try. if you do, he will, and he won't give up and as long as you won't. he's so pookie bear i want to roll him up like sushi and sell him on the conveyor belt for 2 dollars and 90 cents

YEAH i think people are like. a little too quick to make characters ooc for angst. like longtime followers of somehowmags dot tumblr dot edu will know that i am a frequent complainer about people making characters ooc for cheap angst but damn ive seen Some Shit. not as much in the twst fandom as in other fandoms that will be immediately apparent if you scroll down my blog for two seconds but there have been some abysmal takes from twsties as well.

i think people who have this take are misinterpreting vil putting nrc tribe on a diet for vdc (im NEVER calling it sdc my deepest apolocheese to the eng localization) which...i'm going to be honest with yall. granted i am not a dietician i read that in the same way that people do diets when theyre participating in athletic competitions. if you were training to run a marathon, you would probably try changing your diet a little to help you build up your strength, which is the same thing vil is doing. i think its intended to be more of a strength building diet, not a weight loss one. and again as a fat person and as someone who has been put on diets i get the kneejerk reaction of disliking diets, but i don't think that's whats happening here

ultimately i get why people think about vil but by god i do not have to like it alkdsjdfhlaksdfh

[calryuhil]

Greetings, Mutuals! Cahil Ilcidane : In Character.

This post has a lot of notes and important stuff & information. I am hoping that each of you will read plus understand this disclaimer.

chapter one. Cahil Ilcidane an epiphany evanescent visualizzazioni inking on screen. IN CHARACTER : My knowledge will always bleed as my words embodied. My heart meet the ink, not pink but like the blood vampire’s drink. Cast an eye over my unveiled updates , some of it will turn into amazement. Paraphrasers and copycats are not welcome, go ink your own pen.

신류진 🪽 The door in my heart & mind are wide ajar unlatched for amelioration. Do not hesitate to at least leave a private message on this account if I have ever do something that discomfort you, I will fully take the culpability and ramification. As I am writing my point of view, I also want to elucidate my forethought on this account. First of all, the muse which is RYUJIN from ITZY // follow or check their instagram (@itzy.all.in.us) mentioning the face claim I utilize, I ought to clarify such as I do not have any bad scheme en route towards ravaging the persona of the mentioned artist.

카힐. Nourishing the whiteness purity of my timeline is particularly the stuff you need to know and be enlightened au corant of. This account will embrace and accommodate In Character updates. Thereupon, I have in prospect that my mutuals will be synergic and active as well. Leaving a stickers, emojis and in character remarks on my updates will be highly appreciated and loved by the operator. Additionally, I am strict when it comes to confirming friend request from an individual. Moreover, to be accepted you need to at least avoid these :

Roleplayers utilizing and normalizing fonts on their timeline.

20 below mutuals.

Closed, Inactive individuals.

OOC related.

This note is now closed. Thank you!

[spiritwinding]

ameliore replied to your post: SO bear with me for a sec one of the biggest...

//I feel this lowkey because Sonic Canon is honestly a MessTM. But it also gives me the ability to To What I WantTM. Double edged sword unfortunately u_u

YEA i feel that but mostly with characterization? i like that the backstory of everyone is loose and so are their characterizations in a way but thats bc i enjoy character building + backstory a lot more than lore? sonic has No backstory and thats fun to play around with and come up with but in terms of worldbuilding i just dont have braincells dcfvgbhn 

[rude-at-your-service]

Knowing all that he knows now, would Rude still chose to become a Turk? Or would he chose to live a 'normal' life?

//ooc: Ah! Asking the good questions.

It depends on where in the timeline that question is brought up. But since you said now and my default verse for playing Rude takes place after AC and DoC, I'm going to go with that.

Now, being older and more experienced, knowing all that he knows now, would Rude have chosen to join the Turks? The first and simplest answer is YES. Despite all the struggles, the pain, the blood, the traumas, the losses, Rude believes he would do it all over again (and if possibly do it all over again a bit better and flashier). The job did come with great benefits that ameliorated his life. It came with a generous paycheck that not only increased his life quality and safety but helped to pay bills and education for his family back home as well. The job gave him a purpose, a place where his skills was both appreciated and encouraged. For the first time he felt listened and needed, like what he did made some difference. The dangers and risks that came with the job was stimulating for him.And something else came with the job further down, something that Rude hadn't known he wanted or needed. Friends. A new family.

But looking at the bigger picture, looking down at a possible road that he could have taken, the answer might have been a NO. Despite all the appealing benefits becoming a Turk brought, it also put up big roadblocks. Looking back Rude can't ever be certain how his life would have looked like if he hadn't joined the Turks. But there's a hope -a dangerous thing- that he could've had a "normal" life if he hadn't.Dreams of a normal life with a forty hour work week, a wife who loves him, children, family gatherings, maybe a cat, and everything else that comes with a common civilian life.Perhaps it would be dull and stressful at times, but it would be his dull and sometimes stressful life. There would certainly be less critical life-or-death-stress. And if he was lucky he wouldn't be alone, but surrounded by the love from his friends and family.

The older Rude gets, the more appealing a normal life are to him.

However... He is a Turk, and he's not going to leave them.

Once a Turk, always a Turk.

[koalas-koalas-everywhere]

The question of Peter’s choices in Civil War...

Everyone and their mother will agree that Peter’s choice to unmask publicly was out of character. Anyone with any understanding of the character (and the concept of vigilantes and heroes, I mean, really, assault is written into the genre’s very core) will also agree that while he tries to respect the law as much as he can, he will break it and allow it to be broken when it comes into conflict with what’s right. 

Here’s the thing, though. There were ameliorating circumstances, of which being out of character was only a small part, which made his actions more understandable: one was his faith in Tony and the other was the fact that he didn’t have a choice.

Before Peter unmasks, heck, before Civil War even starts, Tony gives him the Iron Spider Suit (IRS) and, when Peter questions him for ulterior motives, admits that he wants his help with something big that’s coming, but he won’t tell him what until he swears that he’ll support him and back him up no matter what, and that he won’t tell anyone else what’s goin on. Peter goes so far as to call it a blood oath, and Tony agrees. In return, Tony would make him his second, his protegé, someone allowed to be at his side as the events unfold and learn, see and hear everything he himself sees and hears.* Peter, thinking he’s doing nothing more than agreeing to help a friend, gives him his oath. (ASM #529) They go to Washington, where Tony had been summoned to testify before the Senate Metahuman Investigation Committee. 

On the plane over, Tony tells Peter what they’ll be discussing: the SHRA, and they both agree that it would be a bad thing and that they’ll have to convince the Committee not to go forward with it. Once there, they argue against it before the court and Tony even hires a super-powered mercenary to fake an assassination attempt which Peter (who didn’t know it was fake, and to whom Tony didn’t reveal it was fake even when he asked) would prevent, in hopes that Spider-Man’s intervention and the mercenary’s speech about how the government’s intolerance of super-heroes would lead to their erradication and the country’s vulnerability (all of this conviniently recorded by the IRS) would tide the Committee’s opinion over to their side. (ASM #531)

I repeat: Tony had been shown to be against the Act.

It would not be such a stretch to think that, when he backed up the Government when it decided to go through with it after Stamford, it was so he’d be better able to do damage control. He (and Reed and Pym) put themselves in charge of how the Act would be carried out, and parts of it were reasonable and downright smart. I mean, yeah, train people so they won’t do harm disproportionate to the good they set out to do. (This is not to say that I agree with the Act in it entirety, of course.)

Another thing Tony had been shown to be was savvy when it came to politics and a capable person in general, so between all this and his promise to always back him up, Peter could have stayed on his side on the hope that he would fix it, either improve the pubilc’s opinion of heroes so everything would be back to normal or work out the worst parts of the Act so that everyone could be happy with it. What we have to accept is that, while the relationship was horribly built, they were friends and, according to JMS, had a sort of father/son relationship (so can we be really surprised when it went to shit?).  It’s not so much that he agrees with everything the Act proposes, but that he trusts his friends and, particularly, Tony, to look after their interests. 

So, we’ve got a reason for why he’d make the decision to be on Tony’s side, and we’re going by this chronologically, so we’re on the ride over to the airport so Peter can fly to New York, so he doesn’t know a lot of stuff, yet. But, we’ve still got to go over how they could justify Peter unmasking on TV.

When Tony asks him to do this, Peter refuses. Tony makes it clear that if he doesn’t, he’ll be a criminal, and he leaves him to think it over on the flight to NY. During it, Peter calls his bank to ask the amount of money he has saved and if he can withdraw it. Once home, he talks it over with Mary Jane and Aunt May, saying that if he unmasks, they get to choose and the decision has to be unanimous.

During the course of this conversation, we see that Peter and MJ reach the conclusion that he's damned if he does, damned if he doesn’t, because his secret identity is compromised already (they only talk about whether Tony can be trusted not to tell on him, but SHIELD knew who he was, too - heck, it was practically common knowledge fuck you Bendis) and Peter seems to make the decision to go on the run, on his own, because taking Aunt May and Mary Jane with him could lead to their arrest. 

Then... Aunt May tells him to unmask (which, okay, might not be too weird for someone whose only experiance with being attacked because people knew who Peter is was when she got kidnapped and promptly drugged until she was saved, so she might not have been able to process the danger beyond the intellectual) and... Mary Jane agrees (which is shit) and still Peter wanted to go on the run, until Aunt May corners him and implies not only that Uncle Ben would have wanted him to unmask, but that it would be the responsible thing to do because she ties it to accountability. 

Now, I can’t actually argue that unmasking, even under all this pressure, was in character. I just can’t. The best thing I can do with all these little facts is No Prize it.

First of all, I’ll talk about a thought I had while writing this. Like I said, there would have been little point in Peter unmasking, even just to the Governemt, because SHIELD and others already knew his id. In fact, he had already made a comment about how he didn’t trust their capability or willingness to prevent leaks, so, in his mind, for all intents and purposes, his secret identity was already shot. So, that being a non-issue, why was he still about to leave? I mean, besides an impulse that by this point was more instictual and visceral than logical to protect his id (which would have been more than fair). I think, when he and MJ started talking about what might be asked of him if he stayed and registered, he realized that he wasn’t willing to compromise that much, but maybe he didn’t want to face the fact that he’d break his promise to Tony that easily, so he stuck with the “I don’t want to unmask” excuse. Truth be told, I think that, at least at first, if he had actually left, he’d have gone Ben’s route and gone to Canada to stay out of it, instead of joining Cap’s team from the start - especially since he’d be leaving his family in the tender mercies of whoever got their hands on his secret id and wanted to make something of it, he might want to be on his best (possible) behaviour.

But why did he stay, then? The clinch was clearly when Aunt May talked to him the morning he was about to slip away, which amounted to “own up to what you’ve, done it’s the responsible thing to do and what your Uncle would have wanted”. So that might have combined with his guilt over breaking his promise to Tony when it was possible that he’d be fighting to make the Act better for supers and in a moment of hysteria he might have gone “you know what? It’s already going to go public. The Government will find out and sooner than later there will be a leak and everyone else will find out too, might as well cooperate and skip the middle man so I can keep some kind of control over it.” Unmasking publicly would also be a show of support to Tony, who did the same thing (at this point, people didn’t know he was Iron Man, although it was heavily suspected, since he’d unmasked before).

So, to summarize: Peter was the proverbial frog boiling over low fire. He started with a promise of support ot a friend, who then asked him for his help in convincing the Government to at least postpone the Act. When the SHRA came to fruition, he might have had the idea that Tony would still be fighting against it, but in a position that might allow him to do it from within, so he might have seen the sides as the one which was willing to compromise and negotiate and the one which refused to give quarter even when some of it made sense, instead of outright pro vs against. It has to be noted, too, that Tony didn’t ask him whether he wanted to be part of the strike team who went after the heroes who didn’t register, and that he fonud out about that with everyone else, through a TV press conference when he had already given up his secret identity.

As for his unmasking, he had plenty of reason to believe that everyone he’d be required to tell his identity to would find out anyway from SHIELD and/or Tony (or any of the inmates who recognized him from the time he was unmasked in Ryker’s, I mean, Bendis was polite enough to include and name The Foolkiller specifically, who had been a student and friend of Peter’s, see his face god Bendis fall off a cliff), and didn’t think they’d be able/willing to keep the secret, so he might have decided to skip the middle man and unmask himself so at least he’d get points for cooperating and to have some control over the narrative. He was also sorta kinda guilt tripped into it by Aunt May. Still something you’d have to suspend your disbelief for, but all in all, that and a little bit of freaking out-induced irrationality might do the trick enough that we can justify it and accept it without going into the territory of “it was in character”.

Now, I’ve also heard people say that going on the run was out of character. That, at the very least, he shouldn’t have taken Mary Jane and Aunt May with him.

I’ll start with the scenario of him going on the run with his family because it’s the easier one. Yes, it was dumb, and you can tell it was ooc because he didn’t want to do it in the first place. He took them out of the tower because he didn’t trust Tony with them (am I the only one who thought “As long as they’re with me, they’re safe.” (ASM #535) as “as long as you behave, they’re safe”? At the very least, it’s what a scared and disillusioned Peter might have thought), but after that he wanted them to take their money and go away, probably even leave the country. Then May (goddamit May!) convinced him to “let” them stay with him. I mean, it’s not like he could actually make them do anything, it’s not as easy as “Peter should have sent them away”. It’s still out of character, but also understandable. We learn later that Peter didn't want to stay with the outlaw heroes so he wouldn't bring trouble to them (it wouldn’t be a stretch to think that Tony might have some way to trace him even without the suit), so if they left, he’d be looking at the life he described to Mary Jane (”on the run [...], going from one dive to another, using different names... The stress will be enormous” ASM #536)... on his own. Certainly not the most attractive prospect. So May’s message of hope would be attractive to him, and he could justify it by saying that at least this way he can keep an eye on them and actively protect them.** 

I’ve also heard it said that he should have stayed with Tony but report back to the other team, to which I have to say... you complain that Peter was out of character for unmasking and then you suggest this? He’s not the cloak and dagger kind. Not only is it not his style, I don’t think he’s cut out for it. I mean, can you imagine Peter as Black Widow 2.0? Would it have been smart? Yes. Would it have been in character? Hell, no. And while I think he’s a better liar than most people are willing to give him credit for, he’d be caught 5 minutes in. People were already thinking he looked suspicious during Bill Foster’s funeral, and everything (except my reding list, ig) points out to that being before the failed transfer attempt in ASM #534, where he was still so committed that he rejected Cap’s offer (and request) to switch sides and fought him. By escaping, at least he put some distance between his family and the repercussions of being a double-agent.

Also to consider is that, the moment he starts thinking of jumping ship, Tony tells him that he wants him in LA the next day, so he’d lose all of his usefulness as a spy. Even if he had managed to stay in NY and close to Tony, it was clear that he wasn’t trusted anymore. It was just not an option. Quite like it wouldn’t have been an option to just contact Cap’s team and offer to report to them because they wouldn’t have trusted them. We know this because they didn’t immediately trust him when Frank took him all beaten up to their hide out and at least Sam still didn’t trust him after he made his speech exposing the pro side’s ruthless and immoral measures (although then he was shown to be appreciative of him in the CW mag, so idk).

So, he was on Tony’s side not so much because he agreed with the Act but because he trusted Tony to try to make the best of it and maybe even change it, he unmasked because the important people already knew who he was and he didn’t trust him to keep the secret, so that combined with his promise to support Tony, Aunt May’s sorta guilt trip and a bit of being out of character that we’ll call “being under a lot of stress for a long time now ang going through a bit of hysteria at just the wrong time” led to that decision. Getting Mary Jane and Aunt May out of the Avengers Tower was alright because he had already seen the measures Tony would go to to ensure a win and doesn’t trust him, but letting them come along with him while he fought the SHRA instead of insisting that they leave was out of character and dumb to boot. While staying on Tony’s team to spy on them would have been smart, it would have been ooc, too, and not an option since by the time he decided to change sides not even Tony trusted him.

*I didn’t mean for that to be so close to an actual quote, but I checked the issue and that’s almost exactly what he says, so go me and my subconcious memory, I guess.

** Now, why would he be willing to endanger his family and not the other heores... yeah, out of character. But also... well, I guess this is my own personal view of the character and the narrative it fits in, but Peter Parker needs family, friends and good things in his life to function. I mean, all humans do, but Peter needs them for the sake of his story, the counterpoint light to the darkness. He can be exposed to all the evil of the world and fight it, but he needs its goodness, too. The tragedy/hope (and even death/birth) dichotomy is at the core of the character: Uncle Ben dies/Spider-Man the hero is born, Gwen Stacy dies/his relationship with Mary Jane starts off, everything goes to shit right before the second Clone Saga/Mary Jane gets pregnant, May dies/she reveals she knew Peter was Spider-Man and is proud of him. The last one is especially important because Norman intended that revelation to drive Peter to despair, but it actually gives him hope. It’s about being open to hope in the worst of times. It’s part of the reason why I hate the “Peter is a loser with a fucked up life whose punchline is that he can never be happy” ideology (besides it being categorically untrue...)

[moonstruck-ffxiv-blog]

(That pic has nothing to do with anything, it’s me that tried to make my irl cat as a miqo’te)

Moonstruck: I Like RP Partners to Know

I like to be called: Mael

My favorite colors are: I’m very fond of pastels, especially pink.

Gender: I’m confused about that.

One thing you should know about me (or several): I started RPing at 12-13 years old on those BBC-type of forums. At first, I was on other’s people, then I created my own. My high school friends, to this day, still remember my primary character I had for years: Chaos, a chthonic devil-god with two dicks and two vaginas, that fucked himself, to create the demonic race. In those years, I was OBSESSED with the idea of evil and was trying to find a solution or explanation to it. It was through my writing I considered what it was - mostly with that OC, which was the most repulsive character I could ever create. A funloving, whimsy, joker-type outside, but a beast of every sin inside. There was no filter when I was RPing him. He was cartoonishly evil, which was the point. I think.

Thank Sobek King of the Nile I outgrew my edgelord teenage years lmao.

I work a lot of myself, ameliorate skills, learning,... I don’t have much time for hobbies anymore. Because of that RP, as much as I like it, is taking a backseat and I have to pick my partners pretty carefully.

I don’t like public RP events, they are all organized the same way, I find lazy and boring. If I had to choose between a public event or the Quicksand, I will pick the latter. In both cases I will stand around touching my dick for 3 hours but at least at the Titsand can hook up with someone and write ERP. That alone makes it not a complete waste of my time.

I play piano and try to get back into dawing. I practice every day and I’m starting to see the result which makes me pretty happy.

My favorite food is Frank’s Red Hot Chicken Wings Sauce.

I’m currently working on a book and trying to be a professional writer. Wish me luck!

PS: If you make me tea I will be your friend forever.

One thing you should know about my muse(s)(Or several): I do have 15 OCs on FFXIV and I don’t feel going through the whole list. I’m lazy, please forgiving me. I’ll probably go through my “Big Fives” as I call them in my inner monologue.

Louis: Louis is an extension of my alienation and loneliness. How he feels about being different and not belonging to anywhere is how I feel myself lot of the time. I have troubling connecting and understand people and so does he.

He’s a Nightkin and even if I initially present him as being “awkward and cute” don’t be mistaken. He is a killer and he is dangerous. He will exploit a weakness when he sees one. Yes, he will feel remorse about it but that won’t stop him for doing it.

Celestin: Hey do you know what happens when you shove one of those rockets you buy from the convenient store and you shove it into my ass? That character happens. His my own pride, exaggerated to the 9th degree;  he’s my salt and my anger. He’s the asshole I become when I get hurt.

Celestin is a very proud man (one could say he has some kind of god complex - which is not completely false) willing to go to unimaginable heights for his goals. He’s Machiavellian: the ends justify the means. It’s all a matter if the sacrifices he does is worth it…

Ezrien: He started as a joke character which I assume. He still got a LOT to do but bit by bit, I’m building him. I would really want to explore more his drug and alcohol addiction, to get GRITTY instead of always be joking with him. Still waiting for the good person to unpack this box of worms.

I really enjoy Ez, and I enjoy him more since I made him and Rochel cousin. They are excellent foils to each other and bring me a lot of joy.

Narcisse: My sad elf prince (tm) and my attempt to try to make a “Lawful Good” type of character. He’s a knight, living to serve other people and get rid of evil on this world. He has a very black/white worldview (which is his weakness) and he’s… well, he’s kinda of intolerant sometimes.

I still have to figure him a lot but I really love his aesthetic. I feel he’s missing, I don’t know what, and that spark of oompf is what holding me back to really enjoy him.

Ephraim: My baby. Oh, do I love Eph hahahaha. When I created him I was “okay dude, stop doing fucking egdelords all the time. No dark, break the mold.” And I succeeded! He’s the softest, gentlest necromancer I ever made -and at the same time, breaking the trope of the ever-so-dark necromancer.- I really like how I can switch my gear with him, he’s an extremely versatile character. Yeah, his backstory is sad and I can still make dark stuff with him but I can do comedy and absurd plots. Which I absolutely adore. When I RP with Cecilia and Ruruka, things get so dumb so fast. I love it.

First language: French. I’m foreign and I tend to use sentences that work in French but doesn’t in English. I do think the way I structure my writing work in my main language but sometimes is lost in translation. When I’m tired I tend to revert back more often to French which can be hilarious… or horrible.

RP blogs/Main Blog I only have this blog so uh that’s it folk

Age range:  under 13  |  14–17 | 18–22 | 23–25 | 26–29 | 30+ |  70+

Am I okay with NSFW?: yes | no | some nsfw  

I’m not particularly “shopping” for porn; I do have more sexually inclined characters than others (Ezrien, Narcisse.) I don’t mind ERP neither I mind people that do it (either regularly or casually). However, I do find it pretty pointless most of the time. What I mean by that is, the consequences of characters having sex will be the same whether you describe or not every moan and cum shot. IN ANY CASE, I’ll be honest, I did write a loooooot of smut in the past. While I don’t really do it anymore (I barely RP at all lmao), I’m not 100% closed to the idea to dip my toes back into it. It’s all a matter of what’s my mood today, what kind of char you got and who you are.

My favorite/most common thing to rp is: angst | fluff (maybe)| smut (a very soft maybe)  | crack (I don’t understand what this means in that context sorry) | action | plots | AUs (maybe, depends) | Violence | Darker themes | Yandere (yes, baby, please) | Comedy | Weird | Horror | Enigmas/Mystery

Yeah dude I added some of my own because I find there wasn’t enough

OC friendly?: yes | no | depends

RP blog: does contain ooc posts | doesn’t contain ooc posts | occasionally contains ooc | Aesthetic

tagged by @ssytxiv

tagging @corbelleterrechant @nerd-ology @lovelyflyingfiend @lichface @avwalya @lulu-ffxiv @housefortempsknight @garlean-nonsense @vashzeibel

[tarthserjaime]

I agree this helps frame Jaime's choices in that episode in a slightly more palliative way, and I might agree with most of this except for:

Having Jaime declare he doesn't give a shit about the innocent = automatically OOC, so everything after that felt like it wasn't really Jaime and was therefore invalid

Having his actions and his affect shift 180° within the same episode without the emotional and narrative framework to support it

Leaving Brienne so cruelly, with zero tenderness or assurance of his true feelings for her ("I love you but she's my sister, I helped make her into this person, and I can't let her die alone" or something) -- anything other than what he did which was treat her like she was a mistake and ride off without looking back, so exactly how does she (or the audience for that matter) know he loved her??? They never showed us anything of them together as a couple except for the first few seconds of their initial drunken hookup.

Continuing with that: neither he nor Tyrion thinking Brienne even warranted a mention in their final conversation, as if their last conversation before that hadn't been all about Jaime started a new life with her. (T asking "Why? You were happy in WF? What about Brienne?" or J: "Tell B I love her and I'm sorry" like in that one ameliorative gif set going around) -- anything to show she had mattered and would be profoundly affected by Jaime's likely death

Show runners/actors not reducing Brienne to some blip in the radar mistake that allowed him to realize that Cersei was the only woman he could love. It's just gross and disrespectful, and frames Brienne and JB's six season relationship as nothing more than if she'd been some random northerner who Jaime had hooked up with out of loneliness or boredom, trying to test the waters and fool himself into thinking there was any love or life for him outside of toxic twincest.

I've started to make my peace with the fact that D&D always planned to have their OTP die together, regardless of what it did to Jaime's character arc. Invalidating every good thing he'd done since killing Aerys didn't matter to them as long as they got their final "romantic" (barf) twincest death, but doing it in such a way that made him feel so *not Jaime* that it's almost easier to bear. Brienne just happened to be an inconsequential speedbump along the way, and I think most of my anger is about how disrespectfully they treated her and destroyed her own character arc without hesitation as a means to an end. Jaime and Brienne and JB were all sacrificed for Cersei's "arc" (which lol is a whole other failure) and giving her her own perfect death to fulfill their twincest obsession.

rocks fall everyone dies

I’m primarily still in the meme stage of grieving for my show at this point, but I thought I’d ramble out some Jaime thoughts. (MASSIVE SPOILERS FOR 8x05 and earlier abound below!)

To me, the point of Jaime going back is not that he loves Cersei (although I believe he does) or is obsessed with Cersei, or that he doesn’t love Brienne or even that he doesn’t want to stay with Brienne. The point is that Cersei is about to be destroyed, and by going back to her, he is making the more courageous and more honorable choice. 

That parting conversation with Brienne, he doesn’t say a single thing that’s not true. He aided and abetted Cersei’s crimes all along. He willingly participated with her in the lie that the two of them were the only ones who mattered, and his heroism in saving King’s Landing or in coming north to fight the dead doesn’t erase everything he did. He doesn’t deserve to live out a happy ending in the North while Cersei dies burning in dragonfire for their shared crimes. It would have been wrong and cowardly of him to leave Cersei to face the consequences alone. 

And I don’t think Brienne weeps because he’s abandoning her. If he was abandoning her, running away to be with Cersei because he loved Cersei more all along and just fucked Brienne for good times in the North, he wouldn’t be worth her tears. But she knows he loves her. She never asks him to stay with her for her sake, any more than she asked him to come North for her sake. She tells him he deserves to stay with her. He tells her why he doesn’t. And he’s right, and she knows it. His courage in facing that truth, that’s what makes him worth weeping over for Brienne and for us. 

I know some people thought after 8x4 that he was going back to stop Cersei; personally, I didn’t get the feeling that he was going back to KL planning either to save Cersei or to stop her. He just needed to be with Cersei to face what came with courage. 

And for him to choose to help Cersei in the circumstances of the episode, it wasn’t a rejection of Brienne or his character arc either. It was a completely stupid waste of story precisely because it did nothing with his character arc either one way or another. He never had to make a choice between saving Cersei and stopping her, with innocent lives in the balance. It could have been one life, it could have been all of KL. Instead the writers created a stupid situation where saving Cersei was just an okay human thing for him to do with no other option available. By the time he got to Cersei, KL was literally falling down around their ears. She had lost. She had no power to hurt anyone anymore. Of course he was going to try and save her and the baby. And when they were down in the tunnels and death was coming, of course he would hold her and comfort her as best he could. Him repeating the lie to her in that moment, it didn’t mean anything. 

It should have meant something. If he’d said it to her as they set off the wildfire caches under KL in order to blow up Dany and Drogon and her armies, it would have been the sad and terrible but complete story of a man who rejected the best parts of himself out of an obsessive and narcissistic love he couldn’t let go. If he’d said it to her and then killed her in order to stop her setting off the wildfire, or to ring the bells and surrender, it would have been a story of redemption bought with pain and sacrifice. Instead it’s just a story that ended literally in “rocks fall, everyone dies.” 

In conclusion, 

[not-a-space-alien]

re: the Hungarian poster - while “kriechen” translates as “to crawl”, “Kriecher” has strong connotations of “brownnosing” - in fact, I can’t think of a single context where “Kriecher” refers to something that is literally, as on acount of its anatomy or such, crawling - a “Kriecher” is a sycophant without even having the merit of being named out of some high-brow dead language. (“Double-Hail Satan, I am your most subservient servant!” This is *way* more OOC than Crawly, which doesn’t fit but can rather simply be ameliorated.) Plus, the word has even more fallen out of fashionable use than Tartan. Also, “Erziraphael” is (to me) certainly funny, but in the sense of odd-not-quirky, and it kinda makes my skin crawl - I immediately relegated it to personal squick, which, by its nature is hard to explain, so, um. “Z” in German is pronounced “ts”, so the name becomes ERR-ts-ee-RAH-fah-ale (“ale” as in “beer”, not sure whether there is more of a stress on the “RAH” than the ERR- gutfeeling, ‘cos I’m no linguist, but - disredarding the names of Elder Gods and funny foreign words - German is pretty consistent in regards of how written words are pronounced; not so much the other way around). The “Ts” forces an odd stop after the “ERR” when pronouncing the name, and while the hissiness might be ironic, that somehow feels wrong? Also, “Erz” may translate as “ore” - don’t know if there’s an etymological connection to “arch” or if it is just homonyms, but “ore” is definitely the more common meaning. Sword-related incidents aside, that doesn’ click with me.

Anyhow, I now have develepoded a debilitating fear of seeing Erziraphael/Rampa in the AO3 tags (I am internally debating whether Eziraphael/Kriecher is somehow worse or not). Thank you. *Cranking up the passive-aggressiveness* THANK YOU. I have survived Cage Omens, hit me, you BASTARDS.

– On a more positive (and more earnest) note: Some sort-of interlingual Good Omens some kind of thing?

It looks like you’re safe for now...

But i can see why it’s harder to pronounce the way you’re describing it

[steadfastspirit]

ameliore replied to your post:OOC;; psst now make fun of him for being short

{{ tfw amelia is taller than him by a few inches > v >

OOC;;

ensue heel war

[ampk-progeria-hiv]

New study confirms that Metformin alleviates accelerated aging defects and activates AMPK in Progeria cells: Hypothesis further substantiated

"Hutchinson-Gilford Progeria Syndrome" by The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T; https://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg#/media/File:HIV-budding-Color.jpg--"HIV-budding-Color" by Photo Credit: C. Goldsmith. Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus.

In line with findings published in November of 2016 demonstrating that the anti-diabetic drug metformin alleviated pathological aging defects in cells derived from Hutchinson–Gilford progeria syndrome (HGPS) patients, a recent study published online in the Journal Experimental Dermatology in February of 2017 also provided startling evidence confirming that metformin alleviated nuclear defects and premature aging phenotypes in fibroblasts derived from HGPS patients [1,2]. The authors demonstrated that metformin delayed cellular senescence, decreased the formation of reactive oxygen species (ROS), decreased the expression of progerin (a toxic protein that leads to accelerated cellular aging defects), and significantly increased the number of cells with normal nuclei [1]. Importantly, metformin treatment also led to a significant increase in the phosphorylation and activation of AMPK in HGPS cells [1]. Interestingly, the study published in November of 2016 in the Journal npj Aging and Mechanisms of Disease (part of the Nature Partner Journals series) also showed that metformin decreased the expression of both progerin and the gene splicing factor SRSF1, a protein that has been previously shown to promote the use of a cryptic splice site in the LMNA gene, thus increasing the levels of progerin [2].

Both of these studies collectively provides direct support and further substantiates a hypothesis published in 2014, in which I proposed for the first time that AMPK activators including metformin will improve accelerated aging defects in HGPS cells by decreasing the levels of SRSF1 and activating AMPK, thus reducing progerin production via modulation of alternative splicing [3].

Indeed, several chemically distinct compounds that have recently been shown to improve accelerated cellular aging defects in HGPS, including rapamycin, methylene blue, sulforaphane, all-trans retinoic acid, MG132, oltipraz, and vitamin D have each been shown to activate AMPK, similar to metformin (see below). Metformin has also recently been shown to beneficially alter gene splicing in cells taken from patients with the genetic disorder myotonic dystrophy type I (DMI) in an AMPK-dependent manner. Additionally, metformin beneficially altered gene splicing in diabetic patients who were taking metformin but who did not have DM1 [4]. The confirmation of my 2014 hypothesis via the studies published in npj Aging and Mechanisms of Disease and Experimental Dermatology that metformin activates AMPK, decreases SRSF1, and improves accelerated aging defects in HGPS cells provides a powerful indication that AMPK activation represents an “indirect yet common mechanism of action” linking the therapeutic effects of chemically distinct compounds in HGPS. Furthermore, as explained below, SRSF1 has been shown to prevent the reactivation of latent HIV-1 viral reservoirs and many chemically distinct compounds, including MG132, have been shown to promote reactivation of latent HIV-1 in immune cells (facilitating detection and destruction of the virus), implicating the novel proposition that latent HIV-1 reactivation is critically dependent on AMPK activation, a proposal that I published for the first time in 2015 [5].

Additionally, AMPK activation is critical for oocyte meiotic resumption and maturation (processes that are essential for efficient oocyte activation) and compounds including the calcium (Ca2+) ionophore ionomycin promote latent HIV-1 reactivation (when combined with the phorbol ester PMA) and induce human oocyte activation, giving rise to normal healthy children (see below). Because oocyte activation is a prerequisite for the creation of all human life and because various compounds such as ionomycin that induce oocyte activation also activate AMPK, it is likely that AMPK activation connects latent HIV-1 reactivation, alleviation of accelerated aging defects in HGPS cells, and the creation of all human life, a hypothesis that I published for the first time in 2016 [6].

HGPS is a rare genetic disorder caused by the faulty splicing of a gene called the LMNA gene, producing large amounts of a mutant protein known as progerin [7]. Progerin accumulation at a very early age in HGPS patients leads to distortions in the shape of the nucleus and aberrations in mechanisms that occur in the nucleus, leading to characteristic symptoms of accelerating aging such as thinning of the hair, wrinkling of the skin, and eventual cardiovascular disease [7]. Interestingly, normal humans produce the same toxic protein progerin via use of the same cryptic splice site in the LMNA gene as progeria patients, just at much lower levels that increase with age [8]. Recent evidence has also shown that inhibition of the splicing factor SRSF1 leads to a reduction in progerin at both the mRNA and protein levels (thus altering the LMNA pre-mRNA splicing ratio) and SRSF1 activity promotes the faulty splicing of genes involved in the maintenance of the vascular system in normal humans (e.g. VEGF, tissue factor, endoglin), leading to accelerated endothelial cell senescence [5,9,10].

In the Experimental Dermatology study, Park et al. initially characterized the cellular phenotypes of primary dermal fibroblasts derived from HGPS patients of different ages and showed increased staining of senescence-associated beta-galactosidase (SA-β-gal, an indicator of cellular senescence) and increased levels of mitochondrial superoxide in HG8 cells (from an 8 year old patient) compared to HG3 (3 year old) and HG5 (5 year old) cells [1]. All cells expressed the toxic protein progerin, superoxide dismutase 2 (SOD2, a mitochondrial antioxidant enzyme) was highest in normal fibroblasts and lowest in HG8 cells, and cellular proliferation rate slowed at an earlier time in HGPS cells compared to normal fibroblasts [1].

Utilizing HG8 cells (which demonstrated the highest levels of senescence), the authors also elucidated the effects of metformin (2mM), rapamycin (200nM), or a combination of both drugs on the nuclear phenotype of HGPS cells. Rapamycin significantly decreased the number of nuclei with abnormal morphology and metformin treatment also led to a significant increase in the number of cells with normal nuclei compared to control-treated cells [1]. Metformin also reduced senescence in HGPS cells (i.e. reduction in SA-β-gal staining) and co-treatment with rapamycin and metformin led to an approximately 34.2 % inhibition of senescence, with similar results observed in HG3 and HG8 cells [1]. Metformin, rapamycin, or co-treatment with both compounds led to a significant reduction in the number of cells containing more than 20 γ-H2AX foci (a marker of DNA damage) in HG8, HG3, and HG5 cells, indicating that metformin increases the efficiency of DNA repair in HGPS cells [1].

Metformin also exerted antioxidant effects in HGPS cells, as evidenced by a significant decrease in ROS production and mitochondrial superoxide formation compared to control cells as well as an upregulation of SOD2 mRNA expression in aged BALB/c mice (>18 months old) [1]. Most importantly, metformin treatment at 2 and 20mM reduced progerin protein expression by approximately 20 % and 60 %, respectively, compared to mock-treated cells and increased the presence of normal nuclear phenotypes in HGPS cells [1]. Metformin treatment also significantly increased the phosphorylation and activation of AMPK in HGPS cells. Furthermore, western blot analysis indicated that rapamycin increased AMPK activation as well. Curiously, treatment of aged mice with metformin significantly increased the proliferation of immune cells (i.e. splenocytes) in response to IL-2 and LPS [1]. As described below, such results may be explained via activation of AMPK, as rapamycin has recently been shown to activate AMPK in vivo in normal aged mice and efficient T cell activation is critically dependent on AMPK activation.  

Again, this study provides compelling evidence and substantiates my hypothesis published in 2014 that proposed for the first time that AMPK activators including metformin will ameliorate accelerated aging defects in cells derived from HGPS patients by activating AMPK and decreasing the levels of SRSF1, thus reducing progerin production via modulation of alternative splicing [3]. However, the results from the npj Aging and Mechanisms of Disease and Experimental Dermatologystudies also provides further support for a novel proposal published for the first time in 2015 in which I proposed that a decrease in the splicing activities of SRSF1 by chemically distinct AMPK activators will also lead to the reactivation of latent HIV-1 viral reservoirs [5]. Known as the “shock and kill” approach, this method is an active area among HIV-1 cure researchers and involves reactivating (i.e. “shock”) a T cell (or another immune cell) that harbors dormant HIV-1, hence reactivating the virus itself and thus inducing destruction of the T cell along with the virus or enhancing recognition and destruction of the virus-infected T cell by the immune system (i.e. “kill”) [5].

Interestingly, as a preponderance of evidence has convincingly shown that metformin’s primary mechanism of action is via AMPK activation, AMPK is also critical for the activation of T cells and the mounting of an effective immune response to eliminate viruses, bacteria, and cancer cells [6,11,12]. Strikingly, the same compounds that have been used to induce a “shock” to initiate the creation of human life/oocyte activation (i.e. ionomycin and A23187) have also been used in combination with other compounds as positive controls to initiate a “shock” to facilitate CD4+ T cell activation and thus reactivate dormant HIV-1 [6,13]. Calcium ionophores including ionomycin have also been used to induce a “shock” to activate cytotoxic CD8+ T cells, a T cell subset that is critical for the destruction of viruses such as HIV-1 and cancer cells. Metformin and AMPK activation has also been shown to promote the formation of long-lived cytotoxic CD8+ memory T cells [11,12,14].

Studies have shown that efficient reactivation of latent HIV-1 involves a reduction in the splicing of the HIV-1 genome by the splicing factor SRSF1, an upregulation in the activity of the splicing-associated protein p32 (an endogenous inhibitor of SRSF1 that is critical for efficient mitochondrial functionality and oxidative phosphorylation), the production of unspliced HIV-1 mRNA (also known as HIV-1 Gag), and the processing of Gag into the HIV-1 p24 antigen, an antigen that is an endpoint that is frequently measured to determine if efficient reactivation of latent HIV-1 by a candidate compound was successful [15-17]. Interestingly, the activity of the splicing factor SRSF1 is also downregulated during activation of T cells not infected with HIV-1 [18].

Because metformin, a well-studied AMPK activator, has been shown to reduce the levels of the splicing factor SRSF1 and thus ameliorate aberrant alternative splicing in HGPS cells and because AMPK activation is critical for T cell activation (and thus latent HIV-1 reactivation) and SRSF1 impedes efficient reactivation of latent HIV-1, it would be expected that compounds that both improve accelerated aging defects in HGPS and reactivate latent HIV-1 would also induce AMPK activation. Indeed, a recent study has demonstrated that metformin, when combined with the protein kinase C modulator bryostatin, induced reactivation of latent HIV-1 in a monocytic cell line in an AMPK-dependent manner. Bryostatin was also shown to induce phosphorylation and activation of AMPK in that study, implying that bryostatin is an indirect AMPK activator as well [19]. Furthermore, the calcium ionophores ionomycin and A23187, both of which activate AMPK and induce human oocyte activation, are often combined with phorbol 12-myristate 13-acetate (PMA) and are extremely efficient in promoting T cell activation-induced latent HIV-1 reactivation [6,13,20,21].          

The compound MG132, a proteasome inhibitor, has also recently been shown in preliminary studies to reduce the levels of the toxic protein progerin via the induction of autophagy and also to reduce progerin production by decreasing the levels of the splicing factor SRSF1, thus beneficially altering splicing of the LMNA gene in HGPS [22,23]. In a separate study, MG132, either alone or in combination with the vitamin A metabolite all-trans retinoic acid, led to a decrease in progerin levels in HGPS cells via the induction of autophagy [24]. MG132 has also been shown to activate AMPK and significantly induce HIV-1 reactivation in two latent HIV-1 primary human CD4+ T cell models that mimic central and effector memory T cells (two memory T cell subsets that are known reservoirs for latent HIV-1) [25,26].

Interestingly, autophagy induction has been shown to be critical for both the removal of the toxic protein progerin in HGPS cells by compounds including MG132 and all-trans retinoic as well as T cell activation. Indeed, autophagy is essential for and upregulated on T cell activation and AMPK activation significantly increases mitochondrial biogenesis, activates ULK1 to induce autophagy, and promotes activation of the master antioxidant transcription factor Nrf2 [27-30]. Because the AMPK activators metformin and MG132 have been shown to inhibit SRSF1 and beneficially alter gene splicing in HGPS cells and because AMPK activation is critical for T cell activation, autophagy induction, mitochondrial biogenesis/functionality, and promotes Nrf2 activation, chemically distinct compounds that have been demonstrated to reduce progerin levels and/or ameliorate accelerated aging defects in HGPS cells would be expected to share a common mechanism of AMPK activation.

Indeed, preclinical studies using the macrolide rapamycin in progeria cells indicated that rapamycin corrected cellular aging defects by inducing the degradation of progerin by activating autophagy [31]. Rapamycin was also recently found to potently activate AMPK in vivo in normal old mice as well as induce autophagy and mitochondrial biogenesis [32]. The induction of ULK1-dependent autophagy by rapamycin was also shown to be significantly decreased when the splicing-associated protein p32 (an endogenous inhibitor of SRSF1) was inhibited, indicating that p32 activity is critical for rapamycin-induced autophagy [33]. Because p32 is critical for rapamycin-induced autophagy by ULK1 and because rapamycin, similar to metformin, activates AMPK and AMPK induces autophagy by phosphorylating and activating ULK1, the beneficial effects of rapamycin in progeria likely involves AMPK-mediated alteration of gene splicing as well as AMPK-mediated induction of autophagy. Both metformin and rapamycin have also been shown to increase the formation of CD8+ memory T cells and rapamycin has been shown to enhance the immune response to viral infections, indicating that rapamycin-induced AMPK activation represents a central node in ameliorating accelerated aging defects in HGPS cells and improving T cell responses to viral pathogens [11,34-36].

Other compounds that have been shown to reduce the levels of progerin and/or improve accelerated aging defects in HGPS cells via autophagy induction, including all-trans retinoic acid and the Nrf2 activator sulforaphane, have also been shown to activate AMPK [37-40]. As AMPK activates PGC-1a, a key transcription factor that promotes mitochondrial functionality/biogenesis and mitochondrial dysfunction characterizes HGPS cells, methylene blue has been shown to correct mitochondrial functioning in HGPS fibroblasts, increase PGC-1a levels, and ameliorate the characteristic nuclear distortion and blebbing observed in HGPS [41,42]. Expectedly, methylene blue has also been shown in independent studies to induce macroautophagy and activate AMPK in vitro and in vivo [43,44].

Interestingly, AMPK activation has also been shown to phosphorylate and induce nuclear retention of Nrf2, a master regulator of the antioxidant response, thus enhancing Nrf2 activity [29,30]. Strikingly, a recent study demonstrated that the transcriptional activity of Nrf2 is impaired in HGPS patient cells, leading to an increase in chronic oxidative stress. The reactivation of Nrf2 in HGPS patient cells by the Nrf2 activator oltipraz reversed nuclear aging defects and also restored the in vivo viability of HGPS patient-derived mesenchymal stem cells (MSCs) that were implanted into animal models [45]. Similar to metformin, all-trans retinoic acid, MG132, rapamycin, and methylene blue, oltipraz and/or its metabolites also induce activation of AMPK, increase expression of genes that encode proteins involved in mitochondrial fuel oxidation, increase mitochondria DNA content and oxygen consumption rate, reduce cellular ROS production, activate LKB1 (an upstream activator of AMPK), and increase the AMP/ATP ratio (an indication of cellular stress induction) [46-50]. Additionally, similar to MG132, which reactivates latent HIV-1 but inhibits active replication of HIV-1, several studies have shown that oltipraz and/or its metabolites inhibit replication of HIV-1, indicating that oltipraz-induced AMPK activation likely also induces immuno-modulatory effects [26,51-53].

Lastly, a recent study demonstrated that 1α,25-dihydroxyvitamin D3 (1,25D), the most potent metabolite of vitamin D, profoundly improved nuclear morphology, significantly reduced DNA damage, improved cellular proliferation, delayed premature cellular senescence, and dramatically reduced progerin production in HGPS patient cells through the promotion of vitamin D receptor (VDR) signaling [54]. Indeed, 1,25D has been shown to activate AMPK in vivo as well as alter gene splicing in cancer cells [55,56]. 1,25D also plays a critical role in immune system regulation, as evidenced by an increase in activated CD4+ T cells in HIV-1 patients administered 1,25D in a placebo-controlled randomized study [57]. VDR signaling plays an integral role in T cell activation, with T cell receptor triggering inducing an upregulation of PLC-γ1 (a protein critical for T cell activation) that is dependent on 1,25D and expression of the VDR [5,58]. Interestingly, as PMA (a positive control extensively used in latent HIV-1 reactivation studies) has been demonstrated to enhance 1,25D-induced promoter binding activity of the VDR, Kitano et al. demonstrated that 1,25D, PMA/TPA, and tumor necrosis factor (TNF) stimulated HIV-1 proviral activation to similar levels in a cell line latently-infected with a monocytotropic strain of HIV-1JR-FL [5,59,60]..

In conclusion, the results from the npj Aging and Mechanisms of Diseaseand Experimental Dermatology studies demonstrating that metformin activates AMPK, decreases the expression of both progerin and the splicing factor SRSF1, and alleviates pathological defects in HGPS patient-derived cells provides direct support and substantiates a hypothesis published in 2014 in which I proposed for the first time that AMPK activators including metformin will ameliorate accelerated aging defects in cells derived from HGPS patients by decreasing the levels of SRSF1, thus reducing progerin production via modulation of alternative splicing [3]. Because AMPK activation is critical for T cell activation, increased SRSF1 activity impedes T cell activation and latent HIV-1 reactivation, and the endogenous SRSF1 inhibitor p32 is upregulated on HIV-1 reactivation, the results from these two new studies also strongly support a hypothesis published in 2015 in which I proposed for the first time that inhibition of SRSF1 by AMPK activators will promote the induction of latent HIV-1 reactivation, facilitating detection and destruction of the virus [5]. Indeed, p32 has been shown to be essential for ULK-1 mediated autophagy induction by rapamycin, a drug that improves immune system responses to viral infections and ameliorates accelerated aging defects in HGPS cells. Additionally, the calcium ionophores ionomycin and A23187, both of which have been shown to activate AMPK and are used in a combinatorial fashion as positive controls to reactivate latent HIV-1, also induce human oocyte activation, leading to the birth of healthy children. As AMPK activation is also essential for oocyte meiotic resumption and maturation, AMPK activation connects amelioration of accelerated aging defects in HGPS not only with latent HIV-1 reactivation, but also with oocyte activation, a process without which there can be no human life [6]. Moreover, phosphorylated/activated AMPK (pAMPK) has recently been discovered for the first time in human sperm, localized along the tail and across the entire acrosome in the head of the sperm [61]. Because the acrosome reaction is critical for oocyte penetration and fertilization and because compounds that increase intracellular levels of calcium, including vitamin D and A23187, have been shown to induce the acrosome reaction in human sperm and activate AMPK, AMPK activation is likely also essential for the induction of the acrosome reaction in human sperm, a process that is indispensable for the creation of all human life outside of a clinical setting [62,63]. That the symptoms of accelerated aging associated with HGPS, reactivation of latent HIV-1, oocyte activation, and the acrosome reaction in human sperm is connected by common pathway, AMPK activation, is no less than astounding. As evidence continues to support and substantiate this connection, a paradigm shift in assessment of disease etiology and the practice of medicine is inevitable.  

https://www.linkedin.com/pulse/new-study-confirms-metformin-alleviates-accelerated-aging-finley

References:

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